Reduced levels of thyroid hormones, insulin, and glucose, and lower body core temperature in the growth hormone receptor/binding protein knockout mouse.

The mechanisms that are responsible for the extension of lifespan in the mouse with targeted disruption (knockout [KO]) of the growth hormone (GH) receptor/binding protein (GHR-KO) are unknown. However, in the long-living Ames dwarf mouse, blood glucose and body core temperature (Tco) are consistently lower than in normal mice. In addition, insulin levels are reduced and corticosterone levels are elevated in male dwarfs. These functional alterations, similar to those seen in animals under caloric restriction, have not been proven to be causally related to the extension of lifespan, but they do provide some insight into what traits may be necessary for long life. Therefore, to investigate which of these parameters are similarly affected in two genetically unrelated, yet similarly long-living mouse models, we measured Tco, thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), and insulin, in addition to morning and afternoon levels of glucose and corticosterone, in young adult male and/or female GHR-KO mice and their normal siblings. Tco in GHR-KO mice was numerically reduced throughout the 24-hr period; however, these differences were only significant 4 hr prior to lights-off (14:00 hr), immediately after lights-off (18:00 hr), and during the 3 hr preceding lights on (03:00 to 06:00 hr). GHR-KO mice had significantly reduced levels of T3 and T4, while the ratio of these hormones was similar to that in normal mice. Insulin levels in GHR-KO mice were lower than in normal mice; levels in male GHR-KO mice were below the detectable limits of the assay used. Glucose levels in GHR-KO mice (male and females) were lower than in normal mice in measurements taken in both morning and afternoon; however, these differences arose from consistent reductions in males, as morning glucose levels in GHR-KO females were similar to those of normal mice. Corticosterone levels measured in blood plasma collected under basal (nonstressed) conditions showed sex-related alterations. Basal corticosterone levels in female GHR-KO mice were similar to normal females, while those in male GHR-KO mice were higher than in normal males in the afternoon. Corticosterone levels in stressed GHR-KO females were similar to those measured in stressed normal females. These data show that the long-living GHR-KO mouse shares a reduction in glucose, insulin, thyroid hormones, and Tco with the Ames dwarf mouse. Reductions in these parameters may be important to the underlying mechanisms of delayed aging in these animals.

Three decades of corneal transplantation: indications and patient characteristics.

PURPOSE: To review the indications and patient characteristics for penetrating keratoplasty (PKP). METHODS: Retrospective review of records at the Pathology Service, Department of Ophthalmology, University of Toronto from 1964 to 1997. RESULTS: The 6,222 records were reviewed. The leading indications for PKP were regraft, keratoconus (KC), pseudophakic bullous keratopathy (PBK), Fuchs' dystrophy, viral infections, and trauma, in that order. During the second half of the 1980s, PBK replaced KC as the leading indication for transplantation. The average age of patients increased from 49 (+/-19) years during the second half of the 1960s to 63 (+/-20) years at the first half of the 1990s. Gender differences (M/F ratio) were significant for KC, viral keratopathy, trauma, PBK, aphakic bullous keratopathy (ABK), edema of unspecified etiology, interstitial keratitis, rheumatoid arthritis, and Fuchs' dystrophy. Diagnostic category differences between all patients for PKPs and regrafts were significant for autoimmune keratolysis, congenital opacities, PBK, ABK, edema of unspecified etiology, scarring, Fuchs' dystrophy, and KC. CONCLUSION: Indications are in accordance with the literature with the exception of regraft, which was higher. An increase in the average age of patients corresponded with the PBK epidemic. The high male-to-female ratio among patients with KC was different from that previously reported for the prevalence of this condition. Sex distribution among patients with PBK and ABK showed a female predominance. Differences in the underlying disease distributions between regrafted patients and the rest of the series coincide with prognostic classifications for PKP.

Low body temperature in long-lived Ames dwarf mice at rest and during stress.

Among homeothermic animals, larger species generally have lower metabolic rates and live longer than do smaller species. Because Ames dwarf mice (dwarfs) live approximately 1 year longer than their larger normal sex- and age-matched siblings (normals), we hypothesized that they would have lower body core temperature (Tco). We, therefore, measured Tco of six dwarfs and six normals during 24-h periods of ad lib feeding, 24-h food deprivation, and emotional stress induced by cage switching. With ad lib feeding, Tco of dwarfs averaged 1.6 degrees C lower than normals; during food deprivation, Tco of both dwarfs and controls was significantly lower than when food was available ad lib; and following cage switch, Tco was elevated in both groups. However, during all three experiments, Tco was significantly lower in dwarfs than in normals. These data support the hypothesis that Ames dwarf mice, which live longer than normal size controls, maintain lower Tco than normals. Because dwarfs are deficient in thyroid stimulating hormone (TSH) and growth hormone (GH), their low Tco may be a result of reduced thermogenesis due to lack of those hormones. However, whether low Tco per se is related to the increased longevity of the dwarf mice remains an interesting possibility to be investigated.

Does growth hormone prevent or accelerate aging?

It is very well documented that plasma growth hormone (GH) levels decline with age in the human and in experimental animals, and there is considerable evidence that age-related changes in body composition may be caused by reduced function of the GH-IGF-I system. However, excessive GH levels are associated with reduced life expectancy in acromegalic patients and with symptoms of accelerated aging in GH transgenic mice. Hereditary dwarf mice deficient in GH, prolactin, and TSH live much longer than their normal siblings. Possible mechanisms of delayed aging in dwarf mice include lower core body temperature and reduced oxidative processes. It is suggested that the controversies concerning the apparent potential of GH to both prevent and accelerate aging may be reconciled by interpreting the results in light of the negative relationship between body size and life span within a species.

Anteroventral third ventricle lesion suppresses fever, but not stress-induced hyperthermia in rats.

Body core temperature (Tco) of unrestrained rats was monitored to compare the effects of electrolytic lesion of the anteroventral third ventricle (AV3V) region on stress-induced hyperthermia or lipopolysaccharide (LPS)-induced fever. We found that stress-induced hyperthermia was not significantly reduced by AV3V lesion, whereas pyrogen-induced fever was significantly lower in rats in which the lesion completely ablated the organum vasculosum laminae terminalis (OVLT), located in the AV3V region. The results indicate that although the central neural elements producing both stress- and pyrogen-induced elevations in Tco may be prostaglandin related, stress hyperthermia is not activated by mechanisms in the OVLT region, as is fever induced by LPS.

p53 expression in uveal malignant melanomas.

Mutation of the p53 gene which is located on chromosome 17p is the single most frequent alteration observed in human cancer. In this study we evaluate malignant melanoma, the most common intraocular neoplasm in adults, for aberrant p53 expression. Twenty enucleation specimens representing one ciliary body and 17 choroidal melanomas and two choroidal nevi were studied by immunohistochemistry utilizing the D07 anti-p53 antibody and the MIB-1 monoclonal antibody. The tumors included two spindle cell and 16 mixed cell (spindle + epithelioid cell) melanomas and two spindle cell nevi. The MIB-1 labelling index ranged from < 1% (two cases), 1-5% (13 cases) and > 5% (five cases). Of the 18 melanomas, 13 cases showed nuclear p53 staining with the p53 index < 1% (two cases), 1-3% (eight cases) and 4-5% (three cases). No p53 staining was observed in two malignant melanomas of the spindle cell type and in two choroidal nevi. In the 13 malignant melanomas of the mixed cell type, there was no correlation between MIB-1 index and p53 immunoreactivity. Immunopositivity was not found in normal choroidal melanocytes. Our study suggests that p53 alterations may be found in uveal melanomas; in our series, p53 positivity was present only in malignant melanomas of the mixed cell type.

Expression of bcl-2 in uveal malignant melanoma.

OBJECTIVE: To evaluate the expression of the bcl-2 proto-oncogene in uveal malignant melanomas. CASE MATERIAL: We studied 20 uveal malignant melanomas (19 choroidal and 1 ciliary body) by immunohistochemistry with the bcl-2 oncoprotein monoclonal antibody and the cell proliferation marker, MIB-1. RESULTS: Expression of bcl-2 was found in 100% of cases and was not correlated with the histologic subtype of melanoma or the MIB-1 proliferative index. Normal choroidal melanocytes were negative for bcl-2. CONCLUSION: Our results suggest that altered expression of bcl-2 is common in uveal melanomas and is not related to histologic grade.

The CR-CO discrepancy and its effect on cephalometric measurements.

The purpose of the present study was to compare cephalometric measurements derived from a centric occlusion (CO) tracing with those of a converted centric relation (CR) tracing. The sample consisted of 68 consecutively treated patients, with a CR-CO discrepancy of 2 mm or greater in either the horizontal and/or vertical planes, measured at the condyles from mounted models. Comparisons were also made within the sample between the 39 females and 29 males; and the 35 skeletal Class I and 33 Class II patients. In analyzing the CR-CO discrepancy, the vertical component was greater than the horizontal in 96% of the sample. Every patient had a vertical component, although 10% had no horizontal component. Correlations between the horizontal discrepancy and the two tracings showed high values for approximately 50% of the measures, whereas little correlation was found with the vertical discrepancy. Paired t tests used to compare the CO and CR cephalometric values demonstrated significant differences (p < 0.05) for the majority of the values studied. However, there generally were no differences between the groups of males and females, or between the skeletal Class I and Class II individuals. The results of this study suggest that to make a correct orthodontic diagnosis the mandible should be placed in centric relation rather than in the more traditional centric occlusion.

An inventory of United States and Canadian growth record sets: preliminary report.

A listing and description of longitudinal craniofacial growth record sets currently extant on the North American continent is provided. An argument is made for the preservation of these resources and for the generation of a pooled or shared image base of duplicate craniofacial physical records. This is a preliminary report and is assumed to be incomplete. In an effort to improve our accuracy and completeness, we invite corrections and additions.

Mandibular growth direction with conventional Class II nonextraction treatment.

The purposes of this study were (1) to compare the direction of mandibular growth (MGD) during treatment and retention for a group of treated Class II patients with untreated controls, and (2) to investigate the relationship between the MGD during treatment and the pretreatment skeletal structure. Pretreatment, posttreatment, and 2 years posttreatment lateral cephalograms of 26 Class II, Division 1 subjects who were treated "nonextraction" with low- or straight-pull headgears were compared with an untreated control group of 15 subjects. Mandibular growth direction was interpreted as the movement of the point gnathion relative to the S-N line when successive tracings were superimposed on the S-N line at S. On average, MGD appeared more vertical during treatment. Posttreatment MGD was generally more horizontal than that during treatment but was also extremely variable. Three of the pretreatment skeletal measures studied, especially the articular angle (SArGo), were significantly related to MGD during treatment. The inclination of the mandibular ramus is apparently an important indicator of how mandibular growth will respond to Class II treatment mechanics.

Validation of the hypothermic action of preoptic norepinephrine in guinea pigs.

Conscious guinea pigs were either microinjected intrapreoptically (iPO) with various doses of norepinephrine (NE) bilaterally or microdialyzed with pyrogen-free saline (PFS) or 10 micrograms/microliters NE unilaterally immediately and unilaterally or bilaterally 2 days after probe insertion. Core temperature (Tco), skin temperature (Tsk), and rate of oxygen consumption (VO2) were monitored continuously. The microinjection of low doses of NE induced Tco rises, whereas that of the highest dose (10 micrograms/microliters) caused an initial Tco fall followed by a rise. The microdialysis of PFS or NE immediately after probe insertion caused Tco rises; the former was abolished and the latter was converted into a fall by indomethacin (Indo, a prostaglandin synthase inhibitor) pretreatment. Two days later, PFS evoked no thermal response whereas NE induced a Tco fall; neither response was affected by Indo pretreatment. The falls in Tco produced by NE microdialyzed uni- or bilaterally were similar. The microdialysis of NE induced a 15% reduction in metabolic rate but no change in Tsk. These results indicate that the Tco rise induced by NE microinjected iPO is a methodological artifact mediated by PGE2, whereas the Tco fall observed in its microdialysis appears to represent the authentic physiological action of this transmitter effected by a reduction in metabolic rate.

Iris sector heterochromia as a marker for neural crest disease.

A 6-month-old female infant with biopsy-proved Hirschsprung's disease had associated sector heterochromia of the irides. The association between sector heterochromia and Hirschsprung's disease has been previously reported and both conditions have been ascribed to neural crest defects. Histologic characteristics of the ocular involvement have not previously been reported, to our knowledge. Histopathologic examination of the globes revealed decreased iris stroma, decreased pigmentation in the anterior stroma, and reduced numbers of pigment-producing cells in the affected areas. Both the ocular and gastrointestinal findings reflect abnormalities in tissues of neural crest origin.

Adenoma of the nonpigmented epithelium of the ciliary body.

A 56-year-old man presented with a left ciliary body mass, anterior vitreous hemorrhage and a subluxed, cataractous lens. The clinical course included rapid enlargement of the mass, anterior uveitis, cataract progression and secondary glaucoma. Investigation included fluorescein angiography, ultrasonography and computed tomography. The eye was enucleated because of progressive enlargement with poor vision and uncontrolled secondary glaucoma. Histopathological examination showed an adenoma of the nonpigmented ciliary epithelium with cystic areas of hyaluronidase-sensitive acid mucopolysaccharide. The mass distorted the iris, occluded the angle structures and produced a complete cataract. The basement membrane of the adjacent ciliary processes was extensively thickened. The authors discuss the clinical association with vitreous hemorrhage and the local damage caused by this benign tumour.

Acanthamoeba keratitis with two species of Acanthamoeba.

We describe a case of Acanthamoeba keratitis related to soft contact lens wear. The patient presented with a 3-week history of severe uniocular pain, radial stromal infiltrates and subepithelial infiltrates with no epithelial defect. Acanthamoeba was cultured from the corneal biopsy specimen, contact lens and lens case. The corneal biopsy culture grew both A. castellani and A. polyphaga as well as Escherichia coli. The patient was treated with topical dibromopropamidine isethionate (Brolene) drops, neomycin and polymyxin B drops and fortified gentamicin drops. Gradual clinical improvement ensued.

Corneal changes in Tay-Sachs disease.

Tay-Sachs disease is a well-known inherited disease leading to an accumulation of gangliosides in the brain and retina. Our report is based on a case of Tay-Sachs disease in a non-Jewish infant where pathologic changes were noted in corneal endothelium as well as in the retina.

Quantitative analysis of collagen content and amino acids in trabecular meshwork.

The purpose of this study was to compare collagen content in the TM of normal and glaucomatous eyes, and to establish whether collagen levels change with age. Collagen content was measured in 30 normal and 27 age matched glaucoma trabeculectomy specimens by the sirius red dye binding technique, and in 14 normal and 15 age matched glaucoma specimens by amino acid analysis. Both dye binding data and amino acid analysis showed no statistical difference between normal and glaucoma samples. Age had no significant effect on mean optical densities or on the collagen-specific amino acids proline, hydroxyproline, and hydroxylysine. Amino acid variability, however, was statistically different between the two groups. These results indicate that mean collagen levels in the trabecular meshwork of glaucomatous eyes do not differ from those in normal eyes.

Acanthamoeba keratitis in a soft-contact-lens wearer.

Acanthamoeba keratitis is an uncommon but potentially devastating complication of contact lens wear. We present a case of Acanthamoeba keratitis in a soft-contact-lens wearer successfully treated with long-term medical therapy and penetrating keratoplasty. To our knowledge this is the first case of Acanthamoeba keratitis diagnosed in Canada.

An in vitro investigation of lingual bonding.

An in vitro investigation was undertaken to evaluate the bonding of orthodontic appliances onto lingual surfaces; 53 maxillary premolars, 37 mandibular premolars, and 37 mandibular incisors were used. Brackets were bonded onto the lingual and labial surfaces and fractured with an Instron machine. Enamel damage associated with debonding also was assessed. Results indicated comparable bond strengths (t test) on lingual (Li) and labial (La) surfaces: maxillary premolars--Li-138.2 kg/cm2, La-127.7 kg/cm2; mandibular premolars--Li-136.2 kg/cm2, La-121.6 kg/cm2; and mandibular incisors--Li-166.3 kg/cm2, La-161.1 kg/cm2. Adaptation of lingual bracket bases resulted in significantly higher lingual bond strengths for maxillary premolars (166.9 kg/cm2) and mandibular premolars (180.4 kg/cm2), but not for mandibular incisors (149.2 kg/cm2). On debonding, the percentages of lingual surfaces exhibiting horizontal "crescent-shaped" fracture lines and enamel fragment fractures were significantly higher (x2 test) than the corresponding percentages for labial surfaces: maxillary premolars--Li-67.9%, La-5.7%; mandibular premolars--Li-62.2%, La-13.5%; and mandibular incisors--Li-43.2%, La-18.9%. Furthermore, an increase in vertical enamel fracture lines (cracks) subsequent to debonding was seen labially and lingually. Bonding procedures for lingual surfaces should be identical to those advocated for labial surfaces. Care during debonding must be exercised to eliminate possible enamel damage.