Ghrelin concentrations reflect body mass index rather than feeding status in obese girls

Ghrelin stimulates both appetite and secretion of growth hormone (GH). We hypothesized that fasting should increase ghrelin, thereby increasing GH concentrations in obesity. Eight obese girls underwent a 48-h fast, receiving 25% of calories for ideal body weight. Blood was obtained every 15 min for the last 24 h of the fast. Four months later, six obese girls had blood obtained in the fed state. Two additional obese and five lean girls had blood obtained in the fed state. Ghrelin was determined in 3-h pools. Mean ghrelin concentrations were 0.41 +/- 0.03 ng/mL for lean girls and 0.16 +/- 0.01 ng/mL in obese fed girls (p < 0.0001). Lean fed girls had diurnal variation of ghrelin whereas obese fed girls did not. Fasting neither increased ghrelin (0.18 +/- 0.01 ng/mL) nor restored diurnal variation. Ghrelin concentrations were related to the body mass index (BMI) SD score (SDS) (r = 0.45, p = 0.005). For the six obese girls who participated in both fasting and fed studies, change in mean ghrelin concentration between studies was related to change in BMI SDS but not fed or fasting state. Ghrelin concentrations are, thus, a function of BMI rather than feeding status in obese girls.     

A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth

Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). We show here, using both Xenopus laevis embryonic neuronal culture and intact X. laevis embryos, that the nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue. Expression of a mutated form of synapsin that prevents phosphorylation at this site, or introduction of phospho-specific antibodies directed against this site, decreased basal and dibutyryl cAMP-stimulated neurite outgrowth. Expression of a mutation mimicking constitutive phosphorylation at this site increased neurite outgrowth, both under basal conditions and in the presence of a PKA inhibitor. These results provide a potential molecular approach for stimulating neuron regeneration, after injury and in neurodegenerative diseases.     

Efficacy of low-dose interferon with antiretroviral therapy in Kaposi's sarcoma: a randomized phase II AIDS clinical trials group study.

We wished to evaluate the efficacy and safety of a low and an intermediate daily dose of interferon-alpha2b (IFN-alpha2b) with didanosine in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). HIV-seropositive subjects with biopsy-confirmed cutaneous KS were randomized to receive either a low (1 million IU) or an intermediate (10 million IU) dose of IFN-alpha2b once daily with twice daily doses of didanosine. Treatment assignment was stratified by CD4 count. Response, toxicity, changes in CD4 counts, and survival were evaluated. Sixty-eight eligible subjects were accrued, 35 to low-dose and 33 to intermediate-dose IFN-alpha2b. The response rate was 40% in the low-dose group (95% CI, 24-58) and 55% in the intermediate-dose group (95% CI, 36-72) (p = 0.338). The median response duration was approximately 110 weeks in both groups. Intermediate-dose IFN induced grade 3/4 neutropenia more often (21% vs. 3%, p = 0.048) and grade 3/4 toxicity faster (p = 0.0231) and necessitated treatment discontinuation earlier for drug-related toxicities (p = 0.0416) than low-dose IFN. There were no significant differences in survival between the treatment groups. Baseline CD4 count was the only significant factor predicting response. Once-daily low-dose and intermediate-dose IFN-alpha2b induced similar response rates, which were achieved without optimal antiretroviral therapy. The slightly higher response rate in the intermediate-dose group was offset by its significantly poorer tolerance. These findings justify the use of lower, well-tolerated IFN doses for treatment of KS with currently used antiretroviral regimens.     

Metabolic determinants of lupus pathogenesis

The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4⁺ T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues.     

Maternal perception of body size as a determinant of infant adiposity in an African-American community

For 10 weeks, a sample of 105 postpartum African-American clients of three inner-city clinics, were recruited for this nine-month prospective study. Data from 54 mother-infant dyads were used to explore the associations between maternal perceptions of infant body size and the development of adiposity at six- to seven months of age. Correlations, chi-square, paired t-test, ANOVA, and logistic regression analyses were performed. Quantitative assessments of BMI using weight and length measures and qualitative assessments of body size perceptions using questionnaires, silhouette, and ranking scales were conducted. At six- to seven months of age, 40% of the infants were above the 85th percentile and 31% were above the 95th percentile of the NCHS standards for weight for height. Maternal perception of infant body size was positively correlated with early introduction of nonmilk foods. Significantly, more infants perceived as small were introduced to nonmilk foods earlier, compared to infants perceived as average, p=0.03. Additionally, it was observed that the earlier the introduction of nonmilk foods, the greater the infant's BMI at six- to seven months of age (r=0.59, p=0.02). Finally, one-third of mothers were obese with BMI's exceeding 30, and 31.1% were overweight with BMI's between 25 and 30.     

Podoplanin (d2-40): a new immunohistochemical marker for reactive follicular dendritic cells and follicular dendritic cell sarcomas

The diagnosis of follicular dendritic cell (FDC) sarcoma can be challenging because of its morphologic overlaps with many other spindle cell neoplasms and, therefore, new phenotypic markers will be helpful in its differential diagnosis. Podoplanin is a mucin-type transmembrane glycoprotein that has recently been detected in reactive FDCs. In this study, we investigated the expression patterns of podoplanin using a new mouse monoclonal antibody D2-40, and compared them with CD21, a well-established FDC marker, in a comprehensive panel of cases. The panel included 4 FDC sarcomas, 38 spindle cell neoplasms of other types, 25 reactive lymphoid hyperplasia, and 117 lymphoid and 5 myeloid malignant hematopoietic neoplasms. Our study revealed that D2-40 strongly stained 3 of 4 FDC sarcomas. In contrast, D2-40 stained only 2/38 other spindle cell neoplasms tested. Furthermore, we observed that D2-40 highlighted more FDC meshworks than CD21 in Castleman's disease, follicular lymphoma, nodular lymphocyte predominance Hodgkin lymphoma, and residual reactive germinal centers in a variety of lymphoma types. D2-40 and CD21 stained an equal number of cases of reactive lymphoid hyperplasia, progressively transformed germinal centers and angioimmunoblastic T-cell lymphoma. No expression of podoplanin was detected in normal or neoplastic lymphoid and myeloid cells. We conclude that podoplanin (D2-40) is a sensitive and specific FDC marker, which is superior or equal to CD21 in evaluating both reactive and neoplastic FDCs. In addition, our results suggest that podoplanin (D2-40) can be used to support the diagnosis of FDC sarcoma.     

The effect of blood phenylalanine concentration on Kuvan™ response in phenylketonuria

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH) with consequent elevation of blood phenylalanine (Phe), reduction in tyrosine (Tyr) and elevation of Phe/Tyr ratio (P/T). Although newborn screening for PKU with early dietary treatment improved severe, irreversible brain damage, older patients suffer reversible losses in executive function when Phe concentrations are elevated. The maintenance of strict nutritional control in older children and adults remains difficult. An adjunct to dietary therapy, oral tetrahydrobiopterin (BH₄) has recently been approved by the Food and Drug Administration as a stable, synthetic BH₄ called Kuvan?. Published studies of Kuvan response in PKU varies and involved primarily children. In this prospective study we evaluated dose–response, response frequency and factors predicting response in 21 patients with PKU (aged 8–30 years), who required life-long dietary treatment. Response to Kuvan was defined at 24 h (acute) and over 4 weeks (chronic) as a ≥ 30% decline in the Phe or P/T ratio. A dose of 20 mg/kg Kuvan was chosen with 29% responding in 24 h and 33% of patients at 4 weeks. We then compared baseline Phe, Tyr, P/T, Phe intake, and frequency of “severe” versus “moderate” mutant PAH alleles among acute and chronic responders and non-responders to Kuvan. Predictors of response to Kuvan, both acute and chronic were baseline Phe and baseline P/T. Baseline Phe and P/T were higher among non-responders (P < 0.05). By contrast baseline Tyr was similar (P = 0.45). Phe intake tended to be higher (18 ± 20 mg/kg/24 h) among Kuvan responders than non-responders (15 ± 11 mg/kg/24 h), P < 0.07 NS. Similarly the frequency of “severe” mutant PAH alleles tended to be more frequent (67%) among non-responders than responders (40%) by Chi² test, P = 0.08 NS. These results were reproducible in a “responder” to Kuvan. To assess directly the effect of elevated blood Phe, Phe was lowered in four, “non-responder” patients, but all failed to respond to Kuvan. We conclude that baseline blood Phe and P/T ratio can predict increased probability for response to Kuvan by patients with classic PKU, but the in vivo mechanisms of response to Kuvan remain enigmatic.     

Melatonin treatment for eastward and westward travel preparation

Introduction  

Melatonin is recommended for hastening adaptation to phase shift, but there is little information on appropriate formulations.     

Patient dose considerations for routine megavoltage cone-beam CT imaging

Megavoltage cone-beam CT (MVCBCT), the recent addition to the family of in-room CT imaging systems for image-guided radiation therapy (IGRT), uses a conventional treatment unit equipped with a flat panel detector to obtain a three-dimensional representation of the patient in treatment position. MVCBCT has been used for more than two years in our clinic for anatomy verification and to improve patient alignment prior to dose delivery. The objective of this research is to evaluate the image acquisition dose delivered to patients for MVCBCT and to develop a simple method to reduce the additional dose resulting from routine MVCBCT imaging. Conventional CT scans of phantoms and patients were imported into a commercial treatment planning system (TPS: Phillips, Pinnacle) and an arc treatment mimicking the MVCBCT acquisition process was generated to compute the delivered acquisition dose. To validate the dose obtained from the TPS, a simple water-equivalent cylindrical phantom with spaces for MOSFETs and an ion chamber was used to measure the MVCBCT image acquisition dose. Absolute dose distributions were obtained by simulating MVCBCTs of 9 and 5 monitor units (MU) on pelvis and head and neck patients, respectively. A compensation factor was introduced to generate composite plans of treatment and MVCBCT imaging dose. The article provides a simple equation to compute the compensation factor. The developed imaging compensation method was tested on routinely used clinical plans for prostate and head and neck patients. The quantitative comparison between the calculated dose by the TPS and measurement points on the cylindrical phantom were all within 3%. The dose percentage difference for the ion chamber placed in the center of the phantom was only 0.2%. For a typical MVCBCT, the dose delivered to patients forms a small anterior-posterior gradient ranging from 0.6 to 1.2 cGy per MVCBCT MU. MVCBCT acquisitions in the pelvis and head and neck areas deliver slightly more dose than current portal imaging but render soft tissue information for positioning. Overall, the additional dose from daily 9 MU MVCBCTs of prostate patients is small compared to the treatment dose (<4%). Dose-volume histograms of compensated plans for pelvis and head and neck patients imaged daily with MVCBCT showed no additional dose to the target and small increases at low doses. The results indicate that the dose delivered for MVCBCT imaging can be precisely calculated in the TPS and therefore included in the treatment plan. This allows simple plan compensations, such as slightly reducing the treatment dose, to minimize the total dose received by critical structures from daily positioning with MVCBCT. The proposed compensation factor reduces the number of MU per treatment beam per fraction. Both the number of fractions and the beam arrangement are kept unchanged. Reducing the imaging volume in the cranio-caudal direction can further reduce the dose delivered for MVCBCT. This is a useful feature to eliminate the imaging dose to the eyes or to focus on a specific region of interest for alignment.     

Ultrastructural study of the spermatozoon of <Emphasis Type="Italic">Nicolla testiobliquum</Emphasis> (Digenea,Opecoelidae) parasite of brown trout <Emphasis Type="Italic">Salmo trutta</Emphasis> (Pisces,Teleostei)

The present paper describes the spermatozoon of Nicolla testiobliquum (Digenea, Opecoelidae), an intestinal parasite of brown trout Salmo trutta, studied by transmission electron microscopy. The mature spermatozoon possess two axonemes of 9 + “1” pattern, two mitochondria, a nucleus, external ornamentation of the plasma membrane, spine-like bodies and cortical microtubules. A comparative study between N. testiobliquum and Nicolla wisniewskii shows mainly two different dispositions of the two mitochondria in these two species of a same genera. Moreover, the comparison of each of these spermatozoon features with others digeneans, in general, and other Opecoelidae in particular, is also presented. It appears that the organisation of the posterior part of the spermatozoon, the disposition of cortical microtubules and external ornamentation associated with spine-like bodies could be interesting elements for phylogeny.