Neurobiology of secure infant attachment and attachment despite adversity: a mouse model.

Attachment to an abusive caregiver has wide phylogenetic representation, suggesting that animal models are useful in understanding the neural basis underlying this phenomenon and subsequent behavioral outcomes. We previously developed a rat model, in which we use classical conditioning to parallel learning processes evoked during secure attachment (odor-stroke, with stroke mimicking tactile stimulation from the caregiver) or attachment despite adversity (odor-shock, with shock mimicking maltreatment). Here we extend this model to mice. We conditioned infant mice (postnatal day (PN) 7-9 or 13-14) with presentations of peppermint odor and either stroking or shock. We used (14) C 2-deoxyglucose (2-DG) to assess olfactory bulb and amygdala metabolic changes following learning. PN7-9 mice learned to prefer an odor following either odor-stroke or shock conditioning, whereas odor-shock conditioning at PN13-14 resulted in aversion/fear learning. 2-DG data indicated enhanced bulbar activity in PN7-9 preference learning, whereas significant amygdala activity was present following aversion learning at PN13-14. Overall, the mouse results parallel behavioral and neural results in the rat model of attachment, and provide the foundation for the use of transgenic and knockout models to assess the impact of both genetic (biological vulnerabilities) and environmental factors (abusive) on attachment-related behaviors and behavioral development.

Erroneous prenatal diagnosis of congenital adrenal hyperplasia owing to a duplication of the CYP21A2 gene.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder where steroidogenesis in the adrenal cortex is impaired. The most common form is caused by 21-hydroxylase deficiency (21OHD). Classical 21OHD is characterized by glucocorticoid and mineralocorticoid deficiency and by overproduction of adrenal androgens. The diagnosis rests on biochemical and genetic analyses. In families with history of CAH, prenatal genetic diagnosis is offered. We herein present a case of an infant whose parents were identified to carry mutations on the CYP21A2 gene. The fetal DNA analysis demonstrated that the fetus carried a paternal exon 8 (Q318X) mutation and a maternal exon 8 (R356X) mutation. The fetus was presumed to be affected with CAH, yet his clinical presentation at birth was not consistent with the diagnosis. Repeated genetic analysis identified a paternal CYP21A2 gene duplication with Q318X mutation on one copy of CYP21A2. We conclude that a duplication of the CYP21A2 gene should be suspected when clinical and hormonal findings do not support the genetic diagnosis. Furthermore, because individuals with Q318X mutation frequently have a duplication of the CYP21A2 gene, when Q318X is detected, it is important to distinguish the severe point mutation in single gene copy alleles from the non-deficient variant in gene-duplicated alleles.

Regulation of intestinal barrier function by signal transducer and activator of transcription 5b.

BACKGROUND: Colon epithelial cell (CEC) apoptosis and nuclear factor-kappaB (NF-kappaB) activation may compromise barrier function, and it has been reported that signal transducer and activator of transcription 5b (STAT5b)-deficient mice exhibit increased susceptibility to colitis. It is hypothesised that the growth hormone (GH) target STAT5b maintains mucosal barrier integrity by promoting CEC survival and inhibiting NF-kappaB activation. METHODS: The GH effect upon mucosal injury due to 2,4,6-trinitro-benzenesulfonic acid (TNBS) administration was determined in STAT5b-deficient mice and wild-type (WT) controls. The effect of STAT5b deficiency upon CEC survival and NF-kappaB activation was determined and related to differences in intestinal permeability and bacterial translocation. RNA interference (RNAi) was used to knock down STAT5b expression in the T84 CEC line, and the effect upon basal and GH-dependent regulation of proapoptotic and inflammatory pathways induced by tumour necrosis factor alpha (TNFalpha) was determined. RESULTS: GH suppression of mucosal inflammation in TNBS colitis was abrogated in STAT5b-deficient mice. STAT5b deficiency led to activation of a proapoptotic pattern of gene expression in the colon, and increased mucosal permeability. The frequency of apoptotic CECs was increased in STAT5b-deficient mice while tight junction protein abundance was reduced. This was associated with upregulation of CEC Toll-like receptor 2 expression and NF-kappaB activation. STAT5b knockdown in T84 CEC increased TNFalpha-dependent NF-kappaB and caspase-3 activation. GH inhibition of TNFalpha signalling was prevented by STAT5b knockdown. CONCLUSION: STAT5b maintains colonic barrier integrity by modulating CEC survival and NF-kappaB activation. STAT5b activation may therefore represent a novel therapeutic target in inflammatory bowel disease.

Glucose metabolism and insulin secretion in a patient with ABCC8 mutation and Fanconi-Bickel syndrome caused by maternal isodisomy of chromosome 3.

Fanconi-Bickel syndrome (FBS) is a rare disorder of glucose transport caused by autosomal recessive mutations in GLUT2. Clinically, FBS results in growth failure, hepatomegaly, renal Fanconi syndrome, and abnormal glucose homeostasis. We report a 23 month old female with FBS characterized by more severe and refractory hypoglycemia than typically seen in this disorder. Although previous reports indicate that FBS patients have diminished insulin secretion, our patient showed evidence of hyperinsulinism (HI). Sequence analysis showed that the patient was homozygous for a known null mutation in GLUT2, confirming the clinical diagnosis of FBS. Parental genotyping showed that the mother was heterozygous for the GLUT2 mutation, while the father was wild type. Tandem repeat marker analysis showed that the patient inherited the GLUT2 mutation via maternal isodisomy of chromosome 3. Further molecular testing showed that the patient was heterozygous for a mutation in ABCC8, a known cause of congenital HI. We discuss the patient's biochemical responses in light of the molecular findings.

Normal and shear strain estimation using beam steering on linear-array transducers.

In current ultrasound elastography, only the axial component of the displacement vector is estimated and used to produce strain images. A method was recently proposed by our group to estimate both the axial and lateral components of a displacement vector following a uniaxial compression. Previous work evaluated the technique using both simulations and a mechanically translated phased array transducer. In this paper, we present initial results using beam steering on a linear array transducer attached to a commercial scanner to acquire echo signals for estimating 2-D displacement vectors. Single-inclusion and anthropomorphic breast phantoms with different boundary properties between the inclusion and background material are imaged by acquiring echo data along beam lines ranging from -15 degrees to 15 degrees relative to the compression direction. 1-D cross-correlation is used to calculate "angular displacements" in each acquisition direction, yielding axial and lateral components of the displacement vector. Strain tensor components are estimated from these displacements. Features on shear strain images generated for the inclusion phantom agree with those predicted using FEA analysis. Experimental results demonstrate the utility of this technique on clinical scanners. Shear strain tensors obtained using this method may provide useful information for the differentiation of benign from malignant tumors. For the linear array transducer used in this study, the optimum angular increment is around 3 degrees. However, more work is required for the selection of an appropriate value for the maximum beam angle for optimal performance of this technique.

Dietary effects on cardiovascular disease risk factors: beyond saturated fatty acids and cholesterol.

Hypercholesterolemia represents a significant risk for cardiovascular disease (CVD). While diet intervention remains the initial choice for the prevention and treatment of CVD, the nature of the dietary modification remains controversial. For example, reducing calories from total fat, without decreasing saturated fat intake results in insignificant changes in low density lipoprotein cholesterol (LDL-C). Similarly, diet interventions that focus solely on lowering dietary cholesterol and saturated fat intake not only decrease LDL-C, but also high density lipoprotein cholesterol (HDL-C) and therefore may not improve the lipoprotein profile. This brief review summarizes dietary interventions that lower LDL-C without affecting HDL-C levels. These interventions include soy protein, soluble fiber, soy lecithin and plant sterols. This review also includes some of the reported dietary interventions, such as polyphenols, isoflavones, folic acid and vitamins B6 and B12, which reduce the risk of CVD without changes in lipoprotein cholesterol.

Airway stability and heterogeneity in the constricted lung.

The effect of bronchoconstriction on airway resistance is known to be spatially heterogeneous and dependent on tidal volume. We present a model of a single terminal airway that explains these features. The model describes a feedback between flow and airway resistance mediated by parenchymal interdependence and the mechanics of activated smooth muscle. The pressure-tidal volume relationship for a constricted terminal airway is computed and shown to be sigmoidal. Constricted terminal airways are predicted to have two stable states: one effectively open and one nearly closed. We argue that the heterogeneity of whole lung constriction is a consequence of this behavior. Airways are partitioned between the two states to accommodate total flow, and changes in tidal volume and end-expiratory pressure affect the number of airways in each state. Quantitative predictions for whole lung resistance and elastance agree with data from previously published studies on lung impedance.

Trans fatty acids and cardiovascular risk.

Trans fatty acids are found in partially hydrogenated vegetable oil, in meats, and in dairy products. Their effect on blood cholesterol concentrations was examined decades ago, but recently there has been renewed interest in understanding how trans fatty acids affect blood lipids and lipoprotein cholesterol concentrations. Current advice to reduce cardiovascular disease (CVD) risk includes decreasing the consumption of saturated and total fat to help manage blood cholesterol concentrations. Saturated fat contributes significantly to total fat intake and markedly raises blood cholesterol concentrations. Trans fatty acids, which are consumed in much smaller quantities, have been shown to be modestly hypercholesterolemic in studies that have substituted hydrogenated vegetable oils for unhydrogenated oils. In contrast, when partially hydrogenated vegetable oils containing trans fatty acids are substituted for cholesterol-raising saturated fats, blood cholesterol levels are reduced. Partially hydrogenated vegetable oils are used in place of saturated fat in many food products. These foods can help consumers lower their saturated fat intake to achieve dietary recommendations. The following review critically examines the role of hydrogenated fats in the food supply, the metabolism of trans fatty acids, and the scientific literature surrounding the effects of partially hydrogenated vegetable oils and trans fatty acids on blood cholesterol concentrations and cardiovascular disease risk.

Mechanics of edematous lungs.

Using the parenchymal marker technique, we measured pressure (P)-volume (P-V) curves of regions with volumes of approximately 1 cm3 in the dependent caudal lobes of oleic acid-injured dog lungs, during a very slow inflation from P = 0 to P = 30 cmH2O. The regional P-V curves are strongly sigmoidal. Regional volume, as a fraction of volume at total lung capacity, remains constant at 0.4-0.5 for airway P values from 0 to approximately 20 cmH2O and then increases rapidly, but continuously, to 1 at P = approximately 25 cmH2O. A model of parenchymal mechanics was modified to include the effects of elevated surface tension and fluid in the alveolar spaces. P-V curves calculated from the model are similar to the measured P-V curves. At lower lung volumes, P increases rapidly with lung volume as the air-fluid interface penetrates the mouth of the alveolus. At a value of P = approximately 20 cmH2O, the air-fluid interface is inside the alveolus and the lung is compliant, like an air-filled lung with constant surface tension. We conclude that the properties of the P-V curve of edematous lungs, particularly the knee in the P-V curve, are the result of the mechanics of parenchyma with constant surface tension and partially fluid-filled alveoli, not the result of abrupt opening of airways or atelectatic parenchyma.

Variance of ventilation during exercise.

Expired gas concentrations were measured during a multibreath washin of He in one female and seven male subjects at rest (seated) and during cycle exercise at work rates of 70-210 W. In a computational model, the ventilation distribution was represented as a log-normal distribution with standard deviation (sigmaV); values of sigmaV were obtained by fitting the output of the model to the data. At rest, sigmaV was 0.89 +/- 0.18; during exercise, sigmaV was 0.60 +/- 0.13, independent of the level of exercise. These values for the width of the functional ventilation distribution at the scale of the acinus are approximately two times larger than those obtained from anatomic measurements in animals at a scale of 1 cm3. The values for sigmaV, together with data from the literature on the width of the functional ventilation-perfusion distribution, show that ventilation and perfusion are highly correlated at rest, in agreement with anatomic data. The structural sources of nonuniform ventilation and perfusion and of the correlation between them are unknown.

Development of a women's wellness center in Almaty, Kazakhstan.

Twelve Women's Wellness Centers were established by American International Health Alliance (AIHA) partnerships in the New Independent States of the former Soviet Union. The services offered by these centers focused on health promotion, disease prevention, and other health and social issues that affect women's health. The innovations in the model include patient-centered care that emphasizes patient choice and the introduction of the role of the nurse educator.

Respiratory effects of the external and internal intercostal muscles in humans.

The current conventional view of intercostal muscle actions is based on the theory of Hamberger (1749) and maintains that as a result of the orientation of the muscle fibres, the external intercostals have an inspiratory action on the lung and the internal interosseous intercostals have an expiratory action. Recent studies in dogs, however, have shown that this notion is only approximate. In the present studies, the respiratory actions of the human external and internal intercostal muscles were evaluated by applying the Maxwell reciprocity theorem. Thus the orientation of the muscle fibres relative to the ribs and the masses of the muscles were first assessed in cadavers. Five healthy individuals were then placed in a computed tomographic scanner to determine the geometry of the ribs and their precise transformation during passive inflation to total lung capacity. The fractional changes in length of lines with the orientation of the muscle fibres were then computed to obtain the mechanical advantages of the muscles. These values were finally multiplied by muscle mass and maximum active stress (3.0 kg cm-2) to evaluate the potential effects of the muscles on the lung. The external intercostal in the dorsal half of the second interspace was found to have a large inspiratory effect. However, this effect decreases rapidly in the caudal direction, in particular in the ventral portion of the ribcage. As a result, it is reversed into an expiratory effect in the ventral half of the sixth and eighth interspaces. The internal intercostals in the ventral half of the sixth and eighth interspaces have a large expiratory effect, but this effect decreases dorsally and cranially. The total pressure generated by all the external intercostals during a maximum contraction would be -15 cmH2O, and that generated by all the internal interosseous intercostals would be +40 cmH2O. These pressure changes are substantially greater than those induced by the parasternal intercostal and triangularis sterni muscles, respectively.

Metastatic congenital adrenocortical carcinoma: a case report with tumor remission at 3 1/2 years.

We describe a case of metastasizing congenital adrenocortical carcinoma and a follow-up of 3 1/2 yr. Treatment with surgery and mitotane was associated with multiple complications. The patient was in remission at 3 1/2 yr. Because of the rarity of this condition, we discuss step-by-step problems encountered during management.

Biaxial constitutive relations for the passive canine diaphragm.

Samples of the muscular sheet excised from the midcostal region of dog diaphragms were subjected to biaxial loading. That is, stresses in the direction of the muscle fibers and in the direction perpendicular to the fibers in the plane of the sheet were measured at different combinations of strains in the two directions. Stress-strain relations were obtained by fitting equations to these data. In the direction of the muscle fibers, for strains up to 0.7, stress is a modestly nonlinear function of strain and ranges up to approximately 60 g/cm. In the direction perpendicular to the fibers, the sheet is stiffer and more strongly nonlinear. At a strain in the perpendicular direction of approximately 0.35, stress increases abruptly. The stress-strain relation in the muscle direction is consistent with observations of passive muscle shortening in vivo. However, the stiffness in the perpendicular direction is not high enough to explain the observation that strains in the perpendicular direction in vivo are nearly zero. We conclude that, in the passive diaphragm in vivo, stress in the direction perpendicular to the muscle fibers is small.

Corn fiber oil lowers plasma cholesterol levels and increases cholesterol excretion greater than corn oil and similar to diets containing soy sterols and soy stanols in hamsters.

The aims of this study were to compare the cholesterol-lowering properties of corn fiber oil (CFO) to corn oil (CO), whether the addition of soy stanols or soy sterols to CO at similar levels in CFO would increase CO's cholesterol-lowering properties, and the mechanism(s) of action of these dietary ingredients. Fifty male Golden Syrian hamsters were divided into 5 groups of 10 hamsters each, based on similar plasma total cholesterol (TC) levels. The first group of hamsters was fed a chow-based hypercholesterolemic diet containing either 5% coconut oil + 0.24% cholesterol (coconut oil), 5% CO, 5% CFO, 5% CO + 0.6% soy sterols (sterol), or 5% CO + 0.6% soy stanols (stanol) in place of the coconut oil for 4 weeks. The stanol diet significantly inhibited the elevation of plasma TC compared to all other dietary treatments. Also, the CFO and sterol diets significantly inhibited the elevation of plasma TC compared to the CO and coconut oil diets. The CFO, sterol, and stanol diets significantly inhibited the elevation of plasma non-high density lipoprotein cholesterol compared to the CO and coconut oil diets. The stanol diet significantly inhibited the elevation of plasma high density lipoprotein cholesterol (HDL-C) compared to all other dietary treatments. The sterol diet significantly inhibited the elevation of plasma HDL-C compared to the CO and coconut oil diets, whereas the CFO diet significantly inhibited the elevation of plasma HDL-C compared to the coconut oil diet only. No differences were observed between the CFO and CO for plasma HDL-C. There were no differences observed between groups for plasma triglycerides. The CO and CFO diets had significantly less hepatic TC compared to the coconut oil, sterol, and stanol diets. The CO and CFO diets had significantly less hepatic free cholesterol compared to the sterol and stanol diets but not compared to the coconut oil diet; whereas the coconut oil and sterol diets had significantly less hepatic free cholesterol compared to the stanol diet. The CFO, sterol, and stanol diets excreted significantly more fecal cholesterol compared to the coconut oil and CO diets. In summary, CFO reduces plasma and hepatic cholesterol concentrations and increases fecal cholesterol excretion greater than CO through some other mechanism(s) in addition to increase dietary sterols and stanols-possibly oryzanols.

Effect of hyperthyroidism on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in adolescent children.

A study was performed on adolescent hyperthyroid patients to determine the effects of hyperthyroidism on insulin-like growth factor (IGF)-I and its binding proteins. Serum concentrations of immunoreactive total and free IGF-I, and IGF binding protein (IGFBP)-2 and IGFBP-3 were determined before and after correction of hyperthyroidism in eight patients with Grave's disease and compared to control patients matched for age, sex and pubertal stage. The concentration of serum total IGF-I was not significantly different in the hyperthyroid state and euthyroid state, and did not differ significantly from euthyroid controls. IGFBP-2 levels were elevated three-fold in hyperthyroid patients at the time of diagnosis of hyperthyroidism compared to control subjects, and fell significantly during treatment. There was also a significant positive correlation between serum IGFBP-2 concentrations and thyroxine (T4) concentrations in all subjects. Serum IGFBP-3 concentrations were also elevated in hyperthyroid subjects and normalized with correction of the hyperthyroidism. There was also a positive correlation between serum T4 and IGFBP-3 concentrations in all subjects. Despite the hyperthyroid-induced elevations in IGFBP-2 and -3, no significant difference in the serum concentration of free IGF-I before or after correction of the hyperthyroid condition was observed. We conclude that hyperthyroidism does not cause alterations in the serum concentrations of either free or total IGF-I. However, both serum IGFBP-2 and IGFBP-3 concentrations were elevated during hyperthyroidism and correlated with serum T4 levels. These abnormalities reversed with normalization of thyroid function.

Comparative cholesterol lowering properties of vegetable oils: beyond fatty acids.

OBJECTIVE: Our laboratory has previously reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Although RBO has up to three times more serum cholesterol-raising saturated fatty acids (SATS) than some unsaturated vegetable oils, we hypothesized that its greater content of the unsaponifiables would compensate for its high SATS and yield comparable cholesterol-lowering properties to other vegetable oils with less SATS. METHODS: To study the comparative effects of different unsaturated vegetable oils on serum lipoprotein levels, nine cynomologus monkeys (Macaca fascicularis) were fed diets, for four weeks, in a Latin square design, containing rice bran, canola or corn oils (as 20% of energy) in a basal mixture of other fats to yield a final dietary fat concentration of 30% of energy. All animals were fed a baseline diet containing 36% of energy as fat with 15% SATS, 15% monounsaturated fatty acids (MONOS) and 6% polyunsaturated fatty acids (POLYS). RESULTS: Despite the lower SATS and higher MONOS content of canola oil and the higher POLYS content of corn oil, RBO produced similar reductions in serum total cholesterol (TC) (-25%) and low density lipoprotein cholesterol (LDL-C) (-30%). In addition, as compared to the baseline diet, the reduction in serum TC and LDL-C cholesterol with RBO was not accompanied by reductions in high density lipoprotein cholesterol (HDL-C) which occurred with the other two dietary oils. Using predictive equations developed from data gathered from several studies with non-human primates, we noted that the observed serum TC and LDL-C lowering capabilities of the RBO diet were in excess of those predicted based on the fatty acid composition of RBO. CONCLUSIONS: These studies suggest that non-fatty acid components (unsaponifiables) of RBO can contribute significantly to its cholesterol-lowering capability.

Congenital nasal pyriform aperture stenosis associated with central diabetes insipidus.

We describe a child who has central diabetes insipidus associated with congenital nasal pyriform aperture stenosis without any apparent anterior pituitary dysfunction. This association further strengthens the concept that congenital nasal pyriform aperture stenosis may be a microform of holoprosencephaly.