Age- and gender-associated changes in the concentrations of serum TGF-1ß, DHEA-S and IGF-1 in healthy captive baboons (Papio hamadryas anubis).

Age-related changes in the concentration of factors like TGF-1ß, DHEA-S and IGF-1 may increase the risk of disease and illnesses in advanced life. A better understanding of these changes would aid in the development of more appropriate treatments and/or preventative care for many conditions associated with age. Due to their similar immune system and vulnerability to pathogens, baboons are an ideal model for humans. However, little research has been done examining the general effects of age in baboons. Therefore, we wanted to further examine the effects of aging in baboons by determining the age-dependent changes in serum TGF-1ß, DHEA-S and IGF-1 concentrations. Blood samples were collected during routine health checks in 113-118 captive baboons. In addition, longitudinal samples from 23 to 27 adult individuals were collected an average of 10.7years apart. Both age and gender influenced the concentrations of serum TGF-1ß and IGF-1. When both genders were analyzed together, TGF-1ß increased 16.1% as adults, compared to younger and older animals, but male and female baboons showed a slightly different temporal pattern of change. IGF-1 decreased with increasing age and males had a 30% greater concentration of IGF-1 than did females. While there was no effect of gender among our population, serum DHEA-S was negatively correlated with age, decreasing by 51.6% in the oldest animals. There were no effects of age or gender on serum IGFBP-3. In longitudinal samples collected from the same individuals, the concentrations of TGF-1ß, DHEA-S and IGF-1 were reduced with age. The results presented herein provide additional knowledge of the aging process in baboons and further validate the use of this species as an appropriate model for aging in humans.

Association of fetal cranial shape with shoulder dystocia.

OBJECTIVE: To evaluate whether fetal cranial shape is related to shoulder dystocia. METHODS: We compared shoulder dystocia cases (n = 18) with controls (normal vaginal deliveries, n = 18) in a retrospective matched-pairs observational study. Subjects were matched for known maternal and fetal risk factors and then evaluated for fetal biometric differences, which were measured by ultrasound near delivery. We tested multivariable risk models to predict shoulder dystocia by logistic regression. RESULTS: Cases had a smaller estimated occipitofrontal diameter (OFD) (P = 0.02) and a larger biparietal diameter/estimated OFD ratio (P = 0.003). A multivariable model including estimated fetal weight, estimated OFD, maternal weight and diabetes mellitus had sensitivity and specificity of 86% and 95%, respectively, and positive and negative likelihood ratios of 18.9 and 0.15, respectively. Estimated OFD significantly increased the predictive value of the model. CONCLUSION: A small estimated OFD is a risk factor for shoulder dystocia in the presence of other significant risk factors. A multivariable model including estimated OFD can predict shoulder dystocia in a clinically useful range.

Low maternal middle cerebral artery Doppler resistance indices can predict future development of pre-eclampsia.

OBJECTIVE: To determine if decreased resistance (vasodilatation) in the maternal middle cerebral artery (MCA) in the second trimester can predict third-trimester development of pre-eclampsia. METHODS: Four-hundred and five low-risk gravidas had MCA transcranial Doppler (TCD) once in the second trimester. Maternal/neonatal outcomes were evaluated after delivery. Mean blood pressure, MCA velocities, resistance index (RI), pulsatility index (PI) and cerebral perfusion pressure (CPP) were compared between normotensive and pre-eclamptic cohorts. RESULTS: Seven subjects (1.7%) developed pre-eclampsia. An RI of < 0.54 and a PI of < 0.81 were clinically useful in predicting subsequent pre-eclampsia. Areas under the receiver-operating characteristics curves for RI and PI were 0.93 and 0.93, respectively, with optimal sensitivity and specificity of 86% and 93% for both variables. Positive and negative likelihood ratios were 11.8/0.15 (RI) and 12.3/0.15 (PI). CONCLUSION: TCD indices of low maternal MCA resistance in the second trimester are predictive of the subsequent development of pre-eclampsia in a low-risk, ethnically homogeneous population.

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Purification and characterization of secretory IgA from baboon colostrum.

In this report, we describe a method for purifying secretory immunoglobulin A (sIgA) from baboon (Papio anubis) colostrum. The colostrum was first clarified by centrifugation and then analyzed with various anti-human Ig-specific immunologic reagents. Cross-reactive IgA in the baboon colostrum was identified by ELISA. Western blot analysis also demonstrated cross-reactive epitopes associated with human IgA1, IgA2, secretory component (SC), and joining (J) chain. To purify the sIgA, colostrum was separated into 4 distinct fractions by gel filtration chromatography. Analysis of the individual fractions by ELISA indicated that the IgA elutes over one peak. The IgA fraction was compared with purified human sIgA on SDS-PAGE, and exhibited heavy (H) chains, light (L) chains, SC, and J chain. The baboon colostrum was also analyzed by ELISA for specific IgG H and L chain epitopes utilizing monoclonal antibodies (MAbs). No significant quantity of IgG was detected in the baboon colostrum or in the individual 4 fractions, while L chain reactivity was observed in the sIgA fraction. The sIgA fraction was pooled, concentrated, and was found to contain approximately 7 mg/ml sIgA. To determine if the baboon sIgA was dimeric like human sIgA, the purified sIgA was sized by molecular sieve chromatography. The molecular size of the sIgA preparation (350 kDa) was determined empirically by comparison to known molecular species used to calibrate the column. In addition, native SDS-PAGE indicated that baboon sIgA, like human sIgA, migrates between IgG and IgM, suggesting it has a dimeric form. The purified baboon sIgA preparation should prove useful in the future study of mucosal immune responses induced in non-human primate species and for the generation of sIgA-specific immunological reagents.

Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli--a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli.

This study was designed to determine the effect of a delayed infusion (T+120 min) of alanyl tissue factor pathway inhibitor (ala-TFPI) on the response to LD100 E. coli. We hypothesized that baboons treated with a low dose of TFPI (5 mg/kg) which did not survive would exhibit thrombosis, infarction and hemorrhage of target tissues such as that seen in untreated animals infused with LD100 E. coli. Eight baboons were infused with 5 mg/kg of ala-TFPI over a 10 h period beginning immediately after a 2 h infusion of LD100 E. coli (experimental group). Four baboons were infused with E. coli followed by a 10 h infusion of saline (control group). Of the 12 baboons, the 11 non-survivors (TFPI = 7 out of 8; controls = 4 out of 4) were evaluated for the extent of thrombosis, necrosis, hemorrhage, and congestion of target tissues and for changes in clinical chemical parameters. We expected that failure to protect would correlate with failure to inhibit thrombosis of target tissue (8). Surprisingly ala-TFPI significantly inhibited thrombosis, hemorrhage and necrosis of adrenal and renal tissues and attenuated the rise in creatinine in the 7 treated non-survivors. The lungs of these non-survivors, however, exhibited intra-alveolar fibrin and a mild degree of hemorrhage and edema. We concluded that low doses of ala-TFPI begun as late as T+120 in minutes failed to protect against the lethal effects of LD100 E. coli in spite of completely preventing thrombosis and hemorrhage in target organs, and that thrombosis, infarction and hemorrhage of adrenal and renal tissue are not part of the lethal chain of events in this IV model of E. coli sepsis.

Analysis of nonhuman primate peripheral blood mononuclear cells for susceptibility to HIV-1 infection and HIV coreceptor expression.

HIV-1 infection of nonhuman primates does not lead to the acquired immunodeficiency syndrome seen in humans. The basis for this lack of disease progression in these animals is still unknown. In this study, primary nonhuman primate peripheral blood mononuclear cells (PBMC) were tested for their susceptibility to in vitro infection by several different primary HIV-1 isolates representing distinct subtypes or clades. None of the five HIV-1 subtypes tested were able to readily establish an infection in chimpanzee or baboon PBMC, as determined by p24 antigen capture assays. To address the mechanism of in vitro resistance to HIV-1 infection, PBMC were analyzed for HIV coreceptor mRNA expression and cell surface expression. Flow cytometry analysis of the nonhuman primate PBMC demonstrated that they do express CD4, CCR3, CCR5, and CXCR4 on their cell surface. Therefore, the level of restriction in the virus replication cycle does not appear to lie at the point of entry in these cells.

Serologic crossreactions among primate immunoglobulins.

We have generated and characterized 50 murine monoclonal antibodies (mAb) specific for baboon IgG. We examined crossreactivity of these mAb to baboon IgM and immunoglobulin (Ig) of various other primates including human, chimpanzee, rhesus monkey, cynomolgus monkey, and African green monkey. Those mAB that crossreacted with human IgG were further examined using myeloma proteins for specificity to human Ig subclasses. One mAB crossreacted with all four human IgG subclasses and with human IgM. We further analyzed this reactivity utilizing Bence Jones proteins representative of various light (L) chain germline gene family products. This mAB reacted with Bence Jones proteins indicating the recognition of a kappa (k) L chain specificity associated with the kappa I, kappa III, and kappa IV subgroups, but not with kappa II. Based on the differences between kappa II germ line gene encoded L chains and the other kappa L chain subgroups, we ascribe this reactivity to six amino acids that define a discontinuous epitope.

Iosulamide: human tolerance study of a new intravenous cholangiographic drug.

A simple dose-ranging human tolerance study of an experimental intravenous cholangiographic agent (iosulamide) was performed. Doses from 10-40 ml were infused in normal, healthy male volunteers. Bile duct opacification appeared adequate at 30-40 ml doses. With higher doses, a large percentage of the drug was excreted in the urine. Forty percent of the subjects manifested symptoms of minimal or mild contrast reactions.

Prevention of the rise in intraocular pressure following neodymium-YAG posterior capsulotomy using topical 1% apraclonidine.

We studied apraclonidine hydrochloride (aplonidine hydrochloride or ALO 2145), an alpha-agonist, for its effect on the intraocular pressure (IOP) rise following neodymium-YAG posterior capsulotomy (YPC). In a prospective multicentered double-masked study, 63 eyes were pretreated with one drop of either 1% apraclonidine hydrochloride or placebo one hour before performing YPC and again following the laser treatment. The greatest IOP rise in the placebo-treated eyes occurred in the third hour after YPC, when the mean (+/- SD) IOP rose from a baseline pressure of 16.4 +/- 3.7 to 20.8 +/- 6.8 mm Hg. In apraclonidine-treated eyes, the IOP fell from a mean of 15.6 +/- 3.8 to 12.8 +/- 6.0 mm Hg three hours postoperatively. There were five times as many eyes that had an IOP rise greater than 10 mm Hg in the placebo-treated group compared with those treated with apraclonidine. Apraclonidine proved to be highly effective in preventing the rise in IOP following YPC.

Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis.

Cooley's anemia is characterized by a deficiency of beta-globin chains, a relative excess of alpha-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the gamma-globin genes to adequately balance excess alpha-globin chains can ameliorate this disorder. Butyrates induce gamma-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent "pulsed" regimen of butyrate was evaluated. Following induction of gamma-globin mRNA and protein synthesis, total hemoglobin increased in beta-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the gamma- and beta-globin gene promoters to which new binding of transcription factors, including alpha CP2 (an activator of gamma globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce gamma globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer gamma-globin inducers (designed hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous gamma-globin genes is a realistic approach to therapy of the beta-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.

Clinical comparison of Provisc and Healon in cataract surgery.

This prospective, randomized, multicenter clinical trial compared the safety and efficacy of the Provisc and Healon viscoelastics. Sixty-one eyes of 61 patients had an extracapsular cataract extraction with implantation of a posterior chamber intraocular lens with the aid of Provisc (n = 32) or Healon (n = 29). Mean changes in preoperative versus postoperative corneal thickness and intraocular pressure and the incidence and magnitude of postoperative corneal edema and iritis were not significantly different between the two groups. Observed complications were considered consequences of the surgery and unrelated to viscoelastic use. No adverse medical events occurred. These results indicate Provisc and Healon are clinically equivalent in terms of safety and efficacy when used as surgical aids.

Hepatocyte-mediated mutagenicity of mononitrobenzo[a]pyrenes in Salmonella typhimurium strains.

The mononitro-substituted isomers of benzo[a]pyrene (B[a]P), 1-, 3- and 6-nitrobenzo[a]pyrene (NB[a]P), are environmental pollutants and are metabolized to mutagens in Salmonella by rat-liver homogenate postmitochondrial supernatant (S9) fractions. In this study, activation of these compounds to mutagens was investigated using the hepatocyte-mediated Salmonella mutagenicity assay. Hepatocytes from rats treated with Aroclor 1254 activated both 3-NB[a]P and 1-NB[a]P to mutagens, while 6-NB[a]P was not mutagenic. The positive mutagenicity responses were functions of both the chemical dose and the hepatocyte concentration. By using a nitroreductase-deficient strain (TA98NR) and a transesterificase-deficient strain (TA98/1,8-DNP6), it was verified that the direct-acting mutagenicities of 1- and 3-NB[a]P primarily were due to metabolic processes involving nitroreduction while the S9- and hepatocyte-mediated mutagenicity responses were also dependent on transesterification. When compared with the mutagenic responses produced with S9, the mutations induced by 1- and 3-NB[a]P in the presence of hepatocytes were relatively more dependent upon nitroreductase metabolism and less on transesterification. Thus, intact hepatocytes were capable of activating 1- and 3-NB[a]P to mutagenic metabolites and some of these metabolites appeared to be different from those produced by S9.

Acute visual loss due to a calcified optic nerve glioma.

Optic nerve gliomas are slow-growing tumours most commonly seen in children under 10 years of age. Rapidly progressive proptosis and rapid visual deterioration are uncommon but may occur owing to accumulation of mucoid material, necrosis or hemorrhage. We describe a patient with an optic nerve glioma who manifested sudden proptosis and blindness caused by hemorrhage within the optic nerve sheath. The visual acuity returned to 20/25 after surgical decompression of the nerve and high-dose steroid therapy. Histopathological examination was required to establish the diagnosis of optic nerve glioma with extensive calcification. Optic nerve decompression or short-term high-dose steroid therapy, or both, may be helpful in recovering visual function in selected patients with optic nerve gliomas who have acute visual loss.

Amelanotic malignant melanoma of the conjunctiva with local metastasis to the eyelid.

Conjunctival melanomas are uncommon. The amelanotic variety is extremely rare. We describe a patient with an amelanotic melanoma of the superior conjunctiva that was primarily excised, followed by extensive conjunctival resection and liquid nitrogen cryotherapy applied to the tumour bed. Eight months later a local metastatic lesion was noted in the lower eyelid. Eyelid metastasis in conjunctival melanoma is uncommon but may occur owing to the rich lymphatic vasculature within the conjunctiva.

In vitro effects of prednisolone sodium succinate and Escherichia coli organisms on neutrophil survival, glucose utilization, and E coli clearance in canine blood.

A concentration of 1.4 X 10(9) Escherichia coli was added to tubes containing 10 ml of freshly collected blood from dogs to determine if prednisolone sodium succinate altered in vitro E coli mortality, glucose utilization, or neutrophil destruction. Group 1 tubes contained organisms plus saline solution, group 2 tubes had E coli plus 140 microgram of prednisolone/ml, and group 3 tubes contained E coli plus 1,400 microgram of prednisolone/ml. Initial and final WBC, RBC, PCV and E coli concentrations were determined on each group. Blood glucose values were measured from zero time through +2 hours. There was a significant (P less than 0.001) reduction in the number of E coli in vitro for all groups, but there was no difference among the groups. Fewer neutrophils (P less than 0.01) were lost in the tubes containing either concentration of prednisolone than in the tubes containing E coli alone. At the therapeutic amount of prednisolone (group 2) the glucose utilization was not significantly (P greater than 0.05) different from the utilization in the control group; however, at 10 X the therapeutic amount of prednisolone (group 3), there was an increase in glucose utilization. Seemingly, prednisolone does not alter in vitro E coli destruction and aids in preserving neutrophils of canine blood.

Disseminated staphylococcal infection in a colony of captive ground squirrels (Citellus lateralis).

Purulent cutaneous and visceral lesions were observed in a colony of 68 golden-mantled ground squirrels, Citellus (Spermophilus) lateralis, used in a hibernation study. The squirrels had been purchased from a commercial supplier. Beginning approximately three weeks after their purchase and during the following five weeks, 21 squirrels died. The predominate gross and histologic findings consisted of multifocal suppurative lesions involving the skin, brain and numerous visceral organs. Staphylococcus aureus was consistently found to be associated with the disease.

Compliance with a standard of care for retinopathy of prematurity in one neonatal intensive care unit.

Standards of care are an integral part of providing safe and proper health care to the public. One such standard is the screening of premature infants for retinopathy of prematurity. In a retrospective chart review of 67 infants in an intensive care nursery, a high incidence of non-compliance with the standard was found in infants with over 1251-g birth weight, but that infants under 1251-g birth weight and eligible for participation in an investigation of retinopathy of prematurity had a high degree of compliance with the standard. These findings resulted in the adoption of recommendations to improve compliance with the standard.

Follow up retrospective study of compliance with a standard of care for retinopathy of prematurity in one neonatal intensive care unit.

A retrospective chart review was conducted to determine the impact of recently instituted guidelines on compliance with the standard of care for retinopathy of prematurity (ROP) in the Newborn Intensive Care Unit at the University of Utah Medical Center. In a previous study, it was found that infants eligible for participation in a National Institutes of Health-funded study of ROP were routinely receiving screening eye examinations, whereas infants who qualified for ROP screening according to the standard of care, but not eligible for the study, were seen infrequently. Consequently, a plan to improve the compliance with the standard of care for all infants who fit the standard criteria was implemented. The comparison revealed significant improvement in compliance rates. In one subgrouping of infants, compliance rose from three of 16 (18.75%) infants screened for ROP according to the standard of care, to nine of 11 (82%) infants screened for ROP according to the revised standard. This increase in compliance appears to be due to adherence to guidelines recommended in an earlier study, which included increasing staff awareness of the standard of care, designating a person to schedule and track infants who fit the screening criteria, and including the need for ROP screening on the admission and discharge summary.

Effectiveness of apraclonidine in preventing the rise in intraocular pressure after neodymium:YAG posterior capsulotomy.

Apraclonidine (para-aminoclonidine) is an alpha agonist that was studied for its effect on the IOP rise following YPC. In a prospective multicentered double-masked study 63 eyes were pretreated with one drop of either 1% apraclonidine or placebo 1 hour prior to performing YAG and again after the laser treatment. The greatest IOP rise in the placebo-treated eyes occurred in the third hour after YPC when the mean IOP rose from a baseline pressure of 16.4 +/- 3.7 mm Hg to 20.8 +/- 6.8 mm Hg (P less than .01). In apraclonidine-treated eyes the IOP fell from a mean of 15.6 +/- 3.8 mm Hg to 12.8 +/- 6.0 mm Hg 3 hours postoperatively (P less than .001). There were five times as many eyes that had a pressure rise greater than 10 mm Hg in the placebo-treated group compared to those treated with apraclonidine. Apraclonidine proved to be highly effective in preventing the rise in IOP following YPC.