Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.

BACKGROUND: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB). OBJECTIVES: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA). SEARCH STRATEGY: We searched international scientific databases, trial registration websites, and references of identified articles. SELECTION CRITERIA: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB. MAIN RESULTS: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75). AUTHOR'S CONCLUSIONS: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Association between small for gestational age and paternally inherited 5' insulin haplotypes.

OBJECTIVE: To test the association between small for gestational age and polymorphisms in the insulin gene in newborns and their mothers, as well as the effect of the parental transmission of haplotypes. SUBJECTS: Pairs of healthy African-American full-term newborns (N=207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g. METHODS: Six single nucleotide polymorphisms (SNPs) located in the insulin (INS) and insulin-like growth factor 2 (IGF2) genes were genotyped in mothers and newborns. Haplotypes composed of three SNPs in the 5' region of the INS-IGF2 locus were computationally inferred. Odds ratios for risk of small for gestational age (SGA) birth were calculated for individual SNPs and inferred haplotypes in the newborns and in the mothers using logistic regression. For 162 mother--newborn pairs the parental transmission of the haplotypes could be inferred, and the risks for SGA birth were calculated for the three common haplotypes in this sample. RESULTS: Three INS SNPs exhibited significant association with risk for SGA birth. The SNP alleles associated with increased risk for SGA were opposite in the maternal and newborn genomes, implying opposing influences on the rate of fetal growth. Consistent with these results, haplotypes composed of complementary nucleotide sequences (CAC at rs3842738, rs689 and rs3842748, respectively, in the newborn versus GTG in the mother) were significantly associated with risk for SGA birth. In analyses of haplotypes according to parental transmission, the same trend in risk for SGA was observed for both maternally and paternally transmitted haplotypes, although a significant difference in risk was observed only for paternally transmitted haplotypes. CONCLUSION: Polymorphisms near the 5' end of the INS-IGF2 locus are significantly associated with risk for SGA birth with a major effect due to the paternally transmitted haplotype, which is preferentially expressed due to imprinting.

Changing patterns of fetal lung maturity testing.

OBJECTIVE: In our laboratory, a decrease in fetal lung maturity (FLM) testing on amniotic fluid occurred over a 10-year period, and we desired to determine if this was a national phenomenon and, if present, ascertain possible etiologies. STUDY DESIGN: Society of Maternal-Fetal Medicine fellows, both in academic centers and private practice, were surveyed with regard to current usage of FLM testing. RESULT: Of 680 surveys, 417 (61%) responses were returned and 60% noted a decrease in FLM testing (range of reduction--foam stability index 65%, fluorescence polarization 35%, phosphatidyl glycerol 71%, lecithin/sphingomyelin ratio 70%). The most common reason suggested for the decline is that the tests were not needed for patient management. CONCLUSION: Obstetric patterns of FLM testing have declined, principally in near-term pregnancies, and this could adversely affect neonatal outcome.

Second trimester placental location as a predictor of an adverse pregnancy outcome.

OBJECTIVE: To determine if the second trimester placental location is associated with perinatal outcomes. MATERIALS AND METHODS: Observational study of placental location and the subsequent risk of an adverse pregnancy outcome. Placental location was divided into three categories, low, high lateral and high fundal. RESULTS: There were 3336 pregnancies analyzed in this study. Low implantation sites had a greater risk of preterm labor (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.38 to 2.90, P<0.001), preterm delivery (OR 1.86, 95% CI 1.36 to 2.54, P<0.001), fewer fetuses with macrosomia (OR 0.56, 95% CI 0.38 to 0.83, P=0.010) and reduced risk of postpartum hemorrhage (OR 0.56, 95% CI 0.46 to 0.95, P=0.026). High lateral implantations had a greater risk of low 1-min (OR 1.80, 95% CI 1.11 to 2.93, P=0.017) and 5-min (OR 3.49, 95% CI 1.46 to 8.36, P=0.005) Apgar scores. CONCLUSIONS: Low placental implantation was associated with an increased risk of preterm labor, preterm delivery and a reduced risk of postpartum hemorrhage, and of a macrosomic fetus. High lateral implantation was associated with low Apgar scores.

Pre-pregnancy body mass index and pregnancy outcomes.

OBJECTIVE: To determine the effect of maternal pre-pregnancy BMI on pregnancy outcomes. METHODS: Pregnancy cohort recruited pregnancies between 16 and 18 weeks. BMI evaluated underweight, BMI<18.5, normal, BMI 18.5-25, overweight BMI 25-30, and obese BMI>30 women. RESULTS: Pre-pregnancy BMI classified 331 women as underweight (11.7%), 1982 normal (69.9%), 326 overweight (11.5%), and 188 as obese (6.6%). Obese women were more likely to develop gestational diabetes (p<0.001), hypertension (p<0.001), preeclampsia (p<0.001), need labor induction (p<0.001), cesarean delivery for fetal distress (p<0.001), postpartum hemorrhage (p=0.003), need neonatal resuscitation (p=0.001) and deliver hypoglycemic infants (p=0.007). Being underweight is correlated with fetal growth restriction (p=0.001). CONCLUSION: Pre-pregnancy obesity is a risk factor for gestational diabetes, preeclampsia, labor induction, cesarean for fetal distress, postpartum hemorrhage and neonatal hypoglycemic and need for resuscitation. Being underweight is risk factor for fetal growth restriction.

The role of fetal inflammatory response syndrome and fetal anemia in nonpreventable term neonatal encephalopathy.

OBJECTIVE: To evaluate asphyxial patterns in term encephalopathic newborns caused by chorioamnionitis or intrapartum blood loss that resulted in cerebral palsy and allegations of obstetrical professional liability. STUDY DESIGN: As an expert witness, JKM identified term newborns with profound neurologic impairment: 18 born in the presence of chorioamnionitis and 14 with significant anemia. RESULT: In both study groups, profound depression with low 10-min Apgars was associated with early-onset seizures (88%), multiorgan failure (94%) and a partial prolonged injury to the cortex and subcortical white matter (94%). A cord arterial pH>7.00 was noted in 68% and deep gray matter injury involving the basal ganglia and thalamus occurred in only 19% of the newborns studied. CONCLUSION: The cord arterial pH and pCO2 values, early-onset seizures and paucity of isolated deep gray matter injury support that significant injury occurred postnatally despite appropriate resuscitation. This unique pattern may refute allegations of obstetrical mismanagement in the intrapartum period.

The effects of dexamethasone and anencephaly on newborn serum levels of apolipoprotein A-1.

Since the control of production and clearance of plasma lipoproteins in utero is largely unknown, we sought to evaluate the effects of glucocorticosteroid (dexamethasone) treatment of developing fetuses and of chronic intrauterine hypercholesterolemia, due to fetal anencephaly, on newborn serum levels of apolipoprotein A-1 (Apo A-1), the major apoprotein of high density lipoproteins (HDL). Among preterm newborn infants (26-32 weeks gestation), the total, HDL, and low density lipoprotein cholesterol levels in umbilical cord serum of 11 newborns exposed to 4 doses of dexamethasone (5 mg each) within 1 week of delivery [mean, 3.05 +/- 1.01 (+/- SD), 0.83 +/- 0.18, and 1.84 +/- 0.69 mmol/L, respectively] and of 3 anencephalic newborns (2.84 +/- 0.57, 0.83 +/- 0.36, and 1.89 +/- 0.54 mmol/L) were increased to a similar extent over those in 17 normal newborns (1.76 +/- 0.16, 0.62 +/- 0.16, and 1.14 +/- 0.13 mmol/L). On the other hand, umbilical cord serum Apo A-1 levels were markedly increased only in the dexamethasone-treated preterm newborns (1.35 +/- 0.55 g/L; anencephalic, 0.78 +/- 0.15 g/L; normal, 0.68 +/- 0.06 g/L). Also, whereas serum total, HDL, and low density lipoprotein cholesterol levels in 5 term anencephalic newborns (3.85 +/- 1.37, 1.06 +/- 0.08, and 2.64 +/- 0.91 mmol/L) were substantially higher than those in 41 normal term newborns (1.42 +/- 0.28, 0.57 +/- 0.12, and 0.74 +/- 0.05 mmol/L), serum Apo A-1 levels were similar at term in anencephalic (1.01 +/- 0.30 g/L) and normal newborns (0.99 +/- 0.08 g/L). Normal Apo A-1 and lipoprotein cholesterol levels were found in an additional newborn who was delivered 30 days after exposure to dexamethasone. We conclude that intrauterine glucocorticosteroid treatment leads to transiently increased serum Apo A-1 levels in the newborn. This increase, however, is not likely to be secondary consequence of the hypercholesterolemia that also occurs in such newborns, since hypercholesterolemia of a similar extent in anencephalic newborns, who have atrophic adrenals, was not associated with marked changes in serum Apo A-1 levels.

The coenzyme A-synthesizing protein complex and its proposed role in CoA biosynthesis in bakers' yeast.

An improved procedure is described for the recovery and purification of the coenzyme A-synthesizing protein complex (CoA-SPC) of Saccharomyces cerevisiae (bakers' yeast). The molecular mass of the CoA-SPC, determined prior to and following its purification, is estimated by Sephacryl S-300 size exclusion chromatography to be between 375,000-400,000. Two previously unreported catalytic activities attributed to CoA-SPC have been identified. One of these is CoA-hydrolase activity which catalyzes the hydrolysis of CoA to form 3',5'-ADP and 4'-phosphopantetheine, and the other is dephospho-CoA-pyrophosphorylase activity which catalyzes a reaction between 4'-phosphopantetheine and ATP to form dephospho-CoA. The dephospho-CoA then reacts with ATP, catalyzed by the dephospho-CoA-kinase, to reform CoA. This sequence of reactions, referred to as the CoA/4'-phosphopantetheine cycle, provides a mechanism by which the 4'-phosphopantetheine can be recycled to form CoA. Each turn of the cycle utilizes two mol of ATP and produces one mol of ADP, one mol of PPi, and one mol of 3',5'-ADP. Other than the hydrolysis of CoA by CoA-SPC, the 4'-phosphopantetheine for the cycle apparently could be supplied by alternate sources. One alternate source may be the conventional pathway of CoA biosynthesis. Intact CoA-SPC has been separated into two segments. One segment is designated apo-CoA-SPC and the other segment segment is referred to as the 10,000-15,000 M(r) subunit. The 5'-ADP-4'-pantothenic acid-synthetase, 5'-ADP-4'-pantothenylcysteine-synthetase, 5'-ADP-4'-pantothenylcysteine-decarboxylase, and CoA-hydrolase activities reside in the apo-CoA-SPC segment of CoA-SPC. Whereas the dephospho-CoA-kinase and the dephospho-CoA-pyrophosphorylase activities reside in the 10,000-15,000 M(r) subunit. Thus, the 10,000-15,000 M(r) subunit mimics the bifunctional enzyme complex that catalyzes the final two steps in the conventional pathway of CoA biosynthesis.

Comparative study of flurbiprofen and morphine for postsurgical gynecologic pain.

This single-dose, double-blind, randomized, placebo-controlled study assessed the efficacy and safety of 50 mg of flurbiprofen (Ansaid, Upjohn) in the relief of postoperative pain following cesarean section, as well as vaginal or abdominal hysterectomies. Results show that both 50 mg of oral flurbiprofen and 10 mg of intramuscular morphine sulfate were significantly superior to placebo in 161 patients with respect to pain intensity after medication, pain relief scores, need for additional analgesia, and overall clinical evaluation of pain relief. By two hours after treatment, there were no significant differences between morphine sulfate and flurbiprofen in terms of pain intensity or degree of pain relief. According to investigators' global evaluations of efficacy, both active treatments were statistically superior to placebo. The only adverse reaction occurred in the morphine treatment group. Flurbiprofen administered orally for the relief of moderate to severe pain following major gynecologic surgery appears to be equal to morphine sulfate and superior to placebo in efficacy and safety. Unlike morphine, flurbiprofen is a nonparenteral, uncontrolled substance, and thus patient acceptance is improved while nursing time is decreased.

A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy.

In a large multicentered, collaborative randomized and blinded trial utilizing antenatal corticosteroids, the goals included determining the effectiveness of these agents in accelerating lung maturation, as well as monitoring any short-term or long-term adverse effects of this treatment on the parturient, fetus, and/or infant. More than 100 specific items, pertaining to diagnoses, complications, and outcomes were recorded for the 696 mothers enrolled in the study and their 745 infants. A significantly decreased incidence of necrotizing enterocolitis (P = .002) was found in the infants treated with steroids. The possibility of accelerated intestinal maturation induced by antenatal maternal steroid therapy exists. This treatment regimen is particularly attractive as adverse aspects of steroid therapy at the dosage utilized have not been demonstrated.

Prompt visualization of the gallbladder with a rim sign--acute or subacute cholecystitis?

An immunosuppressed, neutropenic patient developed symptoms and signs of acute cholecystitis. Gallbladder ultrasound was consistent with acute cholecystitis. Technetium-99m-diisopropyl iminodiacetic acid (DISIDA) scan showed a rim sign, but with normal gallbladder visualization. On restudy 72 hr later when the patient's WBC count was recovering, the 99mTc-DISIDA scan again showed a persistent rim sign, but now there was no gallbladder visualization at 1 hr, a pattern strongly predictive for acute complicated cholecystitis. Biliary drainage was performed by percutaneous cholecystotomy with clinical improvement. Semielective cholecystectomy performed 8 wk later confirmed both acute and chronic cholecystitis. We describe the rim sign and its variants, mechanisms of causation, prognostic importance and correlate our report with a review of the literature.

The canine eye: pectinate ligaments and aqueous outflow resistance.

The contribution of the pectinate ligaments to total aqueous outflow resistance was studied in 30 excised canine eye pairs by means of constant-pressure aqueous perfusion. Incision of these ligaments over one and two quadrants of the angle circumference increased the facility of aqueous outflow significantly more than could be attributed to normal "washout" alone. Neither mechanical nor enzymatic disruption of angle glycosaminoglycans could fully account for this phenomenon. The pectinate ligaments may therefore contribute to the canine aqueous outflow barrier by compartmentalizing the glycosaminoglycans in the spaces of Fontana. In addition, these ligaments, analogous to iris processes in the human, prevent widening of the canine angle and hold the filtration structures in a relatively compressed state, a situation that can be reversed by ligament incision.

Patterns of intraocular pressure elevation after aqueous humor outflow obstruction in rats.

PURPOSE: To determine the diural intraocular pressure (IOP) response of Brown Norway rat eyes after sclerosis of the aqueous humor outflow pathways and its relationship to optic nerve damage. METHODS: Hypertonic saline was injected into a single episcleral vein in 17 animals and awake IOP measured in both the light and dark phases of the circadian cycle for 34 days. Mean IOP for light and dark phases during the experimental period were compared with the respective pressures of the uninjected fellow eyes. Optic nerve cross sections from each nerve were graded for injury by five independent masked observers. RESULTS: For fellow eyes, mean light- and dark-phase IOP was 21 +/- 1 and 31 +/- 1 mm Hg, respectively. For four experimental eyes, mean IOPs for both phases were not altered. Six eyes demonstrated significant mean IOP elevations only during the dark phase. Of these, five showed persistent, large circadian oscillations, and four had partial optic nerve lesions. The remaining seven eyes experienced significant IOP elevations during both phases, and all had extensive optic nerve damage. CONCLUSIONS: Episcleral vein injection of hypertonic saline is more likely to increase IOP during the dark phase than the light. This is consistent with aqueous outflow obstruction superimposed on a circadian rhythm of aqueous humor production. Because these periodic IOP elevations produced optic nerve lesions, both light- and dark-phase IOP determinations are necessary for accurate correlation of IOP history to optic nerve damage in animals housed in a light- dark environment.

Effect of general anesthetics on IOP in rats with experimental aqueous outflow obstruction.

PURPOSE: To determine the effect of several common general anesthetics on intraocular pressure (IOP) after experimental aqueous outflow obstruction in the rat. METHODS: A single episcleral vein injection of hypertonic saline was used to sclerose aqueous humor outflow pathways and produce elevated IOP in Brown Norway rats. Animals were housed in either standard lighting or a constant low-level light environment. Awake IOPs were determined using a TonoPen (Mentor, Norwell, MA) immediately before induction of anesthesia by either isoflurane, ketamine, or a mixture of injectable anesthetics (xylazine, ketamine, and acepromazine). For each anesthetic, IOPs were measured immediately after adequate sedation (time 0) and at 5-minute intervals, up to 20 minutes. RESULTS; Awake IOPs ranged from 18 to 52 mm Hg. All anesthetics resulted in a statistically significant (P: < 0.01) reduction in measured IOP at every duration of anesthesia when compared with the corresponding awake IOP. With increasing duration of anesthesia, measured IOP decreased approximately linearly for both the anesthetic mixture and isoflurane. However, with ketamine, IOP declined to 48% +/- 11% (standard lighting) and 60% +/- 7% (constant light) of awake levels at 5 minutes of anesthesia, where it remained stable. In fellow eyes, the SD of the mean IOP in animals under anesthesia was always greater than the corresponding SD of the awake mean. Anesthesia's effects in normal eyes and eyes with elevated IOP were indistinguishable. CONCLUSIONS: All anesthetics resulted in rapid and substantial decreases in IOP in all eyes and increased the interanimal variability in IOPs. Measurement of IOP in awake animals provides the most accurate documentation of pressure histories for rat glaucoma model studies.

Regional microvascular anatomy of the rabbit ciliary body.

Vascular luminal castings of rabbit eyes were microdissected and studied with the scanning electron microscope to delineate the anatomy of the ciliary body microvasculature. We found regional microvascular differences corresponding to well known gross topographical and ultrastructural differences that may indicate regional functional specialization. The major arterial circle of the iris, derived solely from the long posterior ciliary arteries, supplies the ciliary body via two types of arterioles: anterior and posterior. Spiral iridial process capillaries arise from the anterior (iris) arterioles, are radially arranged along the back of the iris and drain directly into the iris veins. Arterioles from the posterior (ciliary) arterioles enter the head of the process, supplying its tortuous capillaries, some of which drain back into the iris veins. Other capillaries turn posteriorly to form relatively straight, parallel capillaries within the process leaf that drain into the choroidal system via marginal process veins. More posterior arterioles supply capillaries to the base of major processes, to the interprocess ciliary web, and to minor processes. The presence of a dual arteriolar supply to the ciliary processes has also been found in primates and suggests that the rabbit may represent a suitable animal model for the study of factors governing regional ciliary process perfusion.

Comparative microvascular anatomy of mammalian ciliary processes.

Methylmethacrylate lumenal castings of the ciliary body microvasculature were prepared from eight mammalian species and studied with the scanning electron microscope. In all of these species, the ciliary body is supplied by the major arterial circle, which originates solely from the long posterior ciliary arteries without contribution from the anterior ciliary circulation. In contrast to primates and rabbits, the ciliary processes of the eight species we studied are supplied by only one type of arteriole, which travels posteriorly from the major arterial circle to the iris root, where it gives rise to ciliary process arterioles. Using precise microdissection techniques, we found marked interspecies variations in ciliary process angioarchitecture among the mammalian eyes examined. Rodents (rat and guinea pig) demonstrated several interesting similarities to primates, with extensive interprocess connections and irregularly dilated, concentrically parallel capillaries traveling posteriorly to empty into the choroidal veins. In addition, rat ciliary process arterioles displayed marked focal constrictions suggestive of precapillary "sphincter" agonal activity. The carnivore ciliary process (cat and dog) is supplied by a single arteriole traveling posteriorly throughout its length and sending capillary arcades to its margin from where they drain outward into venous sinuses at the base of the process. Ungulate processes (sheep, goat, pig and cow) receive blood from multiple arterioles that occupy the process core along with veins that empty into the choroidal circulation. These vessels serve delicate capillaries lying on the sides, margin and head of each process. The anatomic variations described here should be considered in the design and interpretation of physiologic and immunohistochemical studies of ciliary body vascular perfusion in non-primate animal models.

Chondroitin sulfate proteoglycan distribution in the primate optic nerve head.

PURPOSE: To evaluate the presence and distribution of chondroitin and dermatan sulfate-containing proteoglycans in normal human and monkey optic nerve heads by light microscopic immunohistochemistry. METHODS: Monoclonal antibodies specific for glycosaminoglycan attachment sites remaining after incubation of tissues with chondroitinase ABC and ACII were used to detect proteoglycans containing unsulfated chondroitin (OS), chondroitin-4 and/or dermatan sulfate (4S), and chondroitin-6 sulfate (6S) glycosaminoglycans. RESULTS: 4S antibody labeling after chondroitinase ABC was heavily and evenly distributed within the peripapillary sclera and in the core of laminar beams and optic nerve septa. Preincubation with chondroitinase AC, which exposes only chondroitin sulfate attachment sites, diminished labeling intensity in the lamina cribrosa and sclera and almost completely eliminated it in the retrolaminar optic nerve septa. In contrast, 6S antibodies demonstrated a more intermittent linear distribution throughout the laminar beams and optic nerve septa. No qualitative differences were seen between human and monkey optic nerve heads. CONCLUSION: Chondroitin and dermatan sulfate-containing proteoglycans exist throughout the support tissues of the optic nerve head. The specific distribution patterns demonstrated by these monoclonal antibodies, and, in particular, the unique confinement of one of them to the lamina, indicate the presence of different core proteins or different functional glycosaminoglycan side chains that may influence the behavior of the lamina cribrosa.

Noninvasive measurement of rat intraocular pressure with the Tono-Pen.

PURPOSE: The purpose of this study was to evaluate the Tono-Pen 2 tonometer for measuring intraocular pressure (IOP) in the living rat eye. METHODS: One eye from each of 20 adult, anesthetized brown Norway rats (group 1) was cannulated and simultaneously connected to a syringe and a pressure transducer with a chart recorder. We increased IOP from 15 to 45 mmHg in 5-mmHg increments and obtained 15 consecutive readings (ignoring instrument-generated averages) at each pressure increment with a Tono-Pen 2 tonometer. To test the tonopen's ability to measure unknown IOP, transducer pressures were varied randomly in 20 additional animals (group 2), and tonopen readings were obtained in masked fashion. RESULTS: Plotting the mean tonopen readings for each animal against transducer IOP produced a regression formula of y = 4.54 + 0.79x (r = 0.98). Mean group 2 tonopen values plotted against transducer IOP yielded a regression formula of y = 4.75 + 0.78x (r = 0.94). A method comparison analysis showed that the tonopen significantly overestimates pressures at low IOP (< or = 15 mmHg), and it significantly underestimates pressures at high IOP (> or = 30 mmHg). Using two-way analysis of variance, it was determined that the group 2 data did not differ significantly from the group 1 data (P > or = 0.76). Because of this consistency, we generated a correction factor with 95% prediction intervals for Tono-Pen readings. CONCLUSIONS: The Tono-Pen 2 can be used reliably to measure IOP in the normal rat eye.

Chronology of optic nerve head and retinal responses to elevated intraocular pressure.

PURPOSE: To determine the chronology of optic nerve head and retinal responses to elevated intraocular pressure (IOP). METHODS: After 1 to 39 days of unilaterally elevated IOP, experimental and fellow rat eyes were examined for morphology and immunohistochemical labeling alterations and for ganglion cell DNA fragmentation. RESULTS: Mean IOP for the experimental eyes was 36 +/- 8 mm Hg, an approximately 15-mm Hg elevation above normal values. By 7 days of pressure elevation above 40 mm Hg, endogenous immunostaining for brain-derived neurotrophic factor and neurotrophin 4/5 was absent from the nerve head and superior retina, whereas normal labeling was present in the inferior retina and distal optic nerve of these same eyes. These changes were preceded by a loss of gap junctional connexin43 labeling and astrocytic proliferation in the nerve head and by increased retinal ganglion cell layer apoptosis in the retina. Nerve head depletion of neurotrophins coincided with evidence of axonal degeneration, loss of astrocytic glial fibrillary acidic protein staining, and spread of collagen VI vascular immunolabeling. After longer durations at these same pressures, neurotrophin labeling returned to nerve head glia and scattered retinal ganglion cells. CONCLUSIONS: Optic nerve head and retinal responses, including the depletion of endogenous neurotrophins, are readily identified in the rat eye after experimental IOP elevation. However, the apparent chronology of these responses suggests that the withdrawal of neurotrophic support was not the only determinant of retinal ganglion cell apoptosis and axonal degeneration in response to pressure.