Consultation with the specialist: thyroid nodules.

Based on strong research evidence, thyroid nodules in children and teenagers are more likely to be malignant than in adults. Based on strong research evidence, a history of ionizing radiation to the head or neck is an independent risk factor for the development of thyroid malignancies. There is strong research evidence, including a recent meta-analysis, supporting the use of fine-needle aspiration biopsy in the evaluation of all pediatric and adolescent patients presenting with a thyroid nodule. The surgical management and postoperative care of pediatric and adolescent patients who have well-differentiated thyroid carcinomas remains controversial, because the rarity of the disease limits the ability to conduct randomized, prospective research studies. Numerous studies have demonstrated that, despite presenting with more advanced disease, pediatric and adolescent patients with thyroid carcinoma have a higher survival rate than adults. The American Thyroid Association has issued strong evidence-based recommendations for the management of medullary thyroid carcinoma, including RET mutation testing and early prophylactic total thyroidectomy in children with high-risk mutations.

A nanoemulsion formulation of dacarbazine reduces tumor size in a xenograft mouse epidermoid carcinoma model compared to dacarbazine suspension.

Dacarbazine (DAC) is an anticancer drug that has been used to treat various types of cancers. The aim of the current study was to test whether there is an increased efficacy of DAC as a nanoemulsion on reducing tumor size in an epidermoid carcinoma xenograft mouse model. Tumors were induced in 5-week-old nude mice by subcutaneous injection. The mice were untreated or treated with a suspension of DAC (0.1 mg/kg), a nanoemulsion of DAC (0.1 mg/kg), or Nano-Control (same composition as the suspension and nanoemulsion but no DAC), every 2 days by either intramuscular injection (IM) or topical application. After 40 days, the final tumor size of mice receiving the nanoemulsion of DAC IM (0.83 ± 0.55 mm(3)) was significantly reduced compared to the suspension of DAC IM (4.75 ± 0.49 mm(3)), Nano-Control IM (7.63 ± 0.91 mm(3)), and untreated (10.46 ± 0.06 mm(3)). The final tumor size of mice receiving the nanoemulsion of DAC topically (3.33 ± 0.63 mm3) was also significantly reduced compared to the suspension of DAC topically (7.64 ± 0.68 mm(3)). This increased efficacy maybe partially attributed to: 1) the reduced particle size of the nanoemulsion in comparison with suspension (111 versus > 6000 nm), 2) reduction in zeta potential of the nanoemulsion compared to suspension (-3.2 versus -89.1 mV), 3) production of a stable water dispersion relative to unstable suspension, 4) decreased polydispersity index of the nanoemulsion compared to suspension, and 5) greater stability of drug with the nanoemulsion in comparison with the suspension. FROM THE CLINICAL EDITOR: In this clinically relevant study, the anti-tumor efficacy of dacarbazine was found to be significantly increased as a nanoemulsion in epidermoid carcinoma xenograft mice, both with IM and topical administration.

Reversible pituitary hyperplasia at birth in a macrosomic full-term baby boy.

Pituitary hyperplasia is generally associated with end-organ failure such as primary hypothyroidism, physiological changes such as puberty and pregnancy, or neoplasms secreting releasing factors. We present a full-term infant with an enlarged pituitary height of 8 mm at age 3 days despite a normal endocrinological evaluation. Repeat imaging at 5 months of age revealed a normal-size pituitary gland. To our knowledge, pituitary hyperplasia has not been described in a neonate with normal pituitary function.

Longitudinal impact of gender-affirming endocrine intervention on the mental health and well-being of transgender youths: preliminary results.

BACKGROUND/AIMS: Transgender youths experience high rates of depression and suicidal ideation compared to cisgender peers. Previous studies indicate that endocrine and/or surgical interventions are associated with improvements to mental health in adult transgender individuals. We examined the associations of endocrine intervention (puberty suppression and/or cross sex hormone therapy) with depression and quality of life scores over time in transgender youths. METHODS: At approximately 6-month intervals, participants completed depression and quality of life questionnaires while participating in endocrine intervention. Multiple linear regression and residualized change scores were used to compare outcomes. RESULTS: Between 2013 and 2018, 50 participants (mean age 16.2 + 2.2 yr) who were naïve to endocrine intervention completed 3 waves of questionnaires. Mean depression scores and suicidal ideation decreased over time while mean quality of life scores improved over time. When controlling for psychiatric medications and engagement in counseling, regression analysis suggested improvement with endocrine intervention. This reached significance in male-to-female participants. CONCLUSION: Endocrine intervention may improve mental health in transgender youths in the US. This effect was observed in both male-to-female and female-to-male youths, but appears stronger in the former.

Effect of insulin with oral nutrients on whole-body protein metabolism in growing pubertal children with type 1 diabetes.

Insulin treatment of children with insulin-dependent diabetes mellitus improves whole body protein balance. Our recent study, conducted in pubertal children with type 1 diabetes with provision of both insulin and amino acids, indicated a positive effect of insulin on protein balance, primarily through decreased protein degradation. The current study was undertaken to assess the effect of insulin on protein metabolism in adolescents with type 1 diabetes during oral provision of a complete diet. Whole-body protein metabolism in six pubertal children (13-17 y) with type 1 diabetes mellitus was assessed with L-[1-13C]leucine during a basal (insulin-withdrawn) period and during infusion of 0.15 U/kg/h regular insulin with hourly meals to meet protein and energy requirements. Net leucine balance was significantly higher with insulin and nutrients (13.1 +/- 6.3 micromol leucine/kg/h) than in the basal state (-21.4 +/- 2.8, p < 0.01) with protein degradation decreased from 138 +/- 5.6 mumol leucine/kg/h to 108 +/- 5.9 (p < 0.01) and no significant change in protein synthesis. Even with an ample supply of nutrients, insulin does not increase whole-body protein synthesis in pubertal children with type 1 diabetes mellitus and positive protein balance is solely due to a substantial reduction in the rate at which protein is degraded.

Does pituitary stalk function improve with age?

Ectopic posterior pituitary hyperintensity on MRI is a common feature associated with growth hormone deficiency. The presence of at least some residual components of the pituitary stalk is necessary for adequate anterior pituitary function. Little is known about long-term change in pituitary function or MRI findings in patients with ectopic posterior pituitary and interrupted pituitary stalk. We describe a case of childhood growth hormone deficiency and hyperprolactinemia associated with absent pituitary stalk. As an adult, prolactin levels normalized and GH secretion improved associated with changes in MRI findings.

Nanoemulsions of an anti-oxidant synergy formulation containing gamma tocopherol have enhanced bioavailability and anti-inflammatory properties.

The present study investigated whether MicroFluidizer Processor-based nanoemulsions of an antioxidant synergy formulation (ASF), containing delta, alpha and gamma tocopherol influenced inflammation and bioavailability in CD-1 mice. Croton oil was applied to all animals' right ear lobe to induce inflammation. Auricular thickness was measured after 2 and 6h after the various treatments. The animal plasma and ear lobes were collected and frozen for bioavailability and cytokine analyses. The ASF nanoemulsions of alpha, delta, or gamma tocopherol significantly reduced auricular thickness compared to control (57, -57, and -71%, respectively) and blank nanoemulsion (-50, -50, -67%, respectively). Relative to the suspensions of ASF, only the nanoemulsion of ASF containing gamma tocopherol significantly reduced auricular thickness (-60%), whereas the 40% reduction with nanoemulsions of delta tocopherol compared to suspension was not statistically significant. Auricular concentrations of cytokines TNF-alpha and IL-1 alpha were significantly reduced in mice treated only with ASF nanoemulsions of gamma tocopherol compared to control (-53, -46%, respectively) and blank nanoemulsion (-52, -46%, respectively). Auricular thickness was significantly associated with tissue TNF-alpha (r=0.539, p<0.001) and IL-1 alpha concentrations (r=0.404, p=0.01). Bioavailability for gamma and delta was dramatically enhanced (2.2- and 2.4-folds) with the nanoemulsion compared to suspensions. Only the plasma gamma tocopherol concentration was significantly associated with auricular thickness (r=-0.643, P=0.001). In conclusion, nanoemulsions of ASF containing gamma, alpha, and delta tocopherol, have enhanced anti-inflammatory properties and increased bioavailability, with gamma tocopherol, in particular compared to their suspensions.

Congenital nephrotic syndrome and persistent hypothyroidism after bilateral nephrectomy.

Congenital nephrotic syndrome is commonly associated with hypothyroidism. Thyroid hormone supplementation is recommended as standard of care. The hypothyroidism is postulated to occur secondary to chronic massive proteinuria with loss of thyroid binding globulin, thyroid hormone and iodine. Previous reports have indicated that thyroxin may be discontinued following bilateral nephrectomy. We report our experience with one child with congenital nephrotic syndrome, Finnish type, and hypothyroidism who had a high requirement for thyroxin (100-150 microg/d) from infancy to 4 years of age. Hypothyroidism persisted despite bilateral nephrectomy and later following renal transplantation. However, his thyroxin requirement is now substantially lower (62.5 microg/d) at age 14 years. No goiter was detected clinically and antithyroid antibodies were negative. Thyroid ultrasound and 123I scan revealed a thyroid gland in the anatomically normal location. 123I uptake was elevated, 18% at 6 hours and 51% at 24 hours (normal values: 3-16% at 6 hours and 8-25% at 24 hours). Perchlorate was unavailable for a perchlorate washout study. We speculate that this patient may have an intrinsic problem with thyroid hormone synthesis. It is unclear whether this is related or coincidental to the Finnish nephrotic syndrome. We recommend following thyroid functions closely if thyroxin is discontinued following bilateral nephrectomies in Finnish type congenital nephrotic syndrome.

Effect of inspiration/expiration on height measurement.

BACKGROUND: Growth parameters are a powerful screening tool in pediatric care. Accuracy assumes differing importance in different clinical settings. A small error is not clinically significant when height is obtained as a screening tool during annual well child visits. However, when assessing annual growth velocity using shorter interval visits, an error of equal magnitude might influence further management decisions. AIM AND HYPOTHESIS: To explore the effect of inspiration or expiration on height measurement. Our hypothesis was that height measurements obtained in inspiration would be greater than those obtained in expiration or without specific instructions as to status of respiration (unspecified). METHODS: Heights of 99 individuals 8 years and older were measured in inspiration, expiration and unspecified respiratory status by two pediatric endocrinologists. Patients were measured three times in each mode. The p values were adjusted by Tukey procedure for multiple comparisons among three modes. RESULTS: Height measurement performed in inspiration, expiration or without specific instruction as to breathing (unspecified) did affect height measurement. Mean difference +/- SEM (95% CI) between height obtained in inspiration and expiration was 0.22 +/- 0.03 cm (95% CI: 0.15, 0.29); between inspiration and unspecified 0.31 +/- 0.04 cm (95% CI: 0.22, 0.40); and between expiration and unspecified 0.092 +/- 0.03 cm (95% CI: 0.03, 0.16). CONCLUSIONS: Based on these results, we recommend multiple height measurements using uniform technique including inspiratory/expiratory status, especially when calculating 'annualized' height velocity over short intervals.

Structured triglycerides containing caprylic (8:0) and oleic (18:1) fatty acids reduce blood cholesterol concentrations and aortic cholesterol accumulation in hamsters.

The effects of structured triglycerides containing one long chain fatty acid (oleic acid, C18:1) and one short chain saturated fatty acid (caprylic acid, 8:0) on lipidemia, liver and aortic cholesterol, and fecal neutral sterol excretion were investigated in male Golden Syrian hamsters fed a hypercholesterolemic regimen consisting of 89.9% commercial ration to which was added 10% coconut oil and 0.1% cholesterol (w/w). After 2 weeks on the HCD diet, the hamsters were bled, following an overnight fast (16 h) and placed into one of three dietary treatments of eight animals each based on similar plasma cholesterol levels. The hamsters either continued on the HCD diet or were placed on diets in which the coconut oil was replaced by one of two structured triglycerides, namely, 1(3),2-dicaproyl-3(1)-oleoylglycerol (OCC) or 1,3-dicaproyl-2-oleoylglycerol (COC) at 10% by weight. Plasma total cholesterol (TC) in hamsters fed the OCC and COC compared to the HCD were reduced 40% and 49%, respectively (P<0.05). Similarly, hamsters fed the OCC and COC diets reduced their plasma nonHDL cholesterol levels by 47% and 57%, respectively (P<0.05), compared to hamsters fed the HCD after 2 weeks of dietary treatment. Although hamsters fed the OCC (-26%) and COC (-32%) had significantly lower plasma HDL levels compared to HCD, (P<0.05), the plasma nonHDL/HDL cholesterol ratio was significantly lower (P<0.05) compared to the HCD for the OCC-fed (-27%) and the COC-fed (-38%) hamsters, respectively. Compared to the HCD group, aortic esterified cholesterol was 20% and 53% lower for the OCC and COC groups, respectively, with the latter reaching statistical significance, P<0.05. In conclusion, the hamsters fed the structured triglyceride oils had lower blood cholesterol levels and lower aortic accumulation of cholesterol compared to the control fed hamsters.

Rice bran oil and oryzanol reduce plasma lipid and lipoprotein cholesterol concentrations and aortic cholesterol ester accumulation to a greater extent than ferulic acid in hypercholesterolemic hamsters.

Our laboratory has reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Because RBO has a greater content of the unsaponifiables, which also lower cholesterol compared to most vegetable oils, we wanted to know whether oryzanol or ferulic acid, two major unsaponifiables in RBO, has a greater cholesterol-lowering activity. Forty-eight F(1)B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three per cage) in cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks, at which time they were bled after an overnight fast (16 h) and segregated into 4 groups of 12 with similar plasma cholesterol concentrations. Group 1 (control) continued on the HCD, group 2 was fed the HCD containing 10% RBO in place of coconut oil, group 3 was fed the HCD plus 0.5% ferulic acid and group 4 was fed the HCD plus 0.5% oryzanol for an additional 10 weeks. After 10 weeks on the diets, plasma total cholesterol (TC) and non-high-density lipoprotein cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the RBO (-64% and -70%, respectively), the ferulic acid (-22% and -24%, respectively) and the oryzanol (-70% and -77%, respectively) diets compared to control. Plasma TC and non-HDL-C concentrations were also significantly lower in the RBO (-53% and -61%, respectively) and oryzanol (-61% and -70%, respectively) diets compared to the ferulic acid. Compared to control and ferulic acid, plasma HDL-C concentrations were significantly higher in the RBO (10% and 20%, respectively) and oryzanol (13% and 24%, respectively) diets. The ferulic acid diet had significantly lower plasma HDL-C concentrations compared to the control (-9%). The RBO and oryzanol diets were significantly lower for plasma triglyceride concentrations compared to the control (-53% and -65%, respectively) and ferulic acid (-47% and -60%, respectively) diets. Hamsters fed the control and ferulic acid diets had significantly higher plasma vitamin E concentrations compared to the RBO (201% and 161%, respectively) and oryzanol (548% and 462%, respectively) diets; the ferulic acid and oryzanol diets had significantly lower plasma lipid hydroperoxide levels than the control (-57% and -46%, respectively) diet. The oryzanol-fed hamsters excreted significantly more coprostenol and cholesterol in their feces than the ferulic acid (127% and 120%, respectively) diet. The control diet had significantly greater aortic TC and FC accumulation compared to the RBO (115% and 89%, respectively), ferulic acid (48% and 58%, respectively) and the oryzanol (74% and 70%, respectively) diets. However, only the RBO and oryzanol diets had significantly lower aortic cholesterol ester accumulation compared to the control (-73% and -46%, respectively) diet. The present study suggests that at equal dietary levels, oryzanol has a greater effect on lowering plasma non-HDL-C levels and raising plasma HDL-C than ferulic acid, possibly through a greater extent to increase fecal excretion of cholesterol and its metabolites. However, ferulic acid may have a greater antioxidant capacity via its ability to maintain serum vitamin E levels compared to RBO and oryzanol. Thus, both oryzanol and ferulic acid may exert similar antiatherogenic properties, but through different mechanisms.

Accuracy of self-reported height measurements in parents and its effect on mid-parental target height calculation.

BACKGROUND: Clinical determination of mid-parental height is an important part of the assessment of a child's growth, however our clinical impression has been that parents cannot be relied upon to accurately report their own heights. Therefore, we conducted this study to assess the accuracy of parental height self-reporting and its effect on calculated mid-parental target height for children presenting to a pediatric endocrinology office. METHODS: All parents bringing their children for an initial evaluation to a pediatric endocrinology clinic over a period of nine months were questioned and then measured by a pediatric endocrinologist. Parents were blinded to the study. Mid-parental target heights, based on reported and actual height were compared. RESULTS: There were 241 families: 98 fathers and 217 mothers in our study. Mean measured paternal height was 173.2 cm, self reported 174.9 cm (p < 0.0001), partner reported 177 cm (p = 0.0004). Only 50% of fathers and 58% of mothers reported their height within +/- 2 cm of their measured height, while 15% of fathers and 12% of mothers were inaccurate by more than 4 cm. Mean measured maternal height was 160.6 cm, self-reported 161.1 cm (NS), partner reported 161.7 cm (NS). Inaccuracy of height self-report had a small but significant effect on the mean MPTH (0.4 cm, p = 0.045). Analysis showed that only 70% of MPTH calculated by reported heights fell within +/- 2 cm of MPTH calculated using measured heights, 24% being in +/- 2-4 cm range, and 6% were inaccurate by more than 4 cm. CONCLUSION: There is a significant difference in paternal measured versus reported heights with an overall trend for fathers to overestimate their own height. A large subset of parents makes a substantial error in their height self-report, which leads to erroneous MPTH. Inaccuracy is even greater when one parent reports the other parent's height. When a child's growth is in question, measured rather than reported parental heights should be obtained.

The management of central diabetes insipidus in infancy: desmopressin, low renal solute load formula, thiazide diuretics.

Infants consume most of their calories as formula. Because of this large fluid intake, infants normally produce dilute urine, not far off from that seen in individuals with diabetes insipidus (DI). Infants with DI are therefore prone to water intoxication if fixed antidiuresis is achieved using the long-acting vasopressin analog desmopressin (DDAVP), which induces a state of high urine concentration. DI treatment approaches applied to older children and adults, who consume the their calories as solids, are difficult to apply to infants with DI. When used in infants, oral and intranasal DDAVP can be associated with wide swings in serum sodium concentration (SNA). In comparison, precisely administered subcutaneous doses of DDAVP can be successfully used in infants with DI, and appear to be superior to oral or intranasal DDAVP therapy. Alternatively, consistent eunatremia can be simply achieved in infantile DI using low renal solute load (RSL) formula and thiazide diuretics. Low RSL formula reduces obligatory urinary water losses, and thiazide diuretics concentrate the urine to levels seen in normal formula-fed infants. This report addresses treatment options of DI in infancy and the delicate management issues involved.

Neurocognitive function in children with compensated hypothyroidism: lack of short term effects on or off thyroxin.

BACKGROUND: Although thyroxin therapy clearly is beneficial to children with frank hypothyroidism there is little data on the effects of thyroxin in children with compensated or subclinical hypothyroidism. The objective of this study was to determine the effect of thyroxin therapy on cognitive function in children with compensated hypothyroidism. The hypothesis was that thyroxin therapy would change neuropsychological function. METHODS: Eleven patients with a history of sub clinical hypothyroidism entered the study. At the start of the study, six out of the 11 were on thyroxin therapy, while 5 were off therapy. All patients underwent a battery of neuropsychological testing and thyroid function tests at the start of study. Based on the results of thyroid function tests, two of the 5 patients who were off thyroxin were started back on thyroxin. All of the 6 patients who were on thyroxin were taken off thyroxin. All patients then underwent repeat neuropsychological testing and thyroid functions after an average of 91 days. RESULTS: Thyroxin therapy could not be shown to have an effect on neuropsychological function in this short term study. Our patients had attention problems as compared to the normal population. No significant differences were found between our subjects and normal population standards in verbal processing, visual processing, motor speed/coordination and achievement. CONCLUSION: In this small, short term study, thyroxin therapy could not be shown to affect neuropsychological function in children with compensated hypothyroidism. These children may have attention problems but appear to have normal verbal and visual processing, motor speed/coordination and achievement.

Conjugated linoleic acid isomers reduce blood cholesterol levels but not aortic cholesterol accumulation in hypercholesterolemic hamsters.

The aim of the present study was to characterize plasma lipids and lipoprotein cholesterol and glucose concentrations in hamsters fed either cis-9,trans-11 CLA (9c,11 tCLA); trans-10,cis-12 CLA (10t,12c CLA); or linoleic acid (LA) on the accumulation of aortic cholesterol in hypercholesterolemic hamsters. One hundred male F1B strain Syrian Golden Hamsters (Mesocricetus auratus) (BioBreeders Inc., Watertown, MA) approximately 9 wk of age were housed in individual stainless steel hanging cages at room temperature with a 12-h light/dark cycle. Hamsters were given food and water ad libitum. Following a 1-wk period of acclimation, the hamsters were fed a chow-based (nonpurified) hypercholesterolemic diet (HCD) containing 10% coconut oil (92% saturated fat) and 0.1% cholesterol for 2 wk. After an overnight fast, the hamsters were bled and plasma cholesterol concentrations were measured. The hamsters were then divided into 4 groups of 25 based on similar mean plasma VLDL and LDL cholesterol (nonHDL-C) concentrations. Group 1 remained on the HCD (control). Group 2 was fed the HCD plus 0.5% 9c,11t CLA isomer. Group 3 was fed the HCD plus 0.5% 10t,12c CLA isomer. Group 4 was fed the HCD plus 0.5% LA. Compared with the control, both CLA isomers and LA had significantly lower plasma total cholesterol and HDL cholesterol concentrations (P < 0.001) after 12 but not 8 wk of treatment and were not significantly different from each other. Also, both CLA isomers had significantly lower plasma nonHDL-C concentrations (P < 0.01) compared with the control after 12 but not 8 wk of treatment and were not significantly different from each other or the LA-fed hamsters. Plasma TG concentrations were significantly higher (P < 0.004) with the 10t, 12c CLA isomer compared with the other treatments at 8 but not at 12 wk of treatment. Plasma TG concentrations were also significantly lower (P < 0.03) with the 9c,11t CLA isomer compared with the control at 12 wk of treatment. Also, the 10t,12c CLA isomer and LA had significantly higher plasma glucose concentrations compared with the control and 9c,11t CLA isomer (P < 0.008) at 12 wk of treatment, whereas at 8 wk, only the LA treatment had significantly higher plasma glucose concentrations (P < 0.001) compared with the 9c,11t CLA isomer. Although liver weights were significantly higher in 10t,12c CLA isomer-fed hamsters, liver total cholesterol, free cholesterol, cholesterol ester, and TG concentrations were significantly lower in these hamsters compared with hamsters fed the control, 9c,11t CLA isomer, and LA diets (P< 0.05). The 9c,11t CLA isomer and LA diets tended to reduce cholesterol accumulation in the aortic arch, whereas the 10t,12c CLA isomer diet tended to raise cholesterol accumulation compared with the control diet; however, neither was significant. In summary, no differences were observed between the CLA isomers for changes in plasma lipids or lipoprotein cholesterol concentrations. However, the 9c,11t CLA isomer did appear to lower plasma TG and glucose concentrations compared with the 10t,12c CLA isomer. Such differences may increase the risk of insulin resistance and type 2 diabetes in humans when the 10t,12c CLA isomer is fed separately.

Use of subcutaneous DDAVP in infants with central diabetes insipidus.

Traditional methods for treating central diabetes insipidus during infancy, such as fluid therapy or the use of intranasal hormone replacement, have significant potential limitations. In a retrospective study of infants with diabetes insipidus, we examined outcome using subcutaneous (sc) DDAVP, and compared this to infants treated with intranasal lysine vasopressin or DDAVP. After in-patient dosage titration, outpatients' serum sodium concentrations were maintained in a narrower range in the sc group compared with the intranasal group, and the percentage of serum sodium concentrations within the normal range was greater in the sc group. There were no significant complications in either group. We conclude that DDAVP administered subcutaneously can be a safe and effective alternative to traditionally recommended treatments of central diabetes insipidus during infancy.

Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2.

Integrins are heterodimeric cell-surface adhesion molecules comprising one of 18 possible α-chains and one of eight possible ß-chains. They control a range of cell functions in a matrix- and ligand-specific manner. Integrins can be internalized by clathrin-mediated endocytosis (CME) through ß subunit-based motifs found in all integrin heterodimers. However, whether specific integrin heterodimers can be selectively endocytosed was unknown. Here, we found that a subset of α subunits contain an evolutionarily conserved and functional YxxΦ motif directing integrins to selective internalization by the most abundant endocytic clathrin adaptor, AP2. We determined the structure of the human integrin α4-tail motif in complex with the AP2 C-µ2 subunit and confirmed the interaction by isothermal titration calorimetry. Mutagenesis of the motif impaired selective heterodimer endocytosis and attenuated integrin-mediated cell migration. We propose that integrins evolved to enable selective integrin-receptor turnover in response to changing matrix conditions.

Different palm oil preparations reduce plasma cholesterol concentrations and aortic cholesterol accumulation compared to coconut oil in hypercholesterolemic hamsters.

Several studies have reported on the effect of refined, bleached and deodorized palm oil (RBD-PO) incorporation into the diet on blood cholesterol concentrations and on the development of atherosclerosis. However, very little work has been reported on the influence of red palm oil (RPO), which is higher in carotenoid and tocopherol content than RBD-PO. Thus, we studied the influence of RPO, RBD-PO and a RBD-PO plus red palm oil extract (reconstituted RBD-PO) on plasma cholesterol concentrations and aortic accumulation vs. hamsters fed coconut oil. Forty-eight F1B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three/cage) in hanging polystyrene cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks at which time they were bled after an overnight fast and segregated into four groups of 12 with similar plasma cholesterol concentrations. Group 1 continued on the HCD, Group 2 was fed the HCD containing 10% RPO in place of coconut oil, Group 3 was fed the HCD containing 10% RBD-PO in place of coconut oil and Group 4 was fed the HCD with 10% reconstituted RBD-PO for an additional 10 weeks. Plasma total cholesterol (TC) and non-high-density lipoprotein-cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the hamsters fed the RPO (-42% and -48%), RBD-PO (-32% and -36%) and the reconstituted RBD-PO (-37% and -41%) compared to the coconut oil-fed hamsters. Plasma HDL-C concentrations were significantly higher by 14% and 31% in hamsters fed the RBD-PO and RPO compared to the coconut oil-fed hamsters. Plasma triglyceride (TG) concentrations were significantly lower in hamsters fed RBD-PO (-32%) and the reconstituted RBD-PO (-31%) compared to the coconut oil-fed hamsters. The plasma gamma-tocopherol concentrations were higher in the coconut oil-fed hamsters compared to the hamsters fed the RPO (60%), RBD-PO (42%) and the reconstituted RBD-PO (49%), while for plasma alpha-tocopherol concentrations, the coconut oil-fed hamsters were significantly higher than only the RPO-fed hamsters (21%). The coconut oil-fed hamsters also had significantly higher plasma lipid hydroperoxide concentrations compared to RBD-PO (112%) and the reconstituted RBD-PO (485%). The hamsters fed the coconut oil diet excreted significantly more fecal total neutral sterols and cholesterol compared to the hamsters fed the RBD-PO (158% and 167%, respectively). The coconut oil-fed hamsters had significantly higher levels of aortic total, free and esterified cholesterol compared to the hamsters fed the RPO (74%, 50% and 225%, respectively), RBD-PO (57%, 48% and 92%, respectively) and the reconstituted RBD-PO (111%, 94% and 94%, respectively). Also, aortic free/ester cholesterol ratio in the aortas of hamsters fed RPO was significantly higher than in those fed the coconut oil (124%). In conclusion, hamsters fed the three palm oil preparations had lower plasma TC and non-HDL-C and higher HDL-C concentrations while accumulating less aortic cholesterol concentrations compared to hamsters fed coconut oil.

Balance of unsaturated fatty acids is important to a cholesterol-lowering diet: comparison of mid-oleic sunflower oil and olive oil on cardiovascular disease risk factors.

OBJECTIVE: To evaluate the effects of a trans fat-free monounsaturated fatty acid-rich vegetable oil (NuSun sunflower oil, National Sunflower Association, Bismark, ND) that is a good source of polyunsaturated fatty acids (PUFA) and low in saturated fatty acids on lipid and lipoprotein levels and oxidative stress. DESIGN: A double-blinded, randomized, three period crossover, controlled feeding study. SUBJECTS/SETTING: Thirty-one men (n=12) and women (n=19) with moderate hypercholesterolemia who were 25 to 64 years of age. INTERVENTION: Experimental diets provided 30% fat (olive oil or NuSun sunflower oil contributed one half of the total fat), 8.3% vs 7.9% saturated fatty acid, 17.2% vs 14.2% monounsaturated fatty acid, and 4.3% vs. 7.7% PUFA (olive oil and NuSun sunflower oil, respectively), and 294 mg cholesterol. The control diet was an average American diet (34% fat, 11.2% saturated fatty acid, 14.9% monounsaturated fatty acid, 7.8% PUFA). Subjects consumed each diet for 4 weeks with a 2-week compliance break before crossing over to another diet. MAIN OUTCOME MEASURES: Lipid and lipoprotein levels were measured, and measures of oxidative stress, including lag time, rate of oxidation, total dienes, and lipid hydroperoxides, were assessed. STATISTICAL ANALYSIS: The mixed model procedure was used to test for main effects of diet, feeding period, and order of diets. Tukey-Kramer adjusted P values were used to determine diet effects. RESULTS: The NuSun sunflower oil diet decreased both total and low-density lipoprotein cholesterol levels compared with the average American diet and the olive oil diet. There was no effect of the olive oil diet compared with the average American diet. Total cholesterol decreased 4.7% and low-density lipoprotein cholesterol decreased 5.8% on the NuSun sunflower oil diet vs the average American diet. There was no effect of the experimental diets on triglyceride levels, rate of oxidation, total dienes, lipid hydroperoxides, or alpha-tocopherol. Lag time was the longest following the olive oil diet and shortest following the NuSun sunflower oil diet. CONCLUSIONS: The higher PUFA content appeared to account for the greater total and low-density lipoprotein cholesterol lowering and reduction in lag time of the NuSun sunflower oil diet. However, the fact that there were no differences in the resulting oxidation products suggests there were no adverse effects on low-density lipoprotein oxidation. Since PUFAs are important for cholesterol lowering, foods that replace saturated fatty acids should include a balance of unsaturated fatty acids.

Bisphosphonate treatment of pediatric bone disease.

The science of measuring bone mineral density has developed rapidly and, with it, an improved understanding of the efficacy and safety of various therapeutic interventions in adults. In contrast, the meaning and precision of such measurements in children are equivocal, and the concept of treatment for low bone density in the young patient is still largely undecided. In this report we review the present state of knowledge regarding the use of bisphosphonates during childhood to ameliorate the skeletal abnormalities associated with osteogenesis imperfecta, idiopathic juvenile osteoporosis, fibrous dysplasia of bone and cerebral palsy. Because of the paucity of long-term studies among children regarding the safety and efficacy of these drugs, it is difficult to formulate strong evidence-based recommendations for their use, except perhaps in children with osteogenesis imperfecta.