bluuebunny/crossref_metadata_2025_split huggingface dataset:
Familial thrombocytosis caused by the novel germ‐line mutation p.Pro106Leu in the MPL gene
Authors: El‐Harith El‐Harith Abdelghaffar , Roesl Cornelia , Ballmaier Matthias , Germeshausen Manuela , Frye‐Boukhriss Hildegard , Von Neuhoff Nils , Becker Christian , Nürnberg Gudrun , Nürnberg Peter , Ahmed Mirghani Ali Mohamed , Hübener Jeannette , Schmidtke Jörg , Welte Karl , Stuhrmann Manfred 
Published: November 2008

SummaryFamilial thrombosis (FT) has been described as a rare autosomal‐dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3·3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0·001, Fisher’s exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal‐recessive with possible mild heterozygote manifestation rather than autosomal‐dominant with high penetrance as usually seen in FT.
Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring‐sideroblasts
Authors: Ramirez Jean‐Marie , Schaad Olivier , Durual Stephane , Cossali Dominique , Docquier Mylène , Beris Photis , Descombes Patrick , Matthes Thomas 
Published: November 2008

SummaryThe disturbed erythropoiesis in patients with refractory anaemia with ring‐sideroblasts (RARS) is characterized by intramedullary apoptosis of erythroid precursors and increased iron accumulation in mitochondria. To gain insight into these pathophysiological mechanisms we compared the gene expression profile (GEP) of erythroid precursors from RARS patients to the GEP of normal erythroid precursors. Three hundred sixty four probe sets were up‐, and 253 probe sets downregulated in RARS cells. Interestingly, Growth Differentiation factor 15 (GDF15), a cytokine from the TGFβ family, was dramatically upregulated in all RARS patients. Measurement of GDF15 in the sera from twenty RARS patients confirmed this finding by showing significantly, 7·2‐fold, increased protein levels (3254 ± 1400 ng/ml vs. 451 ± 87 ng/ml in normals). In vitro studies demonstrated erythroid‐specific production of GDF15 and dependence on erythropoietin. Induction of apoptosis by arsenic trioxide, a drug which acts via reduction of the mitochondrial membrane potential, also stimulated GDF15 production. Downregulation of endogenous GDF15 production in erythoblasts by specific siRNA led to diminished erythroid differentiation. Taken together, our findings demonstrate a new role for GDF15 in normal erythropoiesis as well as in the ineffective erythropoiesis of RARS patients.
Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia
Authors: Scheinberg Phillip , Wu Colin O. , Nunez Olga , Young Neal S. 
Published: November 2008

SummaryHorse anti‐thymocyte globulin (h‐ATG) and ciclosporin are the initial therapy for most patients with severe aplastic anaemia (SAA), but there is no practical and reliable method to predict response to this treatment. To determine whether pretreatment blood counts discriminate patients with SAA who have a higher likelihood of haematological response at 6 months to immunosuppressive therapy (IST), we conducted a single institution retrospective analysis on 316 SAA patients treated with h‐ATG‐based IST from 1989 to 2005. In multivariate analysis, younger age, higher baseline absolute reticulocyte count (ARC), and absolute lymphocyte count (ALC) were highly predictive of response at 6 months. Patients with baseline ARC ≥ 25 × 109/l and ALC ≥ 1 × 109/l had a much greater probability of response at 6 months following IST compared to those with lower ARC and ALC (83% vs. 41%, respectively; P < 0·001). This higher likelihood of response translated to greater rate of 5‐year survival in patients in the high ARC/ALC group (92%) compared to those with a low ARC/ALC (53%). In the era of IST, the baseline ARC and ALC together serve as a simple predictor of response following IST, which should guide in risk stratification among patients with SAA.
The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study
Authors: Lindqvist Pelle G. , Epstein Elisabeth , Olsson Håkan 
Published: November 2008

SummaryThere has been a great advance in our knowledge of the role that thrombophilic factors play in the risk of venous thromboembolic events (VTE). However, the effect of lifestyle factors on VTE has been inadequately explored in large scale studies of women. This cohort study comprised one thousand native Swedish women for each age year between 25 and 64 inclusive (total = 40 000) drawn from the South Swedish population registry for 1990 (n = 40 000), who were followed for a mean of eleven years. Seventy‐four percent completed a questionnaire at the inception of the study (n = 29 518) and 24 098 women responded to a follow‐up inquiry between the years 2000–2002. The main outcome was the relationship between VTE and physical exercise, smoking habits, and alcohol consumption. Moderate drinkers of alcohol (10–15 g/d) and women engaged in strenuous exercise were at half the risk of VTE compared to those who consumed little or no alcohol or lived a sedentary life. Heavy smoking was associated with a 30% increased risk of VTE. Lifestyle factors have a major impact on the risk of VTE. Women non‐smokers who were physically active and who consumed alcohol in moderation were at a lower risk of VTE.
Clinical and laboratory phenotypes associated with the aspirin‐like defect: a study in 17 unrelated families
Authors: Rolf Nina , Knoefler Ralf , Bugert Peter , Gehrisch Siegmund , Siegert Gabriele , Kuhlisch Eberhard , Suttorp Meinolf 
Published: November 2008

SummaryAspirin‐like defect (ALD) is a rare, mostly autosomal dominant inherited dysfunction of the intraplatelet arachidonic acid (AA) pathway leading to impaired thromboxane A2 signalling. We aimed to establish diagnostic criteria for ALD diagnosis and present clinical and laboratory phenotypes of 52 individuals from 17 unrelated families. Platelet in vitro function was determined on the basis of platelet aggregation response (PAR) to AA, adenosine diphosphate, collagen and ristocetin as well as PFA‐100® closure times (CT). Using impaired PAR to AA (≤10%) as the mandatory diagnostic criterion, ALD could be confirmed in 17 patients. Subsequently, family members were investigated and among 35 individuals an additional 13 ALD patients as well as 4 individuals with mild ALD (PAR to AA: 19–32%) were identified. At least one bleeding symptom was reported by 25 (74%) ALD patients and prolonged CT was detected in 24 (71%) of the cases, both significantly correlated with impaired PAR to AA (P = 0·001 and P = 0·002, respectively). An estimated 0·6% prevalence was determined for ALD in our paediatric patients with suspected coagulation disorders. Due to the mild bleeding symptoms, ALD is probably underdiagnosed. If ALD is suspected, PAR to AA is suitable for the identification of individuals at risk of increased haemorrhage.
Expression and function of toll like receptors in chronic lymphocytic leukaemia cells
Authors: Muzio Marta , Scielzo Cristina , Bertilaccio Maria T. S. , Frenquelli Michela , Ghia Paolo , Caligaris‐Cappio Federico 
Published: November 2008

SummaryMature B‐cells can recognize microbial antigens via B‐cell‐receptor (BCR) in a specific way and via Toll‐like receptors (TLR) in a costimulatory manner. A wealth of information is gathering on the possible role of antigenic stimulation in the natural history of Chronic Lymphocytic Leukaemia (CLL). However little is known regarding the repertoire and function of TLR in CLL cells. The TLR family includes 10 different transmembrane proteins devoted to recognize specific pathogen‐associated molecular patterns and to alarm immunocompetent cells to trigger an immune response. Here, we studied fresh leukaemic cells for the expression pattern of TLR1 to TLR10, NOD1, NOD2 and SIGIRR (also known as TIR8). CLL cells were found to express several pattern recognition receptors including TLR1, TLR2, TLR6, TLR10, NOD1 and NOD2. The specific TLR expressed by CLL cells were functional. Leukaemic cells, upon stimulation with TLR1/2/6 ligands, such as bacterial lipopeptides, activated the nuclear factor‐κB signalling pathway, expressed CD86 and CD25 activation molecules, and were protected from spontaneous apoptosis. These findings further support the hypothesis that CLL cells resemble antigen‐activated B‐cells and suggest a potential role of TLR in modulating CLL cell response in the context of specific antigen recognition.
Haemoglobin F modulation in childhood sickle cell disease
Authors: Trompeter Sara , Roberts Irene 
Published: November 2008

SummaryWhile supportive care remains the best option for most well children with sickle cell disease (SCD), increasing awareness of early signs of chronic organ damage in childhood has focused attention on therapy which modulates the natural history of the disease. Since cure by stem cell transplantation is only feasible for a minority and gene therapy remains developmental, pharmacological modification by Haemoglobin F (HbF)‐inducers, is the most widely used approach in SCD. Currently, the only HbF modulator with a clear place in the management of childhood SCD is hydroxycarbamide for which the main indications are frequent painful crises and recurrent acute chest syndrome. In the majority of SCD children treated with hydroxycarbamide there is clear evidence of clinical benefit and the drug is well tolerated. The main disadvantages are the need for frequent monitoring and uncertainity about long‐term risks of carcinogenicity and impaired fertility, although these risks appear to be very low. The role of hydroxycarbamide in sickle‐associated central nervous system disease remains to be established. Decitabine and butyrate derivatives show some promise although robust data in children with SCD are lacking. A number of other drugs are currently under investigation for their effects on HbF production including thalidomide and lenolidamide.
Amplification and invasiveness of epithelial progenitors during gastric carcinogenesis in trefoil factor 1 knockout mice
Authors: Karam S. M. , Tomasetto C. , Rio M.‐C. 
Published: November 2008

Abstract.  Objective: It is not known whether or not epithelial progenitors of the pyloric antrum are involved in gastric carcinogenesis. Normally, these progenitors give rise to two main cell lineages: pit and gland mucous cells. This study was designed to examine the changes that occur in pyloric antral mucous cell lineages and their progenitors during development of gastric adenoma and carcinoma in trefoil factor 1 (TFF1) knockout mice. Materials and methods: Pyloric antral mucosal tissues of TFF1 knockout mice at ages from 3 days to 17 months were processed for histochemical analysis using Ulex europaeus and Grifforia simplifolica lectins as markers for pit and gland mucous cells, respectively. The dividing epithelial progenitors were identified by using immunohistochemical and electron microscopy techniques. Results: TFF1 loss was associated with amplification of both mucus‐secreting pit and gland cells. Both lectins examined bound not only to mature mucous cells, but also to most of epithelial progenitors which gradually amplified with age and frequently were seen in mitosis. Analysis of 12‐ to 17‐month‐old TFF1‐deficient stomachs revealed occasional groups of poorly differentiated mucosal cells with features similar to those of epithelial progenitors (or stem cells), in the basal portion of the antral mucosa. These cells eventually invaded the muscularis mucosa while maintaining some capacity to differentiate. Conclusion: This study shows that the progenitors of pit and gland mucous cells contribute to gastric carcinogenesis in the pyloric antrum of TFF1 knockout mice, strongly supporting the concept of stem cell origin of cancer.
Anti‐allergic effects of PG102, a water‐soluble extract prepared from Actinidia arguta, in a murine ovalbumin‐induced asthma model
Authors: Kim D. , Kim S. H. , Park E‐J. , Kang C‐Y. , Cho S‐H. , Kim S. 
Published: November 2008

SummaryBackground
Asthma is a chronic inflammatory disease of the lung and its incidence has been increasing around the world. We previously reported that oral administration of a water‐soluble extract prepared from Actinidia arguta, code‐named PG102, could modulate the level of Th1 and Th2 cytokines and suppress the production of immunoglobulin E (IgE) in the ovalbumin (OVA)‐immunized murine model as well as in the in vitro cell culture system, and furthermore could significantly improve dermatitis conditions in the NC/Nga murine model. These data suggested that PG102 might have therapeutic effects in a broad range of allergic diseases.Objective
To assess the possible anti‐allergic effects of PG102 in the OVA‐induced murine asthma model.Methods
The quality of PG102 was standardized, using its effects on the production of IgE, IL‐5, and IL‐13, in in vitro cell culture systems. To test effects on asthma, BALB/c mice were orally administrated with PG102, followed by OVA sensitization and challenge to induce asthmatic symptoms. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid, serum, and lung tissue were analysed by using various methods.Results
PG102 could decrease the level of IgE, IL‐5, and IL‐13 in in vitro cell culture systems with IC50 being 1.12–1.43 mg/mL. PG102 could ameliorate asthmatic symptoms, including AHR and eosinophilia in the lungs. Such improvement of asthmatic symptoms by PG102 was accompanied by the down‐regulation of IL‐5 and IgE. In PG102‐treated mice, high level expression of heme oxygenase‐1, a potent anti‐inflammatory enzyme, was observed in alveolar inflammatory cells, while the mRNA levels of foxp3, TGF‐β1, and IL‐10, important markers for regulatory T cells, were also up‐regulated in the lung tissue.Conclusions
PG102 may have potential as a safe and effective reagent for the prevention or treatment of asthma.
Antibiotic use in the first year of life and risk of atopic disease in early childhood
Authors: Kusel M. M. H. , De Klerk N. , Holt P. G. , Sly P. D. 
Published: November 2008

SummaryBackground
Reduced post‐natal microbial stimulation resulting from improvements in public health measures, smaller family size, and through increased antibiotic use has been postulated to account for the increasing prevalence of atopic diseases seen predominantly in developed countries.Objective
To investigate use of antibiotics in the first year of life and subsequent development of atopic disease in early childhood.Methods
A prospective birth cohort of 198 children at high atopic risk was recruited prenatally and followed for 5 years. Illnesses and antibiotic use were ascertained through daily diaries, and diagnoses of asthma and hayfever were collected by questionnaire interviews. The children were examined regularly for eczema, and atopic status was defined by skin prick tests and serum total IgE. The effect of antibiotic use on subsequent atopic disease was examined using logistic regression with propensity score adjustment.Results
54.0% (107/198) of children received at least one course of antibiotics, mainly for acute respiratory illnesses (ARI). Thirty‐three percent (329/984) of the ARI involved the lower respiratory tract (LRI). Twenty‐three percent (222/984) of ARI were treated with antibiotics, with LRI significantly more likely to receive antibiotics. Antibiotic use was associated with asthma (unadjusted odds ratio 2.3; 95% confidence interval 1.2–4.5; P=0.01) but this association was reduced after propensity score adjustment. No associations were found between antibiotic use and eczema, current wheeze, current asthma, atopic asthma, allergic rhinoconjunctivitis or atopy.Conclusion
Although this was a small study, systematic and careful monitoring of ARI, antibiotic use, and asthma and atopic diseases did not indicate that receipt of antibiotics early in life led to subsequent asthma or atopy at 5 years.
5,7-dihydroxy-3,4,6-trimethoxyflavone inhibits the inflammatory effects induced byBacteroides fragilisenterotoxin via dissociating the complex of heat shock protein 90 and IκBα and IκB kinase-γ in intestinal epithelial cell culture
Authors: Kim J M , Lee D H , Kim J S , Lee J Y , Park H-G , Kim Y-J , Oh Y-K , Jung H C , Kim S I 
Published: November 2008

SummaryEnterotoxin produced by enterotoxigenic Bacteroides fragilis (BFT) has been associated with mucosal inflammation and diarrhoeal diseases. In this study, the anti-inflammatory molecular mechanism of 5,7-dihydroxy-3,4,6-trimethoxyflavone (eupatilin) was characterized in an HT-29 intestinal epithelial cell line stimulated with BFT. Pre-treatment of HT-29 cells with eupatilin decreased the production significantly of both interleukin (IL)-8 and prostaglandin E2 induced by BFT in a dose-dependent manner. BFT-activated nuclear factor-kappaB (NF-κB) signals in HT-29 cells and pretreatment with eupatilin suppressed NF-κB activation that resulted in the significant inhibition of IL-8 and cyclo-oxygenase-2 expression. BFT-induced phosphorylation of both IκBα and IκB kinase (IKK) signals was prevented in eupatilin-pretreated HT-29 cells. Transfection of siRNA for IKK-α and IKK-β decreased the production of IL-8 and prostaglandin E2; however, the transfection of IKK-β siRNA showed a more significant reduction of BFT-induced IκBα phosphorylation compared with that of IKK-α siRNA. In addition, herbimycin A, a specific inhibitor of heat shock protein 90 (Hsp90), decreased the BFT-induced activation of IKK and NF-κB, suggesting that Hsp90 is associated with a pathway of IKK-NF-κB-IL-8/cyclo-oxygenase-2 gene signalling. Furthermore, eupatilin dissociated the complex between Hsp90 and IKK-γ in BFT-stimulated HT-29 cells. These results suggest that eupatilin can suppress the NF-κB signalling pathway by targeting the Hsp90-IKK-γ complex in intestinal epithelial cells and may attenuate BFT-induced inflammatory responses.
Mutations in the ABCC8 (SUR1 subunit of the KATP channel) gene are associated with a variable clinical phenotype
Authors: Klupa Tomasz , Kowalska Irina , Wyka Krystyna , Skupien Jan , Patch Ann‐Marie , Flanagan Sarah E. , Noczynska Anna , Arciszewska Malgorzata , Ellard Sian , Hattersley Andrew T. , Sieradzki Jacek , Mlynarski Wojciech , Malecki Maciej T. 
Published: November 2008

SummaryObjective  Mutations in the ABCC8 gene encoding the SUR1 subunits of the β‐cell K‐ATP channel cause neonatal diabetes (ND) mellitus. We aimed to determine the contribution of ABCC8 gene to ND in Poland, to describe the clinical phenotype associated with its mutations and to examine potential modifying factors.Patients  The Nationwide Registry of ND in Poland includes patients diagnosed before 6 months of age. In total 16 Kir6·2 negative patients with ND, 14 permanent and 2 relapsed transient, were examined.Measurements  ABCC8 gene mutations were detected by direct sequencing. Mutation carriers’ characteristics included clinical data and biochemical parameters. In addition, we performed the hyperinsulinaemic euglycaemic clamp and tested for islet‐specific antibodies in diabetic subjects.Results  We identified two probands with permanent ND (one heterozygous F132V mutation carrier and one compound heterozygote with N23H and R826W mutations) and two others with relapsed transient ND (heterozygotes for R826W and V86A substitutions, respectively). One subject, a heterozygous relative with the R826W mutation, had adult onset diabetes. There were striking differences in the clinical picture of the mutation carriers as the carrier of two mutations, N23H and R826W, was controlled on diet alone with HbA1c of 7·3%, whereas the F132V mutation carrier was on 0·66 IU/kg/day of insulin with HbA1c of 11·7%. The C‐peptide level varied from 0·1 ng/ml (F132V) to 0·75 ng/ml (V86A). We also observed a variable insulin resistance, from moderate (M = 5·5 and 5·6 mg/kg/min, respectively, in the two R826W mutation carriers) to severe (M = 2·6 mg/kg/min in the F132V mutation carrier). We were able to transfer two patients off insulin to sulphonylurea (SU) and to reduce insulin dose in one other patient. Interestingly, there was no response to SU in the most insulin resistant F132V mutation carrier despite high dose of glibenclamide. All examined auto‐antibodies were present in one of the subjects, the V86A mutation carrier, although this did not seem to influence the clinical picture, as we were able to transfer this girl off insulin.Conclusion  Mutations in SUR1 are the cause of about 15% of Kir6·2 negative permanent ND in Poland. The clinical phenotype of SUR1 diabetic mutation carriers is heterogeneous and it appears to be modified by variable sensitivity to insulin.
Components of the renin‐angiotensin‐aldosterone system in plasma and ascites in hepatic cirrhosis
Authors: Kuiper J. J. , Boomsma F. , Van Buren H. , De Man R. , Danser A. H. J. , Van Den Meiracker A. H. 
Published: November 2008

ABSTRACTBackground  Decompensated liver cirrhosis is characterized by activation of the renin‐angiotensin‐aldosterone system (RAAS). We investigated whether compartmentalization of these components occurs in ascitic fluid.Methods  In 26 patients with cirrhosis RAAS components and albumin were quantified in simultaneously obtained plasma and ascitic fluid samples. Renin degradation was determined in vitro in plasma and ascites.Results  Plasma angiotensinogen was below normal reference values in all but two patients and correlated inversely with plasma renin (r = –0·73, P < 0·001). Plasma renin activity was elevated in most subjects. The plasma and ascites concentrations of renin, prorenin, angiotensinogen and aldosterone were closely (P < 0·001) correlated. Expressed as a percentage of plasma levels, the angiotensinogen level (18 ± 11%) was slightly lower than the albumin level (23 ± 8%), whereas the aldosterone level (43 ± 18%) was considerably higher (P < 0·0001). For renin and prorenin these percentages were much lower (P < 0·0001), despite the fact that their molecular weight is lower than that of albumin and angiotensinogen. This was not due to a more rapid degradation of renin in ascites fluid, since the in‐vitro degradation rates of renin in plasma and ascitic fluid were identical.Conclusion  In hepatic cirrhosis ascites can be regarded as an ultrafiltrate of plasma RAAS components. Since differences in molecular weight or metabolic rate cannot explain the low ascites‐to‐plasma ratio of renin and prorenin, either their transcapillary transport is impaired and/or they selectively bind to (pro)renin binding sites.