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Placenta  2013;34(11):10.1016/j.placenta.2013.08.007.
Maternal obesity (MO) remains a serious obstetric problem with acute and chronic morbidities for both mothers and offspring. The mechanisms underlying these adverse consequences of MOremain unknown. Endocannabinoids (ECB) are neuromodulatory lipids derived from adipocytes. Metabolic crosstalk between placenta and adipocytes may mediate sequelae of MO. The goal of this study was to elucidate placental and systemic ECBs in MO.
Material and methods
Placentas, serum, and subcutaneous fat were collected at Cesarean sections performed near term (0.9 G) in four non-obese (nOB) and four obese (OB) baboons (Papio spp.). Concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled to tandem mass spectrometry. AEA and 2-AG pathways were characterized in placentas by Q-RT-PCR, Western blot, and immunohistochemistry.
Placental 2-AG levels were lower and maternal fat AEA levels were higher in OB (1254.1 ± 401.3 nmol/kg and 17.3 ± 4 nmol/kg ) vs. nOB (3124.2 ± 557.3 nmol/kg and 3.1 ± 0.6 nmol/kg) animals. Concentrations of 2-AG correlated positively between maternal fat and placenta (r=0.82, p=0.013), but correlated negatively with maternal leptin concentrations (r=−0.72, p=0.04 and r=−0.83, p=0.01, respectively).
This is the first study to demonstrate differential ECB pathway regulation in maternal fat and placenta in MO. Differential regulation and function exist for AEA and 2-AG as the major ECB pathways in placenta.
PMCID: PMC3827983  PMID: 24008071
2.  Reductions in serum IGF-1 during aging impair health span 
Aging Cell  2013;13(3):408-418.
In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.
PMCID: PMC4326899  PMID: 24341939
aging; bone; growth hormone; IGF; insulin-sensitivity; LID; lifespan; liver; tumor
3.  Pathology of spontaneous air sacculitis in 37 baboons and 7 chimpanzees and a brief review of the literature 
Journal of Medical Primatology  2012;41(4):266-277.
Air sacculitis is an important clinical condition in non-human primates.
We evaluated 37 baboons and 7 chimpanzees with spontaneous air sacculitis submitted to pathology over a 20 year period.
Air sacculitis was observed almost exclusively in males. Common reported signs were halitosis, coughing, nasal discharges, depression, anorexia, and weight loss. Gross lesions included thickened air sacs and suppurative exudate lining the walls. Microscopic lesions included marked epithelial hyperplasia or hypertrophy, necrosis, fibrosis, cellular infiltrates, and bacterial colonies. Mixed bacterial infections were more common than infections by single species of bacteria. Streptococcus sp. was the most frequent bacteria isolated in both baboons and chimpanzees.
This is the first report describing the gross and microscopic lesions of air sacculitis in chimpanzees. The preponderance of males suggests a male sex predilection in baboons.
PMCID: PMC3402580  PMID: 22765381
Air sac; Airsacculitis; Pan; Papio; Non-human primate
4.  Craniorachischisis and Omphalocele in a Stillborn Cynomolgus Monkey (Macaca fascicularis) 
Nonhuman primates have been a common animal model to evaluate experimentally-induced malformations. Reports on spontaneous malformations are important in determining the background incidence of congenital anomalies in specific species and in evaluating experimental results. Here we report on a stillborn cynomolgus monkey (Macaca fascicularis) with multiple congenital anomalies from the colony maintained at the Southwest National Primate Research Center at the Southwest Foundation for Biomedical Research, San Antonio, Texas. Physical findings included low birth weight, craniorachischisis, facial abnormalities, omphalocele, malrotation of the gut with areas of atresia and intussusception, a Meckel diverticulum, arthrogryposis, patent ductus arteriosus, and patent foramen ovale. The macaque had normal male external genitalia, but undescended testes. Gestational age was unknown but was estimated from measurements of the limbs and other developmental criteria. Although cytogenetic analysis was not possible due to the tissues being in an advanced state of decomposition, array Comparative Genomic Hybridization analysis using human bacterial artificial chromosome clones was successful in effectively eliminating aneuploidy or any copy number changes greater than approximately 3–5 Mb as a cause of the malformations. Further evaluation of the animal included extensive imaging of the skeletal and neural tissue defects. The animal’s congenital anomalies are discussed in relation to the current hypotheses attempting to explain the frequent association of neural tube defects with other abnormalities.
PMCID: PMC3678351  PMID: 21567905
neural tube defects; schisis association; macaque; cynomolgus monkey; non-human primate; congenital defects; malformations
5.  Polymerase Chain Reaction Detection of Trypanosoma cruzi in Macaca fascicularis Using Archived Tissues 
This study describes conventional and real-time polymerase chain reaction (PCR) methods developed to detect and quantify Trypanosoma cruzi DNA in cynomolgus monkeys (Macaca fascicularis) using formalin-fixed paraffin-embedded blocks archived for periods of up to 6 years. The highest concentration of T. cruzi DNA was found in the myocardium, urinary bladder, stomach, lymph node, adrenal gland, and colon. The concentration of T. cruzi DNA detected in cardiac tissues was 10–100-fold greater than found elsewhere; the mean concentrations of T. cruzi DNA in non-cardiac tissues were otherwise comparable. Trypanosoma cruzi DNA was amplified from cerebrum but not cerebellum or kidney. Successful use of DNA from formalin-fixed, paraffin-embedded blocks is important because most pathology laboratories routinely archive wax blocks. This archived resource can be used for further studies on the prevalence of this disease.
PMCID: PMC2740910  PMID: 19635875
6.  Do Ames dwarf and calorie-restricted mice share common effects on age-related pathology? 
Pathobiology of Aging & Age Related Diseases  2013;3:10.3402/pba.v3i0.20833.
Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways. To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.
PMCID: PMC3689900  PMID: 23799173
age-related pathology; Ames dwarf mice; calorie restriction; neoplastic disease; aging
7.  Thioredoxin 1 Overexpression Extends Mainly the Earlier Part of Life Span in Mice 
We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)+/0]. The Tg(TRX1)+/0 mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)+/0 mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1)+/0 mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1)+/0 mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1)+/0 mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.
PMCID: PMC3210956  PMID: 21873593
Thioredoxin; Transgenic mouse; Oxidative stress; Protein carbonylation; Aging
8.  Myxomatous neoplasms in the perineal region of baboons 
Journal of medical primatology  2008;37(6):261-270.
In baboons, Papio sp. neoplasms tend to affect the hematopoietic system most commonly, with rare documentation of myxomatous neoplasms. In contrast, women can develop myxomatous masses within deep peripelvic tissues with some frequency during their reproductive years.
We have identified and examined, retrospectively, myxomatous perineal masses in twelve female baboons within one research facility and compared their histopathologic, immunohistochemical and electron microscopic features to their human variants.
Our results indicate that these myxomatous neoplasms, in humans and non-human primates, share common features.
Further research, particularly molecular genetic analysis, may be needed to identify the baboon as a true animal model for myxomatous perineal neoplasms.
PMCID: PMC3482000  PMID: 19017193
Aggressive angiomyxoma; angiomyofibroblastoma; cdk4; estrogen receptor; MDM2; progesterone receptor
9.  The Prevalence of Colonic Amyloidosis in Baboons. A 22-year Survey at a Large Primate Facility 
In vivo (Athens, Greece)  2008;22(6):725-727.
Colonic amyloidosis has been previously reported in animals, however its prevalence rate has not yet been explored. The aim of the present work was to assess the prevalence of colonic amyloidosis at the Southwest National Primate Research Center since 1986.
Materials and Methods
Colonic amyloidosis was sought in autopsy material from baboons collected under the diagnosis of systemic amyloidosis.
Between 1986 and 2007, a mean of 3,315 baboons per year (range 2,578–3,931) were housed at the Southwest National Primate Research Center. After examination, colonic amyloidosis was detected in 6 (6.8% ) of the 88 baboons with systemic amyloidosis, yielding a prevalence rate of 0.27 cases per year since 1986. Colonic amyloid deposits were found in the interstitial aspect of the lamina propria, often replacing normal mucosal crypts of Lieberkuhn.
It was observed that only 6.8% of animals with systemic amyloidosis examined between 1986 and 2007 developed colonic amyloidosis. The apparent natural resistance to colonic amyloidosis in baboons presenting systemic amyloidosis deserves to be further investigated.
PMCID: PMC3479647  PMID: 19180998
Amyloidosis; colon; baboon
10.  The Columnar-lined Mucosa in the Distal Esophagus. A Preliminary Study in Baboons 
In vivo (Athens, Greece)  2009;23(2):273-275.
For anatomists, the cardia is a portion of the stomach. However, at the histological level, the cardiac mucosa, described as columnar-lined with mucus-producing glands (CLMMG), is for some pathologists part of the stomach (already present at birth) and for others a metaplastic change of the esophagus induced by gastro-esophageal reflux (GER).
Materials and Methods
The distal esophagus and the proximal stomach of 5 adult male baboons were removed en bloc at autopsy. The distance between the most distal part of the squamous epithelium of the esophagus and the first oxyntic fundic gastric gland (representing the entire CLMMG) was assessed using an ocular microscale.
The length of the CLMMG varied from 1.2 mm to 12.4 mm. The CLMMG had replaced the squamous epithelium of the distal esophagus in all 5 baboons.
Regurgitation with rumination is a natural physiological, daily, recurrent process in baboons that leads to GER. The luminal cytoplasmic vacuoles with neutral mucins contained in the columnar cells and the neutral mucins produced by the mucin glands buffer the low pH of the gastric juices that reflux into the distal esophagus. This protective action against the acid refluxate cannot be achieved by the squamous epithelium.
The results of this preliminary investigation suggest that in baboons, CLMMG is an adaptation process of the esophageal mucosal to the low pH microenvironment conveyed by protracted GER.
PMCID: PMC3479648  PMID: 19414413
Metaplasia; esophagus; reflux; baboons
11.  The Frequency of Gastric Amyloidosis in Baboons. A 22-year Survey at a Large Primate Facility 
In vivo (Athens, Greece)  2008;22(6):663-665.
Systemic amyloidosis, caused by abnormal tissue accretion of plasma proteins, affects several organs of the gastrointestinal (GI) tract. Gastric amyloidosis, rare in humans, has only been reported once in animals.
Materials and Methods
Gastric amyloidosis was sought for in baboons with systemic amyloidosis.
During the past 22 years (between January 1986 and January 2007) a mean of 3,315 baboons/year (range 2,578–3,931) were housed at the Southwest National Primate Research Center. Gastric amyloidosis was found in 9 (10.2%) of the 88 baboons having a diagnosis of systemic amyloidosis. Consequently, the prevalence of gastric amyloidosis occurring since 1986 at this facility was 0.41 baboons/year. Gastric amyloid deposits were found in the interstitial aspect of the lamina propria, replacing normal mucosal structures, in the submucosal stroma along the interface with the muscularis mucosae and in the interstitial tissue of submucosal lymphoid aggregates. In one of the animals, lumps of amyloid deposits with giant cells were found in the gastric mucosa.
Baboons with systemic amyloidosis usually show increasing frequency of amyloid deposits in the liver, large intestine, lymph nodes, spleen and the small intestine. We now demonstrate that it may also involve the stomach. Why certain organs of the GI tract in baboons are more susceptible than others to be affected by the process of systemic amyloidosis remains unexplained. The apparent natural resistance of the stomach of baboons to be affected by systemic amyloidosis deserves further investigation. The review of the literature indicates that this is only the second report on gastric amyloidosis in baboons.
PMCID: PMC3468905  PMID: 19180988
Amyloidosis; stomach; baboons
12.  The Frequency of Histological Features Mimicking Reflux Esophagitis: A Study in Non-human Primates 
In vivo (Athens, Greece)  2008;22(6):721-724.
The frequency of histological changes mimicking those described for reflux esophagitis in humans was assessed in a cohort of non-human primates (NHP).
Materials and Methods
A total of 121 consecutive esophagi (from 103 baboons and 18 macaques) were classified according to Ismail-Beiji for reflux esophagitis in humans into grade 1, grade 2 and grade 3 esophagitis.
Histological features compatible with reflux esophagitis were found in 28.2% of the baboons and in 22.2% of the macaques. Esophagitis grade 1 was more common in baboons (24%) than in macaques (6%), while esophagitis grade 2 was more common in macaques (17%) than in baboons (2%).
Although the prevalence of reflux esophagitis in man is at least 2%, only a fraction of patients demonstrate histological features consistent with grades 1, 2 or 3 esophagitis. Hence, the finding that 27% of a cohort of consecutive, unselected NHP had grades 1, 2 or 3 esophagitis at histology is remarkable. The possible causes for the difference between species, such as the oblique position often adopted by NHP during the gastric phase of digestion, the diet, regurgitation and subsequent re-ingestion, as well as the stress of NHP when kept in captivity, are reviewed.
PMCID: PMC3468915  PMID: 19180997
Esophagitis; reflux; non-human primates indent
13.  Thioredoxin, oxidative stress, cancer and aging 
The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age-related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways.
PMCID: PMC3886257  PMID: 24764510
Thioredoxin; Transgenic mouse; Knockout mouse; Oxidative stress; Cancer; aging
14.  The Frequency of Glassy Cells in Barrett’s Mucosa: A Study in Baboons 
In vivo (Athens, Greece)  2009;23(6):925-927.
Glands with glassy cells (GGCs) were recently found in 1.8% of patients showing Barrett’s mucosa in esophageal biopsies. Similar GGCs were more recently detected in a baboon having glandulo-metaplastic esophageal mucosa (GMEM). The aim was to assess the frequency of baboons with GMEM having GGCs.
Materials and Methods
GGCs were searched for in 68 consecutive baboons having GMEM. Sections were stained with H&E and with alcian blue (pH 2.5), to detect sialomucins in goblet cells (a marker of Barrett’s mucosa in GMEM).
Two out of the 68 baboons with Barrett’s mucosa (2.9%) showed GGCs.
In similarity to humans, the Barrett’s mucosa in baboons may show GGCs. Although the significance of GGCs in baboons (and in humans) remains poorly understood, their presence might not be a fortuitous event but linked to the molecular events leading to the development of intestinal metaplasia in Barrett’s mucosa, a known pre-neoplastic mucosal change in the distal esophagus in humans.
PMCID: PMC3420813  PMID: 20023234
Nonhuman primate; pathology; disease; intestinal metaplasia
16.  Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats 
Age  2010;33(2):167-183.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
PMCID: PMC3127467  PMID: 21153712
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
17.  Natural pathology of the Baboon (Papio spp.) 
Journal of medical primatology  2011;40(2):142-155.
Baboons are useful animal models for biomedical research, but the natural pathology of the baboon is not as well defined as other non-human primates.
A computer search for all morphologic diagnoses from baboon necropsies at the Southwest National Primate Research Center was performed and included all the natural deaths and animals euthanized for natural causes.
A total of 10,883 macroscopic or microscopic morphologic diagnoses in 4297 baboons were documented and are presented by total incidence, relative incidence by sex and age-group, and mean age of occurrence. The most common diagnoses in descending order of occurrence were hemorrhage, stillborn, amyloidosis, colitis, spondylosis, and pneumonia. The systems with the most diagnoses were the digestive, urogenital, musculoskeletal, and respiratory.
This extensive evaluation of the natural pathology of the baboon should be an invaluable biomedical research resource.
PMCID: PMC3167160  PMID: 21226714
diseases; monkey; non-human primates; pathology; spontaneous; survey
18.  Does Reduced IGF-1R Signaling in Igf1r+/− Mice Alter Aging? 
PLoS ONE  2011;6(11):e26891.
Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo- insufficiency of the IGF-1 receptor (Igf1r+/−) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r+/− mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r+/− mice show reduced IGF-1 signaling. Aged male, but not female Igf1r+/− mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r+/− mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r+/− mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r+/− and wild type mice was observed; and the mean lifespan of the Igf1r+/− females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r+/− and wild type mice. These data show that the Igf1r+/− mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.
PMCID: PMC3223158  PMID: 22132081
19.  Trypanosoma cruzi in non-human primates with a history of stillbirths: a retrospective study (Papio hamadryas spp.) and case report (Macaca fascicularis) 
Journal of medical primatology  2008;37(6):318-328.
Congenital transmission of Trypanosoma cruzi has been described in humans and experimental work has been conducted with mice, but not with non-human primates (NHPs).
We conducted a retrospective study of female baboons (Papio hamadryas spp.) naturally seropositive or seronegative for T. cruzi with history of fetal loss, and we report a stillbirth in a cynomolgus macaque (Macaca fascicularis) with placental T. cruzi amastigotes.
There were no differences in menstrual cycle parameters and the number of fetal losses between seropositive and seronegative baboons with history of fetal loss. The amount of parasite DNA detected using quantitative polymerase chain reaction (Q-PCR) in M. fascicularis placenta was within the range detected in infected baboon tissues.
There is no evidence that chronic maternal T. cruzi infection causes fetal loss in baboons. Q-PCR is a useful diagnostic tool to study archived NHP placentas.
PMCID: PMC3149842  PMID: 18671769
Baboon; macaque; placental lesions; reproductive performance; serology; trypanosomiasis
20.  Differential bone marrow stem cell mobilization by G-CSF injection or arterial ligation in baboons 
Bone marrow stem cells (BMSCs) are mobilized in response to ischemic attacks, e.g. myocardial infarction, to repair the damage, or by cytokines, e.g. granulocyte colony-stimulating factor (G-CSF), which is used to harvest BMSCs for autologous transplantation. In order to optimize BMSC mobilization strategy for cardiovascular repair, we investigated whether BMSCs mobilized by G-CSF share the same subtype profile as that by ischemia in a nonhuman primate model.
Methods and results
We subjected 5 baboons to subcutaneous G-CSF injection and 5 baboons to femoral artery ligation. Blood BMSCs were measured by surface antigens; functional differentiation to endothelial cells (ECs) was assessed by colony forming capacity, expression of mature EC antigens and tube-like formation. The number of circulating CD34+/CD45RA- cells spiked on day 3 post-stimulation in both groups. While the number of CD34+ cells released by artery ligation was 2-fold lower by comparison with the number released by G-CSF administration, significantly more CD133+/KDR+/CXCR4+/CD31+ cells were detected in the baboons that underwent artery ligation. After culture in endothelial growth medium, mononuclear cells from baboons with artery ligation formed more EC colonies and more capillary-like tubes (p<0.05), expressed higher vWF and phagocytosed more Dil-Ac-LDL (p<0.05).
While G-CSF and artery ligation can mobilize BMSCs capable of differentiating into ECs, BMSCs mobilized by the artery ligation simulating in vivo ischemic attacks have higher potential for vascular differentiation. Our findings demonstrate that different mobilization forces release different sets of BMSCs that may have different capacity for cardiovascular differentiation.
PMCID: PMC3032010  PMID: 20187303
Bone marrow stem cells; nonhuman primate; endothelial progenitor cells
21.  Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense 
BMC Cancer  2011;11:43.
Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.
The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors
We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.
We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.
PMCID: PMC3038980  PMID: 21276246
22.  The baboon model (Papio hamadryas) of fetal loss: Maternal weight, age, reproductive history and pregnancy outcome 
Journal of medical primatology  2008;37(6):337-345.
Several risk factors are associated with the incidence of human stillbirths. The prevention of stillbirths in women is a pressing clinical problem.
We reviewed 402 pathology records of fetal loss occurring in a large baboon (Papio spp.) colony during a 15-year period. Clinical histories of 565 female baboons with one or more fetal losses during a 20-year period were analyzed for weight, age, and reproductive history.
Fetal loss was most common at term (35.57%) and preterm (28.61%) and less common in the first half of gestation (11.20%) and post-term (5.22%). Greater maternal weight, older age, history of stillbirth and higher parity were independent predictors for stillbirth. An exponential increase in the incidence of fetal loss was observed beginning at age 14 years in baboons.
Fetal loss and maternal risk factors associated with stillbirths in baboons were similar to those documented in women.
PMCID: PMC3016714  PMID: 19017195
fetal loss; reproduction; animal model; epidemiology; non-human primates
23.  The anti-tumor effects of calorie restriction are correlated with reduced oxidative stress in ENU-induced gliomas 
Pathobiology of Aging & Age Related Diseases  2011;1:10.3402/pba.v1i0.7189.
The anti-tumor effects of calorie restriction (CR) and the possible underlying mechanisms were investigated using ethylnitrosourea (ENU)-induced glioma in rats. ENU was given transplacentally at gestational day 15, and male offspring were used in this experiment. The brain from 4-, 6-, and 8-month-old rats fed either ad libitum (AL) or calorie-restricted diets (40% restriction of total calories compared to AL rats) was studied. Tumor burden was assessed by comparing the number and size of gliomas present in sections of the brain. Immunohistochemical analysis was used to document lipid peroxidation [4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA)], protein oxidation (nitrotyrosine), glycation and AGE formation [methylglyoxal (MG) and carboxymethyllysine (CML)], cell proliferation activity [proliferating cell nuclear antigen (PCNA)], cell death [single-stranded DNA (ssDNA)], presence of thioredoxin 1 (Trx1), and presence of heme oxygenase-1 (HO-1) associated with the development of gliomas. The results showed that the number of gliomas did not change with age in the AL groups; however, the average size of the gliomas was significantly larger in the 8-month-old group compared to that of the younger groups. Immunopositivity was observed mainly in tumor cells and reactive astrocytes in all histological types of ENU-induced glioma. Immunopositive areas for HNE, MDA, nitrotyrosine, MG, CML, HO-1, and Trx1 increased with the growth of gliomas. The CR group showed both reduced number and size of gliomas, and tumors exhibited less accumulation of oxidative damage, decreased formation of glycated end products, and a decreased presence of HO-1 and Trx1 compared to the AL group. Furthermore, gliomas of the CR group showed less PCNA positive and more ssDNA positive cells, which are correlated to the retarded growth of tumors. Interestingly, we also discovered that the anti-tumor effects of CR were associated with decreased hypoxia-inducible factor-1α (HIF-1α) levels in normal brain tissue. Our results are very exciting because they not only demonstrate the anti-tumor effects of CR in gliomas, but also indicate the possible underlying mechanisms, i.e. anti-tumor effects of CR observed in this investigation are associated with reduced accumulation of oxidative damage, decreased formation of glycated end products, decreased presence of HO-1 and Trx1, reduced cell proliferation and increased apoptosis, and decreased levels of HIF-1α.
PMCID: PMC3417672  PMID: 22953030
calorie restriction; ethylnitrosourea; glioma; oxidative stress; HIF-1α
24.  Feto-placental adaptations to maternal obesity in the baboon 
Placenta  2009;30(9):752-760.
Maternal obesity is present in 20–34% of pregnant women and has been associated with both intrauterine growth restriction and large-for-gestational age fetuses. While fetal and placental functions have been extensively studied in the baboon, no data are available on the effect of maternal obesity on placental structure and function in this species. We hypothesize that maternal obesity in the baboon is associated with a maternal inflammatory state and induces structural and functional changes in the placenta. The major findings of this study were 1) decreased placental syncytiotrophoblast amplification factor, intact syncytiotrophoblast endoplasmic reticulum structure and decreased system A placental amino acid transport in obese animals; 2) fetal serum amino acid composition and mononuclear cells (PBMC) transcriptome were different in fetuses from obese compared with non-obese animals 3) maternal obesity in humans and baboons is similar in regard of increased placental and adipose tissue macrophage infiltration, increased CD14 expression in maternal PBMC and maternal hyperleptinemia. In summary, these data demonstrate that in obese baboons in the absence of increased fetal weight, placental and fetal phenotype are consistent with those described for large- for-gestational age human fetuses.
PMCID: PMC3011231  PMID: 19632719
25.  Spontaneous Pathology of the Baboon Endocrine System 
Journal of medical primatology  2009;38(6):383-389.
Study of endocrine pathology in animal models is critical to understanding endocrine pathology in humans.
We evaluated 434 endocrine-related diagnoses from 4,619 baboon necropsies, established the incidence of spontaneous endocrine pathology, and analyzed the clinical and biochemical data associated with the individual cases.
The most common diagnoses in descending order, were pancreatic islet cell amyloidosis (n=259), ovarian cysts (n=50), pituitary adenoma (n=37), pancreatic islet cell adenoma (n=20), granulosa cell tumor (n=15), thyroid adenoma (n=11), adrenal hyperplasia (n=10), thyroid carcinoma (n=8), and pheochromocytoma (n=6). The incidence of pancreatic islet cell amyloidosis progressively increased with age. Pheochromocytomas were associated with renal and heart failure. The incidence of pancreatic islet cell amyloidosis and adrenal pathology was similar to humans; the incidence of pituitary adenoma and thyroid pathology was lower than in humans.
Endocrine disease in baboons is common and shares clinical and biochemical characteristics with endocrine disease in humans.
PMCID: PMC2783813  PMID: 19793179
Papio; nonhuman primate; thyroid; pancreas; endocrine; disease; cancer

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