bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing
Authors: Ellard S. , Hattersley A. T. , Brewer C. M. , Vaidya B. 
Published: January 2005

SummaryObjective  Diagnostic molecular genetic testing for multiple endocrine neoplasia type 1 (MEN1) has been available since the identification of the MEN1 gene in 1997. Mutation screening of the MEN1 gene has been recommended for patients who meet clinical criteria for MEN1 (at least two of the following: parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma) and those in whom a diagnosis of MEN1 is suspected. We examined the appropriateness of these clinical criteria.Patients and Methods  A total of 292 patients were referred for diagnostic testing. The coding region of the MEN1 gene was sequenced in 186 index cases and mutation testing was requested for 106 subjects, including 83 asymptomatic relatives.Results  MEN1 gene mutations were identified in 68/186 index cases (37%). Twenty‐nine of the 60 MEN1 mutations reported are novel. The likelihood of finding a mutation was correlated with the number of MEN1‐related tumours (mutation detection rate of 79%, 37% and 15% in patients with three, two and one main MEN1‐related tumours; P ≤ 0·00001) and increased in the presence of a family history (mutation detection rate of 91%, 69% and 29%vs. 69%, 23% and 0% in sporadic cases with three, two or one main MEN1‐related tumours, respectively; P ≤ 0·00001). The pick‐up rate in the 83% of subjects who met proposed criteria for diagnostic testing was 42%, but in those who did not meet these criteria this fell to 0%.Conclusions  The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.
Insulin sensitivity is impaired in adults with varying degrees of GH deficiency
Authors: Murray Robert D. , Shalet Stephen M. 
Published: January 2005

SummaryBackground  Severe GH deficiency (GHD) is arbitrarily defined by a peak GH (pGH) response to provocative tests of less than 3 µg/l. The impact of lesser degrees of GHD (pGH of 3–7 µg/l) in the adult is less well defined. Hypopituitary adults with severe GHD are insulin resistant as defined by the short insulin tolerance test (ITT), homeostatic model assessment (HOMA) or the hyperinsulinaemic euglycaemic clamp. Whether insulin action is impaired in the presence of lesser degrees of GHD (GH insufficiency, GHI) is not known.Patients and Methods  We studied 30 patients with GHD (median pGH 0·5 µg/l; 0·3–1·3 µg/l), 24 with GHI (median pGH 4·0 µg/l; 3·6–4·9 µg/l), and 30 age‐, sex‐ and body mass index (BMI)‐matched controls. A short ITT was performed in a subset of 20 patients from each group and the rate constant for glucose disappearance (KITT) calculated.Results  Both GHD and GHI hypopituitary adults were found to be insulin resistant from the KITT values compared with the control group [analysis of variance (anova) on ranks, −0·0210 vs. −0·0223 vs. −0·0261, P < 0·05]. No difference in KITT values was detected between the GHD and GHI groups. Calculation of insulin resistance using the HOMA did not detect a significant difference between groups (anova on ranks, 2·04 vs. 1·54 vs. 1·34, P = 0·40). No significant difference in the fasting glucose, insulin or IGFBP‐I levels between groups was detected. Insulin resistance estimated from the KITT correlated with the serum IGF‐I (r = −0·30, P = 0·01), and pGH level to the ITT (r = −0·31, P = 0·03). KITT also correlated with total body percentage fat mass (r = −0·28, P = 0·03). Multivariate analysis found KITT to be dependent on percentage fat mass, gender and age (r = 0·53, P = 0·0002). Insulin resistance increased in concert with percentage fat mass, age and male gender.Conclusions  Although not detected under basal conditions, hypopituitary adults with both severe GHD and GHI are insulin resistant under conditions of insulin stimulation. This finding may be explained by the concomitant adverse changes in body composition observed in both these states of varying degrees of GHD. Insulin resistance is associated with a number of adverse cardiovascular risk factors that may place patients with GHI at risk of premature cardiovascular disease.
Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin‐sensitivity, lipid profile and macronutrient preference
Authors: Magni Paolo , Liuzzi Antonio , Ruscica Massimiliano , Dozio Elena , Ferrario Silvia , Bussi Isabella , Minocci Alessandro , Castagna Alessandra , Motta Marcella , Savia Giulio 
Published: January 2005

SummaryObjective  The adipose‐borne hormone leptin circulates in free and protein‐bound forms but little information is available about their biological significance. Free leptin (FL) levels are related to changes in fat mass, whereas bound leptin (BL) appears to be associated with resting energy expenditure (REE). Our aim was to assess FL and BL levels in normal weight and obese subjects and correlate them with metabolic and nutritional variables.Design and Patients  The partitioning of plasma leptin between FL and BL was evaluated in a population (n = 44) including both genders and different degrees of adiposity [body mass index (BMI) range 18·6–79·6 kg/m2].Measurements  Total leptin and FL and BL concentrations were measured by fast protein liquid chromatography (FPLC) followed by radioimmunoassay (RIA). Body composition, REE, insulin sensitivity, lipid parameters associated with cardiovascular risk and macronutrient preference were also assessed.Results  The BL/FL ratio was significantly reduced in obese subjects due to a major increase in FL compared with BL. Consequently, the gender difference of the %BL/%FL ratio present in lean subjects (35/65 in women; 65/35 in men) was lost in obese subjects. REE was negatively correlated with total leptin (P < 0·0001) and %FL (P < 0·0001), and positively with %BL (P < 0·001). Total leptin and FL were correlated with the diet carbohydrate content in all subjects.Conclusions  FL increases with the amount of fat mass; the prevalence of FL in normal weight women in comparison to men suggests that this fraction is particularly linked to the amount of subcutaneous fat. Moreover, the correlation of BL with REE and the relationship of FL with food intake favours the view of different biological activities for the two circulating forms of leptin.
Preserved inhibitory effect of recurrent hypoglycaemia on the male gonadotrophic axis
Authors: Oltmanns Kerstin M. , Peters Achim , Kern Werner , Fehm Horst L. , Born Jan , Schultes Bernd 
Published: January 2005

SummaryObjective  Hypoglycaemia‐induced decreases in male LH and testosterone concentrations are possibly mediated by activation of the hypothalamus–pituitary–adrenal (HPA) axis or by an increase in PRL. As counterregulatory stress hormone release is attenuated during recurrent hypoglycaemia, we questioned whether the gonadotrophic axis and PRL adapt similarly.Design  We performed two consecutive hypoglycaemic clamps on day 1 and one clamp on the following day in 15 healthy men. Blood concentrations of gonadotrophins, PRL, testosterone, ACTH and cortisol were measured during the first and the third clamp, taking place at the same time of day.Results  During hypoglycaemia, serum concentrations of LH and testosterone decreased (P < 0·003 for both), PRL, ACTH and cortisol increased (P < 0·001), and FSH remained unchanged (P = 0·90). The hypoglycaemia‐induced decreases in LH and testosterone concentrations were similar during the first and the last clamp (P > 0·28 for both) whereas the increase in PRL, ACTH and cortisol was markedly attenuated during the third clamp (P < 0·001).Conclusions  LH and testosterone responses do not adapt to recurrent hypoglycaemia, whereas the increase in PRL is attenuated, indicating adaptation. Considering the marked decrease in the responses of PRL and the HPA axis after antecedent hypoglycaemia, the data suggest that the hypoglycaemia‐induced decreases in LH and testosterone concentrations, not adapting to recurrent hypoglycaemia, are mediated independently, probably by blood glucose itself.
Tetraplegic subjects have hyperleptinaemia with marked circadian variation
Authors: Hjeltnes Nils , De Groot Patricia , Birkeland Kåre I. , Falch Jan A. , Iversen Per O. 
Published: January 2005

SummaryObjective  The disruption between the brain and the spinal cord leads to a decentralized sympathetic nervous system in people with chronic, cervical spinal cord lesions. These tetraplegic subjects are prone to disorders of energy metabolism and osteoporosis, and they experience alterations in their body composition with a relative accumulation of fat. The adipocyte‐derived cytokine leptin is a key signal in caloric intake and energy expenditure, and it might modify bone remodelling, possibly regulated by sympathetic neuronal signalling. In able‐bodied subjects leptin exhibits circadian variations, possibly mediated via sympathetic neurones. We have examined the plasma concentration of leptin among tetraplegics, to determine whether plasma leptin in these subjects exhibits circadian variations.Measurements and Results  Blood samples were collected during a 24‐h study period from tetraplegic subjects (n = 6) and from able‐bodied controls (n = 8). Fasting, tetraplegic subjects had mean plasma concentrations of leptin about four times those of able‐bodied controls (P < 0·05). In tetraplegia, plasma leptin was negatively correlated with total lean mass (r =−0·88, P < 0·05) but correlated positively with total fat mass (r = 0·89, P < 0·05). A marked circadian variation in plasma leptin concentrations was more evident in tetraplegia than in able‐bodied controls.Conclusion  Plasma leptin is markedly elevated and it shows more prominent circadian variations in tetraplegia compared with able‐bodied subjects. Possibly the regulation of leptin metabolism is impaired among these patients. This might distort thermogenesis and energy expenditure, thus explaining the enhanced risk of the metabolic syndrome and of osteoporosis among tetraplegic subjects.
Effect of aromatase inhibition on lipids and inflammatory markers of cardiovascular disease in elderly men with low testosterone levels
Authors: Dougherty Ryan H. , Rohrer Jacqueline L. , Hayden Douglas , Rubin Stephen D. , Leder Benjamin Z. 
Published: January 2005

SummaryObjective  Although androgen replacement has been shown to have beneficial effects in hypogonadal men, there is concern that androgens may deleteriously affect cardiovascular risk in elderly men.Design  Anastrozole is an oral aromatase inhibitor that normalizes serum testosterone levels and decreases oestradiol levels modestly in elderly men with mild hypogonadism. Thirty‐seven elderly hypogonadal men were randomized to receive either anastrozole 1 mg daily (n = 12), anastrozole 1 mg twice weekly (n = 11), or daily placebo (n = 14) for 12 weeks in a double‐blind fashion.Patients  Men aged 62–74 years with mild hypogonadism defined by testosterone levels less than 350 ng/dl.Measurements  Serum levels of fasting lipids, C‐reactive protein (CRP), interleukin‐6 (IL‐6), intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1) and homeostatic model assessment (HOMA) scores were measured at 4‐week intervals.Results  Treatment with anastrozole did not significantly affect fasting lipids, inflammatory markers (IL‐6, CRP), adhesion molecules (ICAM‐1, VCAM‐1) or insulin sensitivity (HOMA). There was, however, a positive correlation between changes in serum triglycerides and changes in serum oestradiol levels (P = 0·04).Conclusions  While short‐term administration of anastrozole is an effective method of normalizing serum testosterone levels in elderly men with mild hypogonadism, it does not appear to adversely affect lipid profiles, inflammatory markers of cardiovascular risk or insulin resistance.
Haptoglobin dampens endotoxin‐induced inflammatory effects both in vitro and in vivo
Authors: Arredouani Mohamed S. , Kasran Ahmad , Vanoirbeek Jeroen A. , Berger Frank G. , Baumann Heinz , Ceuppens Jan L. 
Published: January 2005

SummaryWe report that haptoglobin, an acute‐phase protein produced by liver cells in response to interleukin‐6 (IL‐6), can modulate the inflammatory response induced by endotoxins. We provide evidence that haptoglobin has the ability to selectively antagonize lipopolysaccharide (LPS) effects in vitro by suppressing monocyte production of tumour necrosis factor‐α, IL‐10 and IL‐12, while it fails to inhibit the production of IL‐6, IL‐8 and IL‐1 receptor antagonist. In two animal models of LPS‐induced bronchopulmonary hyperreactivity and endotoxic shock, haptoglobin knockout mice were more sensitive to LPS effects compared to their wild‐type counterparts. The present data suggest that haptoglobin regulates monocyte activation following LPS stimulation. The increase in haptoglobin levels during an acute‐phase reaction may generate a feedback effect which dampens the severity of cytokine release and protects against endotoxin‐induced effects.
Comparison of the expressed porcine Vβ and Jβ repertoire of thymocytes and peripheral T cells
Authors: Butler John E. , Wertz Nancy , Sun Jishan , Sacco Randy E. 
Published: January 2005

SummaryTranscripts of more than 300 unique T‐cell receptor‐β (TCR‐β) V‐D‐J rearrangements recovered from porcine thymocytes and peripheral T cells were compared. We identified 19 groups (families) of porcine Vβ genes in seven supergroups and provisionally named 17 groups based on their sequence similarity with recognized human Vβ gene families. TRBV4S, 5S, 7S and 12S accounted for > 80% of all Vβ usage, and usage of these groups by thymocytes and peripheral T cells was highly correlated. No TRBV group was uniquely expressed in significant numbers in thymocytes, although small numbers of TRBV groups 2S, 9S and 15S were only recovered from T cells. Usage of Jβ segments from the 5′ D‐J‐C duplicon in thymocytes and peripheral T cells directly correlated with their 5′ position in the locus, and Jβ1·1, 1·2 and 1·3 accounted for ≥ 35% of all Jβ usage in both cell types. This contrasts with the usage of Jβ2 segments in that Jβ2·4, 2·5 and 2·7 accounted for ≈ 30% of Jβ usage by T cells and thymocytes. Jβ2·7 was threefold more frequent among T cells than thymocytes. The Vβ/Jβ combination was not random. Jβ1·1 and 1·2 were used in 29% of rearrangements with high frequency among the major Vβ groups. Combinations of TRBV4 and V12 with Jβ2·7 were only found in T cells and accounted for half of all Jβ2·7 usage. These studies show that unlike porcine heavy chain VH genes, the occurrence and relative usage of porcine TCR‐Vβ groups resembles that of humans. Thus, highly related gene systems can individually diverge within a species.
Follicular dendritic cell dedifferentiation reduces scrapie susceptibility following inoculation via the skin
Authors: Mohan Joanne , Bruce Moira E. , Mabbott Neil A. 
Published: January 2005

SummaryTransmissible spongiform encephalopathies (TSEs) are a group of subacute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrPSc, an abnormal isoform of the host prion protein (PrPc). Following peripheral exposure, TSE infectivity and PrPSc usually accumulate in lymphoid tissues prior to neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of TSE transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of TSEs to the brain, but until now, it has not been known which components of the immune system are required for efficient neuroinvasion. Temporary dedifferentiation of follicular dendritic cells (FDCs) by treatment with an inhibitor of the lymphotoxin‐β receptor signalling pathway (LTβR‐Ig) 3 days before or 14 days after inoculation via the skin, blocked the early accumulation of PrPSc and TSE infectivity within the draining lymph node. Furthermore, in the temporary absence of FDCs before inoculation, disease susceptibility was reduced and survival time significantly extended. Treatment with LTβR‐Ig 14 days after TSE inoculation also significantly extended the disease incubation period. However, treatment 42 days after inoculation did not affect disease susceptibility or survival time, suggesting that the infection may have already have spread to the nervous system. Together these data show that FDCs are essential for the accumulation of PrPSc and infectivity within lymphoid tissues and subsequent neuroinvasion following TSE exposure via the skin.
Human monocyte isolation methods influence cytokine production from in vitro generated dendritic cells
Authors: Elkord Eyad , Williams Paul E. , Kynaston Howard , Rowbottom Anthony W. 
Published: January 2005

SummaryThere is growing interest in the in vitro generation of dendritic cells (DC) from peripheral blood monocytes, but the effect of the method chosen to isolate CD14+ monocytes for subsequent DC generation is poorly documented. The method used to isolate monocytes may have an impact on the subsequent function of DC by affecting their ability to express costimulatory molecules (CD80/86), maturation marker (CD83) and/or to produce important immunomodulatory cytokines. In this study, we show that the positive selection of monocytes by anti‐CD14‐coated microbeads inhibits the lipopolysaccharide (LPS)‐induced production of interleukin (IL)‐12, IL‐10 and tumour necrosis factor‐α (TNF‐α) from human DC. However, when DC were grown from monocytes isolated by plastic adherence, LPS induced the production of much higher levels of these cytokines. DC derived from adherence‐isolated monocytes induced the development of potent cytotoxic T lymphocytes of the Tc1 subset specific for influenza matrix protein, as confirmed by interferon‐γ (IFN‐γ) enzyme‐linked immunosorbent spot‐forming cell assay (ELISPOT), cytotoxicity assay, major histocompatibility complex (MHC)–peptide tetrameric complexes and T helper 1/T helper 2 (Th1/Th2) cytokine production assays.
Tick saliva inhibits differentiation, maturation and function of murine bone‐marrow‐derived dendritic cells
Authors: Cavassani Karen A. , Aliberti Júlio C. , Dias Alexandra R. V. , Silva João S. , Ferreira Beatriz R. 
Published: January 2005

SummaryHaematophagous arthropod vectors such as mosquitoes, tsetse flies, sandflies and ticks have evolved salivary immunomodulatory factors that prevent the vertebrate host from rejecting them meanwhile enhancing pathogen transmission. As dendritic cells (DC) play a major role in host immune responses, we studied the effects of Rhipicephalus sanguineus tick saliva on DC differentiation and maturation. Flow cytometry analysis revealed that the addition of saliva to bone marrow cells inhibits the differentiation of DC and decreased the population of differentiated immature DC, increasing the levels of major histocompatibility complex (MHC) class II while not altering the expression of costimulatory (CD40, CD80 and CD86) and adhesion (CD54) molecules. Furthermore, maturation of DC stimulated by lipopolysaccharide (LPS) in the presence of saliva resulted in a lower expression of costimulatory molecules, but did not alter the up‐regulation of MHC class II and CD54. The lipopolysaccharide (LPS)‐matured DC cultured with saliva also presented reduced production of interleukin‐12, whereas interleukin‐10 production was unaltered. Assessment of the function of DC cultured with tick saliva revealed them to be poor stimulators of cytokine production by antigen‐specific T cells. Our data indicate a novel modulatory role for the saliva of arthropod vectors at an initial step of the immune response through the inhibition of differentiation and maturation of DC into functional antigen‐presenting cells.
Mucosal delivery of CpG oligodeoxynucleotides expands functional dendritic cells and macrophages in the vagina
Authors: Sajic Dusan , Patrick Amy J. , Rosenthal Kenneth L. 
Published: January 2005

SummaryAntigen‐presenting cells (APC) are specialized sentinel cells that sense pathogens within tissues and then activate appropriate immune effector cells in lymphoid organs. Recent evidence, however, suggests that APC can also induce effector cells in non‐lymphoid organs. The purpose of this study was to determine the effect of intravaginal (IVAG) delivery of CpG‐oligodeoxynucleotide (ODN) on expansion of resident genital APC. Our results show that delivery of CpG‐ODN to the murine genital tract induced a rapid and significant, but transient expansion of genital APC in situ. As early as 12 hr post CpG‐ODN delivery, we observed an enhanced level of F4/80+ major histocompatibility complex (MHC) class II‐negative macrophages in the genital tissue. This was followed by increased levels of F4/80/MHC class II double‐positive cells, as well as MHC class II, CD11c and CD86 triple‐positive dendritic cells (DC) at 48 hr. Expanded APC levels at 48 hr post CpG‐ODN resulted in increased ability of genital cells to induce an allogenic mixed leucocyte reaction. By 72 hr after CpG‐ODN treatment, APC levels were not distinguishable from naïve levels. Therefore, these results clearly show that administration of CpG‐ODN to the genital tract induced a marked but transient enhancement of APC within the genital tissue, and that these APC appear to possess functional capacity. Furthermore, these results indicate that IVAG–CpG‐ODN may be an important factor for the enhancement of local antigen presentation in the genital tract through increased DC numbers.
Major histocompatibility class II molecules prevent destructive processing of exogenous peptides at the cell surface of macrophages for presentation to CD4 T cells
Authors: Von Delwig Alexei , Musson Julie A. , Gray Joe , Mckie Norman , Robinson John H. 
Published: January 2005

SummaryWe studied factors affecting major histocompatibility complex class II (MHC‐II)‐restricted presentation of exogenous peptides at the surface of macrophages. We have previously shown that peptide presentation is modulated by surface‐associated proteolytic enzymes, and in this report the role of the binding of MHC‐II molecules in preventing proteolysis of exogenous synthetic peptides was addressed. Two peptides containing CD4 T‐cell epitopes were incubated with fixed macrophages expressing binding and non‐binding MHC‐II, and supernatants were analysed by high‐performance liquid chromatography and mass spectrometry to monitor peptide degradation. The proportion of full‐length peptides that were degraded and the number of peptide fragments increased when non‐binding macrophages were used, leading to reduction in peptide presentation. When MHC‐II molecules expressed on the surface of fixed macrophages were blocked with monoclonal antibody and incubated with peptides and the supernatants were transferred to fixed macrophages, a significant reduction in peptide presentation was observed. Peptide presentation was up‐regulated at pH 5·5 compared to neutral pH, and the latter was found to be the pH optimum of the proteolytic activity of the surface enzymes involved in the degradation of exogenous peptides and proteins. The data suggest that MHC‐II alleles that bind peptides protect them from degradation at the antigen‐presenting cell surface for presentation to CD4 T cells and we argue that this mechanism could be particularly pronounced at sites of inflammation.