Long-term global retinal microvascular changes in a transgenic vascular endothelial growth factor mouse model.

AIMS/HYPOTHESIS: Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of diabetic retinopathy. We investigated whether transgenic mice with moderate VEGF expression in photoreceptors (trVEGF029) developed changes similar to diabetic retinopathy and whether retinopathy progressed with time. MATERIALS AND METHODS: Human VEGF(165) (hVEGF(165)) expression was analysed using ELISA and quantitative RT-PCR; serum glucose levels were also measured. Fundus fluorescein angiography (FA) was used to screen the degree of retinopathy from 6 weeks. Dynamic changes in the density of retinal microvasculature, as well as other changes similar to diabetic retinopathy, including retinal leucostasis, capillary endothelial cell and pericyte loss, and numbers of acellular capillaries, were quantified. RESULTS: trVEGF029 mice were normoglycaemic and showed a moderate, short-term hVEGF(165) upregulation for up to 3 weeks. Changes in the retinal microvasculature not only mimicked those seen in diabetic retinopathy, but also showed similar pathological progression with time. FA at 6 weeks identified two phenotypes, mild and moderate, which were distinguished by the extent of vascular leakage. Quantitative analysis of diabetic retinopathy-like changes revealed that these parameters were tightly correlated with the initial degree of vascular leakage; low levels reflected slow and limited retinal microvascular changes in mild cases and high levels reflected more rapid and extensive changes in moderate cases. CONCLUSIONS/INTERPRETATION: The data suggest that even an early short-term elevation in hVEGF(165) expression might set a train of events that lead to progressive retinopathy. Induction of many features characteristic of diabetic retinopathy in trVEGF029 enables mechanisms leading to the disease state to be examined, and provides a relevant animal model for testing novel therapeutics.

Generation of transgenic mice with mild and severe retinal neovascularisation.

AIM: To generate a mouse model for slow progressive retinal neovascularisation through vascular endothelial growth factor (VEGF) upregulation. METHODS: Transgenic mice were generated via microinjection of a DNA construct containing the human VEGF165 (hVEGF) gene driven by a truncated mouse rhodopsin promoter. Mouse eyes were characterised clinically and histologically and ocular hVEGF levels assayed by ELISA. RESULTS: One transgenic line expressing low hVEGF levels showed mild clinical changes such as focal fluorescein leakage, microaneurysms, venous tortuosity, capillary non-perfusion and minor neovascularisation, which remained stable up to 3 months postnatal. Histologically, there were some disturbance and thinning of inner and outer nuclear layers, with occasional focal areas of neovascularisation. By contrast, three other lines expressing high hVEGF levels presented with concomitantly severe phenotypes. In addition to the above, clinical features included extensive neovascularisation, haemorrhage, and retinal detachment; histologically, focal to extensive areas of neovascularisation associated with retinal folds, cell loss in the inner and outer nuclear layers, and partial retinal detachment were common. CONCLUSIONS: The authors generated four hVEGF overexpressing transgenic mouse lines with phenotypes ranging from mild to severe neovascularisation. These models are a valuable research tool to study excess VEGF related molecular and cellular changes and provide additional opportunities to test anti-angiogenic therapies.

Phototherapeutic keratectomy for recurrent erosion syndrome in anterior basement membrane dystrophy.

PURPOSE: To determine the outcome of patients who received phototherapeutic keratectomy (PTK) for recurrent erosion syndrome due to anterior basement membrane dystrophy (ABMD). DESIGN: A retrospective, noncomparative case series. PARTICIPANTS: Forty-eight eyes of 43 consecutive patients who underwent PTK for recurrent erosions occurring in ABMD at the Hunkeler Eye Center from 1991 to April 1995. All patients had previously failed at least one method of medical or surgical treatment for recurrent erosions and had slit-lamp findings of ABMD on initial evaluation. INTERVENTION: The eyes each underwent manual superficial keratectomy and PTK with the Summit Omnimed excimer laser. MAIN OUTCOME MEASURES: Data were analyzed by a retrospective chart review for 1, 3, 6, and 12 months for the 36 eyes with at least 12 months of follow-up data available. They were analyzed for preoperative and postoperative visual acuity, change in spherical equivalent, recurrence rate, and patient satisfaction. RESULTS: The preoperative mean visual acuity was not statistically significantly different at 1 month after PTK. Statistically significant improvement in mean visual acuity was present at 3, 6, and 12 months. Recurrence of symptoms of recurrent erosion was present in 5 (13.8%) of 36 eyes during the 12-month follow-up period, which was managed with repeat PTK over the area of the cornea initially treated with PTK; 1 of 5 required a third PTK treatment. All recurrences presented within 6 months of PTK or repeat PTK. The mean dioptric change in spherical equivalent was not statistically significant. Patient satisfaction levels after PTK for recurrent erosions in ABMD were assessed in 21 (58%) of 36 patients on a scale of 0 to 5 (5 = most satisfied); the mean response was 4.14 of 5. CONCLUSIONS: Phototherapeutic keratectomy is an effective treatment for recurrent erosions occurring in the setting of ABMD, is well tolerated, and may improve visual acuity. The rate of recurrence of erosions in ABMD treated with PTK is low during a 12-month follow-up period.

Morton's interdigital neuroma: a comprehensive treatment protocol.

One hundred fifteen patients with signs and symptoms of Mortons' interdigital neuroma were studied in an attempt to evaluate the efficacy of a staged treatment program. The first stage consisted of patient education, footwear modifications, and metatarsal head relief. The second stage consisted of a steroid/local anesthetic injection into the affected interspace. The third stage was surgical excision of the inflamed interdigital nerve. Overall, 97 of 115 patients (85%) believed that they had improved with the treatment program. Twenty-four patients (21%) eventually required surgical excision of the nerve and 23 of 24 patients (96%) had satisfactory results. The results of the staged treatment protocol were very satisfactory and patient satisfaction was high.

Triple arthrodesis in adults.

Twenty-two adult patients who underwent a triple arthrodesis because of hindfoot pain and/or deformity were reviewed retrospectively with a minimum 3-year follow-up. All procedures were performed by the same surgeon using a two-incision technique and internal fixation. Objective results were good in eight (36%) patients, fair in 13 (59%), and poor in one (5%). There were two asymptomatic nonunions of the talonavicular joint, no infections, and no neuromas. Eleven patients had radiographic evidence of tibiotalar arthritis, and eleven patients had midfoot arthritic changes that had progressed after the operation. Patient satisfaction with the procedure was high, and 21 of 22 (95%) patients felt that they were improved overall and would have the surgery again if indicated. Although the procedure is technically demanding, patient satisfaction is high and complications can be kept to a minimum if proper surgical technique is utilized.

Comparison of Oculab Tono-Pen readings obtained from various corneal and scleral locations.

When estimating intraocular pressure in patients who are uncooperative or who have central corneal disturbances, the physician may find it either impractical or undesirable to place the small tip of a portable electronic applanation tonometer (Tono-Pen) over the central cornea. To gauge better the usefulness of Tono-Pen readings obtained from various locations, we compared such readings measured through the central cornea, midperipheral cornea, limbal cornea, and sclera of 15 cannulated eye bank eyes. Mean Tono-Pen readings from the midperipheral and clear limbal cornea did not differ significantly from central corneal readings over a 10- to 35-mm Hg range of intraocular pressures and were within +/- 2.4 mm Hg of mean central corneal readings. Mean readings taken from the sclera, however, were 8.8 to 17.0 mm Hg higher than mean central corneal readings over the 10- to 40-mm Hg range. We concluded that multiple noncentral corneal readings with the Tono-Pen provided a useful approximation of intraocular pressure, whereas scleral readings did not.

Effect of contact lens removal or displacement on intraocular pressure.

We conducted a controlled, prospective study involving 102 healthy volunteers to determine the effects of contact lens removal and contact lens displacement on subsequent intraocular pressure measurements. Intraocular pressure was measured at baseline, immediately after contact lens removal or displacement, and 5 minutes thereafter. The method of lens removal was either sliding displacement (51 eyes) or plucking (51 eyes). Right eyes were used for the test, and left eyes served as controls. Compared with baseline measurements, mean intraocular pressure immediately after plucking the lens was 0.8 mm Hg lower (P less than .01) and after sliding the lens was 0.5 mm Hg higher (P less than .05). Intraocular pressure changes of 4.0 mm Hg or more occurred in eight (15.6%) of 51 eyes in the pluck group vs four (7.8%) of 51 control eyes and in two (3.9%) of 51 eyes in the slide group vs zero of 51 control eyes. Compared with baseline, significant differences (P less than .05) were not found 5 minutes later. Clinicians who wish to minimize the influence of contact lens removal on tonometry readings should wait several minutes after contact lens removal before measuring intraocular pressure.

Percutaneous posterolateral lumbar discectomy. An alternative to laminectomy in the treatment of backache and sciatica.

The evacuation and decompression of the herniated lumbar disc (HLD) through a sheath or cannula inserted dorsolaterally represent a new concept in the treatment of backache and sciatica associated with disc herniation. Under local anesthetic and Valium (Roche, Nutley, New Jersey) sedation, 20 patients with sciatica, restricted straight-leg raising, and neurological impairment were treated by this simple and safe technique. All patients had computed tomographic evidence of L4-L5 protrusion. The introduction of a sheath with an internal diameter of 4.9 mm permitted removal of the nuclear material by means of a small pituitary forcep. Using the self-assessment method of Coventry and Stauffer, it was concluded that 12 of the 20 patients had a good or fair result. Predictably, the compensation patients fared poorly. There were no complications. This technique appears applicable in HLD to properly selected patients, and it would seem that it is safe, effective, and cost efficient.

Painful heel syndrome: radiographic and treatment assessment.

From July 1980 to January 1986, 170 patients who had unilateral heel pain were examined, x-ray filmed, and treated in a similar fashion. Radiographs of painful and nonpainful heels were measured. There was a statistically significant increased thickness of the heel fat pad and subfascial area compared with that of the control subject (the nonpainful side). A tightness of the Achilles tendon and a new sign, which the authors are designating as the "saddle" sign, were other prominent features. A treatment program of stretching exercises and walking seemed to be effective in relief of symptoms.

Ureaplasmas and mycoplasmas in chimpanzees of various breeding capacities.

Adult chimpanzees (24 male, 76 female) with low and high rates of conception were examined for ureaplasmas, arginine-metabolizing mycoplasmas and chlamydiae. Ureaplasmas were isolated from the throat of only 1 male and 1 female animal, but from the urethra of 29% of the males and from the vagina of 95% of the females. Mycoplasmas were isolated from the throat more often than were ureaplasmas, but from the genital tract with about the same frequency as ureaplasmas. The numbers of organisms, of either type, isolated from the vagina were larger than the numbers isolated from the male urethra. Chlamydiae were not isolated from any animal. The occurrence of ureaplasmas and mycoplasmas and the numbers of these organisms isolated were similar in animals with low or high rates of conception. Furthermore, no association was noted between the organisms in the lower genital tract and the occurrence of abortion and/or stillbirth.

Tolerance to effects of clonidine and morphine on sulfobromophthalein disposition in mice.

Chronic treatment of mice with clonidine or morphine caused tolerance to the analgesic and thermoregulatory effects of these drugs. After chronic morphine, mice also became tolerant to the analgesic and thermoregulatory effects of clonidine. Cross tolerance to the hypothermic effect of morphine was demonstrated after chronic clonidine administration, but no diminution of morphine-induced analgesia could be shown. Morphine and clonidine acutely increased the retention of sulfobromophthalein (BSP) in plasma and liver. Chronic dosing with morphine or clonidine caused partial tolerance and cross-tolerance to the rise in hepatic BSP caused by an acute challenge with either agonist. However, both drugs elevated plasma BSP levels similarly in tolerant and non-tolerant mice. Thus, regimens which readily induced tolerance to the analgesic and hypothermic effects of morphine or clonidine were only partially effective in modifying the acute hepatobiliary effects of these drugs.

Urogenital challenge of primate species with Mycoplasma genitalium and characteristics of infection induced in chimpanzees.

Eighteen male and eight female primates, representing five subhuman species, were inoculated urogenitally with Mycoplasma genitalium, a microorganism recovered from men with nongonococcal urethritis. Male rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys apparently were resistant. Female squirrel monkeys (Saimiri sciureus) and female tamarins (Saguinus mystax) exhibited low-level, genital-tract infections. Male chimpanzees (Pan troglodytes) developed an obvious genital-tract infection, with some shedding organisms for 21 weeks. M. genitalium was recovered from the blood of two of the male chimpanzees, usually when large numbers of organisms were in the urethra. Female chimpanzees generally shed organisms for 12-15 weeks. Most chimpanzees colonized with the organism exhibited increased numbers of polymorphonuclear leukocytes in the genital tract and developed a significant antibody response. The results offer substantial evidence for the pathogenicity of M. genitalium for the urogenital tract of higher primates and suggest the microorganism may have a role in human genital-tract infections.