Urinary excretion kinetics of [¹⁷⁷Lu]Lu-PSMA-617

Introduction: For the implementation of suitable radiation safety measures in [177Lu]Lu-PSMA-617 therapy, additional insight into excretion kinetics is important. This study evaluates this kinetics in prostate cancer patients via direct urine measurements. Methods: Both the short-term (up to 24 h, n = 28 cycles) and long-term kinetics (up to 7 weeks, n = 35 samples) were evaluated by collection of urine samples. Samples were measured on a scintillation counter to determine excretion kinetics. Results: The mean excretion half-time during the first 20 h was 4.9 h. Kinetics was significantly different for patients with kidney function below or above eGFR 65 ml/min. Calculated skin equivalent dose in case of urinary contamination was between 50 and 145 mSv when it was caused between 0 and 8 h p.i. Measurable amounts of 177Lu were found in urine samples up to 18 days p.i. Conclusion: Excretion kinetics of [177Lu]Lu-PSMA-617 is especially relevant during the first 24 h, when accurate radiation safety measures are important to prevent skin contamination. Measures for accurate waste management are relevant up to 18 days.</p

Quality of life and behavioral functioning in Dutch pediatric patients with hereditary spherocytosis

The objective of this study was to evaluate health-related quality of life (HRQoL) and behavioral functioning in pediatric patients with hereditary spherocytosis (HS). A cross-sectional study was conducted in 132 Dutch children and adolescents with HS and aged 8-18 years of whom 48 underwent splenectomy prior to the study. HRQoL was assessed using the KIDSCREEN-27, and behavioral functioning was evaluated using the strength and difficulties questionnaire (SDQ). Scores of pediatric patients with HS were compared to a Dutch norm population. Additionally, the effects of three factors were assessed: fatigue, self-image, and parents' perceived vulnerability (measured with the checklist individual strength, the self-perception profile for children and adolescents, and the child vulnerability scale). Both unsplenectomised and splenectomised pediatric patients reported lower HRQoL on the domain physical well-being (KIDSCREEN-27) compared to Dutch peers. For behavioral functioning, parents of both groups reported more emotional problems (SDQ) compared to the norm population. Pediatric patients with lower scores on physical well-being experienced more fatigue. The patients' perceived social acceptance and parents' perceived vulnerability appeared as determinants of emotional problems. Conclusion: Pediatric patients in the current study generally report few complaints, and the results suggest that these patients overall have a strong ability to cope with HS. Despite these few complaints, fatigue and parents' perceived vulnerability seem to be important determinants for lower HRQoL and more emotional problems. Therefore, screening on these factors could serve as an addition to the treatment of HS, to help pediatric patients who are at risk for lower HRQoL or more emotional problems

Investigations into metabolism, transport and function of sulfonated steroids in the porcine testicular-epididymal compartment

Sulfonated steroids have been traditionally regarded as inactive metabolites destined for excretion, as they are incapable of binding to classical nuclear steroid receptors. However, by the enzyme steroid sulfatase (STS) they may be converted into free steroids, which may be biologically active directly or after a few additional enzymatic reactions. Thus, as sulfonated steroids commonly circulate at relatively high concentrations, they may form an important pool of precursors for the local (intra-tissue) production of active free steroids. This so-called sulfatase pathway has received increased attention over recent years especially with respect to estrogen metabolism in human hormone-dependent breast cancer, where the intratumoral estrogen production from sulfonated precursors obviously has a much higher capacity in comparison to the de novo synthesis via free steroids. This study is composed of two parts of which the first one addresses the secretory patterns of free and sulfonated steroids in vivo, whereas in the second part the expression of STS and of the steroid sulfotransferases SULT1E1 (estrogen specific) and SULT2B1 (specific for beta-hydroxysteroids) was characterized in the testis and in different segments of the epididymis. Other subjects of the second part of this study were hydrolysis of steroid sulfates and the sulfonation of estrone (E1), dehydroepiandrosterone (DHEA) and pregnenolone (P5) in the tissues investigated. Concentrations of androstenedione, testosterone, pregnenolone sulfate (P5S), dehydroepiandrosterone sulfate (DHEAS), estrone-3-sulfate (E1S)and 17beta-estradiol-3-sulfate were performed in the Steroid Research & Mass Spectrometry Unit, Division of Pediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus-Liebig-University, Giessen (head: Prof. Dr. S. Wudy) applying liquid chromatography tandem mass spectrometry (LC-MS-MS). Moreover, 17beta-estradiol (E2) and E1 were measured by inhouse radioimmunoassays to cope with the low concentrations of free estrogens in boars. In order to get new information on the sulfonation of free steroids and the hydrolysis of steroid sulfates in the porcine testicular-epididymal compartment, subcellular fractions were prepared from tissue samples collected from the testis and from defined sites of the epididymis (EH1, EH2: proximal/distal part of epididymal head; EB1-4: epididymal body, from proximal to distal; ET1, ET2: proximal/distal part of epididymal tail) using differential centrifugation. STS and steroid sulfotransferase activities were measured based on the differential distribution of free and sulfonated steroids between an aqueous phase and an organic solvent, tert butyl-methylether. The immunostaining results were shown that SULTs 1E1 and 2B1, immunostaining was especially prominent in superficial epithelial protrusions. Sporadic staining of weaker intensity was also found in the muscular layer and in the vascular endothelium. With WB, a specific band of the expected molecular size (approx. 61 kDa) was found in the testis and all segments of the epididymis. These results show that STS is widely expressed in the porcine testicular-epididymal compartment, indicating a high potential for sulfatase pathways especially in Leydig cells and the epithelial cells of the rete testis and epididymis. The co-expression of STS with SULTs 1E1 and 2B1 in the epididymal epithelium and especially their colocalization in superficial protrusions are very intriguing. In the epididymal duct, apocrine secretion has been described to give rise to the formation of epididymosomes, small vesicles which are considered as vehicles for the transfer of certain molecules to the maturing sperm cells. Other intriguing findings are the virtual absence of a sulfonation of E1, DHEA and P5 in testicular cytosols as well as the absent or questionable detection of SULTs 1E1 and 2B1 in light of the high efflux of various steroid sulfates from the testis. A plausible explanation could be a significant use of sulfonated steroids as precursors/intermediates in porcine testicular steroidogenesis starting from cholesterol sulfate. The concept of a “sulfate pathway” of steroidogenesis would not only provide an explanation for the production of high amounts of steroid sulfates in the virtual absence of relevant steroid sulfotransferase activities but also for the high STS expression in Leydig cells. According to this concept, STS could play a crucial role in the control of the substrate flow through the steroidogenic enzyme cascade by mediating the transition of sulfonated precursors into the pool of free steroids, with the exact subcellular localization being of importance for the step of the enzyme cascade at which this transition(s) may occur. Thus, in order to corroborate this concept investigations into the utilization of sulfonated substrates by steroidogenic enzymes and on the subcellular localization of STS are necessary

The effect of unfiltered coffee on potential biomarkers for colonic cancer risk in healthy volunteers: a randomized trial

Background: Epidemiologic studies suggest that coffee use might protect against colorectal cancer. Inconsistencies as to the effect of coffee use and colorectal cancer between epidemiologic studies might be related to the type of coffee brew. Objective: We studied the effect of unfiltered coffee consumption on putative biomarkers for colonic cancer risk. Design: A total of 64 healthy volunteers (31 men and 33 women), with a mean age of 43 ± 11 years were randomly assigned to two groups in a crossover design, with two intervention periods of 2 weeks separated by a washout period of 8 weeks. Treatments were 1 L of cafetiere (French press) coffee daily or no coffee. At the end of each intervention period, fasting blood samples, colorectal biopsies and 48 h faeces were collected. Results: No effect of coffee on colorectal cell proliferation, assayed by estimating the Proliferating Cell Nuclear Antigen labelling index, was seen. Additionally, no effects were seen on the concentrations of faecal soluble bile acids and colorectal mucosal glutathione S-transferase activity. However, unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Other aminothiols in plasma also increased on coffee. Conclusion: Unfiltered coffee does not influence the colorectal mucosal proliferation rate, but might increase the detoxification capacity and anti-mutagenic properties in the colorectal mucosa through an increase in glutathione concentration. Whether this effect indeed contributes to a lower colon cancer risk remains to be established

Relativistic effects in electromagnetic nuclear responses in the quasi-elastic delta region

A new non-relativistic expansion in terms of the nucleon's momentum inside nuclear matter of the current for isobar electro-excitation from the nucleon is performed. Being exact with respect to the transferred energy and momentum, this yields new current operators which retain important aspects of relativity not taken into account in the traditional non-relativistic reductions. The transition current thus obtained differs from the leading order of the traditional expansion by simple multiplicative factors. These depend on the momentum and energy transfer and can be easily included together with relativistic kinematics in non-relativistic, many-body models of isobar electro-excitation in nuclei. The merits of the new current are tested by comparing with the unexpanded electromagnetic nuclear responses in the isobar peak computed in a relativistic Fermi gas framework. The sensitivity of the relativistic responses to the isobar's magnetic, electric and Coulomb form factors and the finite width of the isobar is analyzed.Comment: 26 pages plus 6 figure

Theoretical Analysis of a Large Momentum Beamsplitter using Bloch Oscillations

In this paper, we present the implementation of Bloch oscillations in an atomic interferometer to increase the separation of the two interfering paths. A numerical model, in very good agreement with the experiment, is developed. The contrast of the interferometer and its sensitivity to phase fluctuations and to intensity fluctuations are also calculated. We demonstrate that the sensitivity to phase fluctuations can be significantly reduced by using a suitable arrangement of Bloch oscillations pulses

Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association

Type 1 diabetes is characterized by an immune-mediated depletion of β-cells that results in lifelong dependence on exogenous insulin. While both type 1 and type 2 diabetes result in hyperglycemia, the pathophysiology and etiology of the diseases are distinct and require us to consider each type of diabetes independently. As such, this position statement summarizes available data specific to the comprehensive care of individuals with type 1 diabetes. The goal is to enhance our ability to recognize and manage type 1 diabetes, to prevent its associated complications, and to eventually cure and prevent this disease. The exact number of individuals with type 1 diabetes around the world is not known, but in the U.S., there are estimated to be up to 3 million (1). Although it has long been called “juvenile diabetes” due to the more frequent and relatively straightforward diagnosis in children, the majority of individuals with type 1 diabetes are adults. Most children are referred and treated in tertiary centers, where clinical data are more readily captured. The SEARCH for Diabetes in Youth study estimated that, in 2009, 18,436 U.S. youth were newly diagnosed with type 1 diabetes (12,945 non-Hispanic white, 3,098 Hispanic, 2,070 non-Hispanic black, 276 Asian-Pacific Islander, and 47 American Indian) (2). Worldwide, ∼78,000 youth are diagnosed with type 1 diabetes annually. Incidence varies tremendously among countries: East Asians and American Indians have the lowest incidence rates (0.1–8 per 100,000/year) as compared with the Finnish who have the highest rates (>64.2 per 100,000/year) (3). In the U.S., the number of youth with type 1 diabetes was estimated to be 166,984 (4). The precise incidence of new-onset type 1 diabetes in those over 20 years of age is unknown. This may be due to the prolonged phase of onset and the subtleties in distinguishing the different

CD34+ cells home, proliferate, and participate in capillary formation, and in combination with

Objective - Emerging evidence suggests that human blood contains bone marrow (BM)-derived endothelial progenitor cells that contribute to postnatal neovascularization. Clinical trials demonstrated that administration of BM-cells can enhance neovascularization. Most studies, however, used crude cell populations. Identifying the role of different cell populations is important for developing improved cellular therapies. Methods and Results - Effects of the hematopoietic stem cell-containing CD34+ cell population on migration, proliferation, differentiation, stimulation of, and participation in capillary-like tubule formation were assessed in an in vitro 3-dimensional matrix model using human microvascular endothelial cells. During movement over the endothelial monolayer, CD34+ cells remained stuck at sites of capillary tube formation and time- and dose-dependently formed cell clusters. Immunohistochemistry confirmed homing and proliferation of CD34+ cells in and around capillary sprouts. CD34+ cells were transduced with the LNGFR marker gene to allow tracing. LNGFR gene-transduced CD34 + cells integrated in the tubular structures and stained positive for CD31 and UEA-1. CD34+ cells alone stimulated neovascularization by 17%. Coculture with CD34- cells led to 68% enhancement of neovascularization, whereas CD34- cells displayed a variable response by themselves. Cell-cell contact between CD34+ and CD34- cells facilitated endothelial differentiation of CD34+ cells. Conclusions - Our data suggest that administration of CD34+-enriched cell populations may significantly improve neovascularization and point at an important supportive role for (endogenous or exogenous) CD34- cells. © 2005 American Heart Association, Inc. Chemicals / CAS: nitric oxide, 10102-43-9; Antigens, CD34; Biological Marker