The developmental consequences of early adverse care on infant macaques: A cross-fostering study.

Early life adversity/stress (ELA/ELS), particularly adverse caregiving experiences such as child maltreatment (MALT), is a main risk factor for psychopathology, including psychiatric disorders such as anxiety, depression, ADHD, and substance abuse. Yet how these alterations unfold during development and the underlying mechanisms remain poorly understood, as it is difficult to prospectively and longitudinally study early developmental phases in humans, and nearly impossible to disentangle postnatal caregiving effects from heritable traits. This study examined the specific effects of "nurture" (maternal care) versus "nature" (heritable, biological maternal factors) on nonhuman primate infant socioemotional, stress neuroendocrine, and physical development. For this we used a translational and naturalistic macaque model of infant maltreatment by the mother with randomized assignment at birth to either mothers with a history of maltreating their infants (MALT group, n = 22) or to competent mothers (Control group, n = 20). Over the first 6 months of life (roughly equivalent to 2 years in humans), we examined the development of the mother-infant relationship, as well as infants' social behavior and emotional reactivity. In parallel, we assessed hypothalamic-pituitary-adrenal (HPA) axis function longitudinally, using measures of hair cortisol accumulation, and basal morning plasma cortisol. We identified broad impairments in maternal care exhibited by MALT foster mothers, beyond maltreatment (physical abuse, rejection) events, suggesting that MALT foster mothers provide an overall lower quality of care to their infants compared to Controls. MALT infants exhibited alterations in their initiations and breaks of proximity towards their mothers, as well as heightened emotional reactivity in comparison to Controls. Most striking are the HPA axis findings, with MALT infants showing higher levels of plasma cortisol across the first 6 postnatal months as well as higher hair cortisol accumulation from birth through month 6 (a signature of chronic stress) than Controls. No caregiving effects were detected on physical growth, which ruled out confounding effects of maternal nutrition, metabolism, etc. Taken together, these results suggest that the developmental trajectory of MALT and Control infants is different, marked by heightened levels of emotional reactivity, increased HPA activity and alterations in mother-infant interactions in MALT animals. These findings appear to be due to specific effects of postnatal maternal care, and not to biological/ behavioral traits inherited from the mother, or due to prenatal programming caused by prenatal stress, as the cross-fostering design controlled for these potential factors. However, we also detected a couple of interesting biological effects suggesting heritable transmission of some phenotypes. The prolonged HPA axis activation during the first 6 postnatal months of life is expected to have long-term consequences for brain, physiological, and behavioral development in MALT offspring.

The EuroPhysiome, STEP and a roadmap for the virtual physiological human.

Biomedical science and its allied disciplines are entering a new era in which computational methods and technologies are poised to play a prevalent role in supporting collaborative investigation of the human body. Within Europe, this has its focus in the virtual physiological human (VPH), which is an evolving entity that has emerged from the EuroPhysiome initiative and the strategy for the EuroPhysiome (STEP) consortium. The VPH is intended to be a solution to common infrastructure needs for physiome projects across the globe, providing a unifying architecture that facilitates integration and prediction, ultimately creating a framework capable of describing Homo sapiens in silico. The routine reliance of the biomedical industry, biomedical research and clinical practice on information technology (IT) highlights the importance of a tailor-made and robust IT infrastructure, but numerous challenges need to be addressed if the VPH is to become a mature technological reality. Appropriate investment will reap considerable rewards, since it is anticipated that the VPH will influence all sectors of society, with implications predominantly for improved healthcare, improved competitiveness in industry and greater understanding of (patho)physiological processes. This paper considers issues pertinent to the development of the VPH, highlighted by the work of the STEP consortium.

Comparative study of wound healing in porcine skin with CO2 laser and other surgical modalities: preliminary findings.

BACKGROUND: The CO2 laser is a common surgical modality in dermatology. To clarify conflicting reports on the histological healing properties of CO2 laser on incisional or ablative wounds, we have applied it in a miniature hairless porcine skin model at power settings similar to those used in clinical practice. METHODS: Histological parameters of wound healing in skin incisions using the CO2 laser were compared with those using scalpel, hot scalpel, and electrosection, and in dermal ablation using CO2 laser, fraize, wire brush, and electrofulguration alone or with curettage. RESULTS: In incisional wounds, tissue damage was most extensive in CO2 laser wounds, with delayed dermal healing and reepithelialization. In ablative wounds, CO2 laser caused a similar degree of tissue damage as did the electrosurgical modalities, and more damage than did fraize or wire brush. Reepithelialization was complete in CO2 laser, fraize, and wire brush wounds before electrosurgical wounds. Final histology of both incisional and ablative wounds at 6 weeks was similar with all surgical modalities. CONCLUSION: The CO2 laser and electrosurgery both produce greater focal tissue damage in incisional and ablative applications than the other modalities. Delayed epithelialization of the wound occurs with both modalities in incisional wounds but only with electrosurgery in ablative wounds. At 6 weeks, the appearance of the scar in all incisional and ablative modalities is similar grossly and histologically. Confirmation of these findings requires standardization of power density of the CO2 laser in incision and ablation.

Comparison of Dolichos biflorus lectin and other lectin-horseradish peroxidase conjugates in staining of cutaneous blood vessels in the hairless mini-pig.

Angiogenesis is necessary for normal growth, wound healing, and plays a key role in many pathologic processes. A variety of endothelial markers have been used to investigate angiogenesis. Unfortunately, excellent markers for vascular endothelium in human tissues exhibit little or no staining of endothelia in tissues of other animal species, including the pig. We are interested in the hairless Yucatan strain of mini-pig as an animal model for studying cutaneous wound healing because its skin is histologically and functionally very similar to that of man. Hoping to find a specific marker to identify vascular endothelium in the mini-pig, we therefore screened a battery of 11 different lectin-horseradish peroxidase conjugates. Based on specificity and staining intensity, Dolichos biflorus agglutinin (DBA) was chosen from this battery to investigate vascular changes in the healing of cutaneous wounds in the mini-pig. When compared with routine histologic sections stained with hematoxylin and eosin, blood vessels were much easier to identify in sections stained histochemically with DBA. Lectin histochemistry was particularly useful in investigations of early events in angiogenesis during wound healing when newly derived capillary buds and minute blood vessels were obscured in normal histologic sections by an inflammatory cell infiltrate associated with the healing wound. Ultrastructural lectin cytochemistry revealed staining along the luminal surface and the basolateral plasmalemma of endothelial cells. Histochemical staining with DBA promises to provide a useful method for further investigation of angiogenesis and other vascular phenomena in a variety of normal and pathologic processes using the hairless Yucatan strain of mini-pig as the animal model.

Microprobe analysis of chlorpromazine pigmentation.

We describe the histochemical, ultrastructural, and microanalytical features of a skin biopsy specimen obtained from a patient with chlorpromazine pigmentation. Golden-brown pigment granules were present in the dermis, predominantly in a perivascular arrangement. The granules stained positively with the Fontana-Masson stain for silver-reducing substances and negatively with Perl's stain for iron. Electron microscopy revealed dense inclusion bodies in dermal histiocytes, pericytes, endothelial cells, and Schwann cells, as well as lying free in the extracellular matrix. These "chlorpromazine bodies" were quite dense even in unosmicated, unstained ultrathin sections, indicating that the pigmentation is related, at least in part, to the inclusions. Microprobe analysis of the chlorpromazine bodies revealed a striking peak for sulfur, which strongly suggests the presence of the drug or its metabolite within these inclusions.

Immature omental teratoma.

Immature omental teratomas are extremely rare neoplasms. To our knowledge, only two cases have been reported in the literature. In some anatomic locations, the malignant potential of immature teratomas correlates with the presence and quantity of neuroectoderm within the tumor mass. We describe the first immature omental teratoma with prominent neuroectodermal differentiation.

Right ventricular subendocardial infarction in a patient with pulmonary hypertension, right ventricular hypertrophy, and normal coronary arteries.

Right ventricular infarction is usually associated with coronary artery disease and concomitant left ventricular infarction. Isolated right ventricular subendocardial necrosis was discovered at autopsy in a 52-year-old woman with pulmonary hypertension, right ventricular hypertrophy, and normal coronary arteries, who died with septicemia 41 days after mitral valve replacement. This represents the first well-documented report of isolated right ventricular subendocardial infarction associated with normal coronary arteries.

Percutaneous absorption, disposition, and excretion of 4,4'-methylenebis(2-chloroaniline) in dogs.

Percutaneous (pc) absorption, disposition, and excretion of 14C-MBOCA (4,4'-methylenebis(2-chloroaniline) ) were investigated in male beagle-type dogs by HPLC and compared to intravenously (iv) administered controls. Following application of 115 muCi MBOCA to a 25 cm2 area of the skin, no measurable radioactivity was detected in blood for the subsequent 24-hr period, but 14C-MBOCA and metabolites were excreted in urine and bile. During the 24-hr collection period, a total of 1.3% of the administered dose was recovered in the urine (0.4% of which was unchanged MBOCA). At 24 hr 0.62% of the dose was recovered in gallbladder bile. Approximately 90% of the administered dose was recovered in skin at the application site. Liver, kidney, and fat were the tissues with highest radioactivity. After a bolus iv injection, MBOCA disappeared rapidly from blood (t 1/2 beta = 0.70 hr). In the 24 hr following iv injection, 46% of the administered dose was excreted in urine (0.54% of which was unchanged MBOCA). At 24 hr 32% of the dose was recovered in gallbladder bile. Tissue radioactivity was 10-20 X higher after iv than pc administration and highest in liver, kidney, fat, and lung. The results demonstrated in a canine model that skin absorption was a viable route of entry for MBOCA and that unmetabolized MBOCA was a small percentage (0.4-0.5%) of the total urinary excretion. MBOCA was rapidly and extensively metabolized and excreted in urine and bile following both iv and pc administration.

The effect of prenatal methylmercury administration on postnatal renal functional development.

In utero exposure of rats to methylmercury has been reported to produce degenerative and hyperplastic changes in renal proximal and distal tubules, although no assessment of postnatal renal functional capacity was made. CH3HgCl was administered ip to Sprague-Dawley rats on Day 8 of gestation at 4 or 6 mg Hg/kg or on Days 8, 10, and 12 at 4 mg Hg/kg (3 x 4 mg Hg/kg). These doses produced no overt toxicological effects nor had any effect on litter size, body weight, or kidney weight to body weight ratios. The concentration of mercury in kidneys, liver, and brain at 1 and 7 days postpartum was dose-related but was not detectable at 42 days. In vitro renal function was assessed in renal cortical slices from rats at 1, 7, and 42 days postpartum by determining the ability to accumulate organic ions and to generate glucose. Additionally, parameters of in vivo renal function were determined in normopenic, hydropenic (5 pressor units/kg ADH, sc, 18 hr water deprived), and in volume-loaded male rats at 42 days postpartum. At 42 days postpartum in the 3 x 4 mg Hg/kg treatment group, p-aminohippurate accumulation was depressed slightly as was the ability to eliminate Na+ and water in volume-loaded rats. These data suggest that postnatal renal physiological sequelae to prenatal administration of methylmercury may be less than predicted from histological studies.

Cardiac and hepatic effects of pre- and postnatal exposure to polybrominated biphenyls in rats.

Body weight gain and hepatic concentrations of vitamin A were reduced in Sprague-Dawley rats by pre- and postnatal exposure to 100 ppm polybrominated biphenyls (PBBs). The ratio of liver weight to body weight, activity of hepatic delta-aminolevulinic acid (ALA) synthetase, and urinary excretion of uro- and coproporphyrins were increased by PBBs. Treatment with PBBs also increased the left atrial inotropic response to calcium. However, PBBs had no effect on development of the adrenergic neuronal transport system in heart, left atrial baselike peak tension, or inotropic response to ouabain. Thus PBBs retarded body weight gain and produced a variety of alterations in liver, but had little effect on cardiac contractile function.

Nonrespiratory metabolic function and morphology of lung following exposure to polybrominated biphenyls in rats.

Exposure to polybrominated biphenyls (PBBs) resulted in increased activity of microsomal arylhydrocarbon hydroxylase and ethoxyresorufin-O-deethylase in rat lung. Clearance of 5-hydroxytryptamine (5-HT) and angiotensin 1 by perfused lungs was decreased by PBBs. However, PBBs had no effect on the activity of epoxide hydrolase, monoamine oxidase, or angiotensin-converting enzyme in lung. The only histopathologic change detected in lungs from PBB-treated rats was an increase in alveolar type II cell lamellar bodies. Selective accumulation of certain PBB congeners by lung was not observed in this investigation.

Effect of polybrominated biphenyls on hepatic microsomal metabolism of estrogens and uterotropic action of administered estrogen in rats.

Perinatal exposure to polybrominated biphenyls (PBBs) increased the hepatic microsomal metabolism of estradiol, estrone, and ethynylestradiol in vitro. Pretreatment with PBBs decreased the effect of estradiol administered exogenously on uterine estrogen cytosolic receptor concentration. The effect of exogenous estradiol on uterine weight and uterine RNA content was also reduced by perinatal exposure to PBBs. Therefore, metabolism of estrogens is altered by PBBs.

The effects of aluminum on microtubular integrity using in vitro and in vivo models.

Since neuronal lesions produced by aluminum (Al) are morphologically similar to lesions produced by microtubule inhibitors, the effect of aluminum on microtubule integrity was investigated. Aluminum inhibited microtubule formation at concentrations as low as 0.1 mM. This approaches the aluminum concentrations found in brains of patients with several disorders which result in progressive dementia.

Postnatal morphology and functional capacity of the kidney following prenatal treatment with dinoseb in rats.

Dinoseb has produced alterations that are suggestive of renal damage in mice and rats. Therefore it was of interest to determine the postnatal morphology and functional capacity of the kidney following prenatal treatment with dinoseb in rats. Fetal and neonatal rats treated with dinoseb on gestational d 10-12 had dilated renal pelves and ureters. Kidneys had dilated tubules and excessive mesenchymal tissue when examined perinatally. These pathological changes were reduced in incidence (kidney) or not detected (ureter) at 42 d postpartum and were not correlated with alterations in postnatal renal function. Livers from rats treated prenatally with dinoseb were vacuolated and necrotic even at 42 d postpartum. Rats treated prenatally with dinoseb had reduced body weights at 1 and 7 d postpartum. However, body weights of control and dinoseb-treated rats were not significantly different at 42 d of age. These results emphasize the need to determine the pesistence and functional consequences of anomalies detected in near-term fetuses for safety assessment of a chemical.