Effect of ocular hypertension on the pattern of retinal ganglion cell subtype loss in a mouse model of early-onset glaucoma.

Glaucoma is a neurodegenerative disease with elevated intraocular pressure as one of the major risk factors. Glaucoma leads to irreversible loss of vision and its progression involves optic nerve head cupping, axonal degeneration, retinal ganglion cell (RGC) loss, and visual field defects. Despite its high global prevalence, glaucoma still remains a major neurodegenerative disease. Introduction of mouse models of experimental glaucoma has become integral to glaucoma research due to well-studied genetics as well as ease of manipulations. Many established inherent and inducible mouse models of glaucoma are used to study the molecular and physiological progression of the disease. One such model of spontaneous mutation is the nee model, which is caused by mutation of the Sh3pxd2b gene. In both humans and mice, mutations disrupting function of the SH3PXD2B adaptor protein cause a developmental syndrome including secondary congenital glaucoma. The purpose of this study was to characterize the early onset nee glaucoma phenotype on the C57BL/6J background and to evaluate the pattern of RGC loss and axonal degeneration in specific RGC subtypes. We found that the B6.Sh3pxd2bnee mutant animals exhibit glaucoma phenotypes of elevated intraocular pressure, RGC loss and axonal degeneration. Moreover, the non-image forming RGCs survived longer than the On-Off direction selective RGCs (DSGC), and the axonal death in these RGCs was independent of their respective RGC subtype. In conclusion, through this study we characterized an experimental model of early onset glaucoma on a C57BL/6J background exhibiting key glaucoma phenotypes. In addition, we describe that RGC death has subtype-specific sensitivities and follows a specific pattern of cell death under glaucomatous conditions.

Subtype-specific response of retinal ganglion cells to optic nerve crush.

Glaucoma is a neurodegenerative disease with retinal ganglion cell (RGC) loss, optic nerve degeneration and subsequent vision loss. There are about 30 different subtypes of RGCs whose response to glaucomatous injury is not well characterized. The purpose of this study was to evaluate the response of 4 RGC subtypes in a mouse model of optic nerve crush (ONC). In this study, we also evaluated the pattern of axonal degeneration in RGC subtypes after nerve injury. We found that out of the 4 subtypes, transient-Off α RGCs are the most susceptible to injury followed by On-Off direction selective RGCs (DSGC). Non-image forming RGCs are more resilient with ipRGCs exhibiting the most resistance of them all. In contrast, axons degenerate irrespective of their retinal soma after ONC injury. In conclusion, we show that RGCs have subtype specific cell death response to ONC injury and that RGC axons disintegrate in an autonomous fashion undergoing Wallerian degeneration. These discoveries can further direct us towards effective diagnostic and therapeutic approaches to treat optic neuropathies, such as glaucoma.

One-peg versus three-peg patella component fixation in total knee arthroplasty.

In many designs of total knee arthroplasty, the patella with one central peg has been replaced by a patella with three small pegs for cement fixation. There have been recent reports of failure of this design. This is a prospective, consecutive study of two types of patella component fixation in 228 posterior-stabilized knee arthroplasties done by one surgeon. A central peg all-polyethylene component was used for 84 consecutive knees in 63 patients (Group A) and a three-peg patella was used for the next 144 consecutive knees in 99 patients (Group B). The mean followup was 6.7 years (range, 2-10 years) for Group A and 3.5 years (range, 2-6 years) for Group B. Except for the patellar component fixation, all knees had the same posterior-stabilized prosthesis using a specific protocol for patellar resurfacing. No patient required reoperation for a patellofemoral complication. The prevalence of patella fracture was higher in Group A, 4.7% (four knees), compared with 2.1% (three knees) in Group B, but this difference was not statistically significant. The presence of anterior knee pain referable to the patella was 7.1% (five patients, six knees) in Group A (one patient with two knees had severe anterior knee pain) and 9% (13 knees in 13 patients) in Group B. There was no patella clunk syndrome, subluxation, or fracture of a fixation peg in either group. With this specific protocol for patella resurfacing, there was a higher rate of complications with the one central peg patella (4.7%) than with the three-peg patella (2.1%), but this did not reach statistical significance. The results do not support an increased risk of component failure with this three-peg patella design, but do not, at this length of followup, show any significant advantage of three-peg fixation.

Pregnancy after total hip arthroplasty.

BACKGROUND: Younger patients are having total hip arthroplasty now, and a woman who has had such a procedure may want to become pregnant. The purposes of this study were to report on a series of women who had completed a pregnancy after a total hip arthroplasty and to determine if pregnancy affects the function and longevity of the prosthesis. METHODS: Five women, with a total of seven uncemented total hip replacements, had six successful pregnancies. The mean age at the arthroplasty was twenty-nine years (range, twenty-two to thirty-eight years), and the mean time from the hip arthroplasty to the pregnancy was 2.5 years (range, one to seven years). These patients (Group A) were compared with a matched group of five women with a total of eight uncemented total hip prostheses (Group B) who had not completed a pregnancy. The mean follow-up time was eight years (range, two to thirteen years) for Group A and seven years (range, two to twelve years) for Group B. Patients were clinically evaluated with the Harris hip score. Radiographs were evaluated for component fixation and osteolysis. RESULTS: The five women completed a total of six successful pregnancies. One patient, with a bilateral total hip arthroplasty, had two successful pregnancies, 2.5 years apart. Three children were delivered vaginally (with the mother in the lithotomy position) and three, by cesarean section. There were no complications related to the total hip arthroplasty after delivery. The mean weight gain during the pregnancy was 13 kg (range, 8 to 14.2 kg). In Group A, the mean Harris hip score was 94 points prior to the pregnancy and 97 points at the time of the most recent follow-up. In group B, the mean Harris hip score was 91 points at one to two years after the arthroplasty and it was unchanged at the time of the most recent follow-up. There were six excellent results and one good result of the hip arthroplasty in Group A and five excellent and three good results in Group B. The mean total arc of hip motion was 217 degrees in Group A before the pregnancy and 241 degrees at the time of the most recent follow-up. The mean total arc of hip motion was 193 degrees in Group B at one to two years postoperatively and 190 degrees at the time of the most recent follow-up. The difference in the total arc of hip motion between the two groups at the latest follow-up evaluation was significant (p = 0.025). There were no reoperations in either group. Radiographs showed osteolysis of the femur in three hips in Group A and three hips in Group B. CONCLUSIONS: It appears that successful pregnancy and normal vaginal delivery can occur safely after total hip arthroplasty. The overall result, function, and radiographic appearance after the total hip arthroplasty was not adversely affected by pregnancy in this small group of patients.

Open reduction and cementation for femoral head fracture secondary to avascular necrosis: preliminary report.

Current treatment for femoral head avascular necrosis has shown good results in early stages of disease, but are not as impressive after progression to collapse. We treated 19 patients (20 hips) with Stage III avascular necrosis (AVN) by open reduction augmented by methylmethacrylate cementation. Follow up ranges from 6 months to 2 years (average = 8.7 months). We followed patient progress with pre- and post-operative Harris Hip Scores, Womac Osteoarthritis Index and a Health Status Questionnaire (SF36). All patients realized immediate post-operative pain relief and improvement in function. Harris Hip, Womac Osteoarthritis Index and SF36 physical health scores improved significantly from 54.0 to 79.5 (p < 0.05), 54.3 to 29.8 (p < 0.05) and 28.4 to 42.4 (p < 0.05), respectively. Three patients had a conversion to total hip arthroplasty. Cementation is technically simple, burns no bridges and enables patients a rapid recovery. The long term results, in regards to progression of disease and secondary arthritis, are unknown.

Development of a progestin-based estrus synchronization program: II. Reproductive response of cows fed melengestrol acetate for 14 days with injections of progesterone and prostaglandin F2alpha.

We tested the efficacy of an estrus control system designed to provide optimal control of follicular development. In Exp. 1, postpartum cows (n = 133) and yearling heifers (n = 57) were fed either .5 mg x female(-1) x d(-1) of melengestrol acetate (MGA) or the carrier for MGA from d -13 to d 0 (d 0 = last day of MGA feeding). All females received 25 mg of PGF2alpha (i.m.) on d -13 and 0. On d -6, cows and heifers fed MGA were administered an i.m. injection of progesterone (200 mg; MGA/P4), and those fed the corn carrier (2XPGF2alpha) received no progesterone. Beginning on d 1, females were bred by AI from d 1 to at least d 5. During the estrus synchronization period (d 1 to d 5), more (P < .05) postpartum cows were observed in estrus (70.1 vs 42.4%), the timing of estrus was more (P < .05) precise, conception rate was similar, and pregnancy rate was higher (P < .05) in the MGA/P4 than in the 2XPGF2alpha treatment. More (P < .05) cows that were anestrous at the beginning of the breeding season were in estrus during the synchronization period in the MGA/P4 (55.8%) than in the 2XPGF2alpha (28.6%) treatment. In heifers, estrus was synchronized in over 90% of females, and neither conception nor pregnancy rate during the synchronization period differed between treatments. In Exp. 2, postpartum cows (n = 122) and heifers (n = 84) received treatments (MGA/P4 or 2XPGF2alpha) as described for Exp. 1 with one exception. In the MGA/ P4 treatment, progesterone was administered on d -7 rather than d -6. Females were bred by AI from d 1 to 5. The estrus response and conception rate during the synchronization period did not differ between treatments for either cows or heifers. We conclude that the progestin-based estrous synchronization system used in this study effectively synchronized an estrus of normal fertility in cyclic cows and induced a majority of anestrous cows to reinitiate estrous cycles.

Duration of treatment with progesterone and regression of persistent ovarian follicles in cattle.

The objective of the present study was to determine the duration of elevated concentrations of progesterone necessary to induce atresia of persistent ovarian follicles. Heifers were administered 25 mg of PGF2alpha on d 6 and 7 (d 0 = d of synchronized estrus) and a norgestomet implant from d 6 to 14. Ovaries were monitored by ultrasonography, and blood samples were collected on d 3, 5, 7, 9, 11, and 12 and daily from d 14 until ovulation. On d 12, heifers received either two progesterone-releasing intravaginal devices (PRID) for 6 h (6-h; n = 5), two PRID for 24 h (24-h; n = 5), or no treatment (CON; n = 5). Blood samples were collected at 15-min intervals from h -6 to 30 (PRID insertion = h 0) and analyzed for concentrations of LH. Characteristics of LH secretion were determined for consecutive 6-h periods (Period 0 to 5). Hourly blood samples, collected from h 0 to 29, were analyzed for concentrations of 17beta-estradiol (estradiol) and progesterone. The dominant ovarian follicles present on d 7 increased in size to 15.4+/-.3 mm on d 12 ("persistent follicle"). Following removal of the PRID and norgestomet implants, atresia of persistent follicles and ovulation of new follicles were induced in one of five and in four of five heifers in the 6-h and 24-h treatments, respectively. Persistent follicles ovulated after withdrawal of norgestomet in all other heifers. Concentrations of progesterone were increased from h 1 to 7 in the 6-h and h 1 to 26 in the 24-h treatment. Frequency of LH pulses was reduced (P < .05) during Periods 1 to 2 in the 6-h and Periods 1 to 5 in the 24-h treatment relative to the CON treatment. By h 10, concentrations of estradiol in the 6-h and 24-h treatments were lower (P < . 05) than in the CON treatment. This suppression continued through h 29 in the 24-h treatment (P < .05), whereas concentrations in the 6-h treatment were intermediate to those of the CON and 24-h treatments after h 14. Suppression of pulsatile LH release and estradiol secretion was evident with 6 and 24 h of treatment with progesterone, but only the 24-h treatment induced atresia of persistent follicles in a majority of the heifers.

Progestin-induced puberty and secretion of luteinizing hormone in heifers.

Two experiments were designed to investigate the endocrine mechanisms by which progestin administration induces puberty in heifers. In experiment 1, prepubertal heifers were randomly assigned by age to receive either a single norgestomet implant for 10 days (NORG; n = 15) or to serve as unimplanted controls (CONT; n = 14). Serial blood samples were obtained on Days -0.5, 8.5, and 10.5 (Day 1 = day of implant insertion) and were analyzed for concentrations of LH. On days 9 and 11, 4 heifers in each treatment were slaughtered, and the reproductive tracts were obtained. Weekly progesterone analyses were performed to estimate the day of puberty in heifers not slaughtered. Puberty was induced in 6 of 7 heifers in the NORG treatment, resulting in an earlier (p < 0.05) day of puberty in the NORG than in the CONT treatment. The frequency of LH pulses was higher (p < 0.05) on Days 8.5 and 10.5 in the NORG as compared to the CONT treatment. Although no difference (p > 0.10) was observed between treatments in follicular development, uterine weight was greater (p < 0.05) in NORG than in CONT heifers on Day 11. In experiment 2, prepubertal heifers (n = 47) were administered either 1 (1NORG; n = 16), 3(3NORG; n = 16), or 0 (CONT; n = 15) norgestomet implants for 10 days, and serial blood samples were obtained as described for experiment 1. Transrectal ultrasonography was used to determine the diameter of the largest follicle on Day 9. Plasma samples were obtained after each serial sample collection period and were analyzed for estradiol concentrations. Puberty was induced in 75% (12 of 16) and 81% (13 of 16) of heifers in the 1NORG treatments, respectively. Four heifers in the 1NORG treatment, from which serial blood samples were collected, ovulated before removal of the progestin implant, and the LH data for this treatment were deleted. In the 3NORG treatment, LH pulse frequency was suppressed (p < 0.05) on Day 8.5, but was greater (p < 0.05) 12 h after removal of the progestin (Day 10.5) than in the CONT treatment. We conclude that progestin administration hastens puberty by increasing LH secretion after progestin withdrawal and propose that progestin administration induces puberty by accelerating the peripubertal decrease of estradiol negative feedback on LH secretion.