bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of gene expression following norepinephrine stimulation in the rat pineal gland using DNA microarray technique
Authors: Fukuhara Chiaki , Dirden James C. , Tosini Gianluca
Published: August 2003

Abstract: Several studies have demonstrated that norepinephrine (NE) is the critical neurotransmitter for the regulation of gene expression in the pineal gland. We studied the acute effect of NE stimulation in cultured rat pineal glands using Affymetrix rat genome microarray GeneChip probe arrays. Our data demonstrate that NE stimulation affects regulation of several genes; 44 and 29 genes were up‐ or down‐regulated more than 2.5‐fold, respectively. As shown in previous studies, arylalkylamine N‐acetyltransferase, cyclic AMP responsive element modulator, jun‐B and c‐fos mRNA levels were increased by NE stimulation. Genes that were not previously reported and increased by NE stimulation in the pineal gland were protein tyrosine phosphatase, nuclear receptors, and activity and neurotransmitter‐induced early genes. Unlike up‐regulated genes, most of the down‐regulated genes were not reported previously. Genes encoding enzymes involved in metabolism and structural proteins were decreased following NE stimulation. Identification of genes affected by NE stimulation would provide valuable information to understanding pineal biology fully.
Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication
Authors: Dzie˛giel Piotr , Murawska‐Ciałowicz Eugenia , Jethon Zbigniew , Januszewska Lidia , Podhorska‐Okołów Marzena , Surowiak Paweł , Zawadzki Marcin , Rabczyński Jerzy , Zabel Maciej
Published: August 2003

Abstract: The study aimed at determining the effect of melatonin on the activity of protective antioxidative enzymes in the heart and of lipid peroxidation products in the course of intoxication with doxorubicin (DOX). The rats were categorized into four groups, receiving: 0.9% NaCl i.p. (NaCl control); melatonin [20 mg/kg body weight (b.w.)] s.c. (control Mel); DOX (2.5 mg/kg b.w.) i.p.; melatonin plus DOX in doses as above. All the substances were administered once in a week for four consecutive weeks. Homogenates of heart tissue were examined for activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), levels of reduced glutathione (GSH) and of lipid peroxidation indices (MDA + 4‐HDA). Administration of melatonin alone did not induce alterations in levels of MDA + 4‐HDA, GSH, or in activity of GPx, SOD or CAT, as compared to the group receiving 0.9% NaCl. GSH levels decreased following DOX but remained at normal levels following DOX and melatonin. The level of MDA + 4‐HDA increased following DOX, as compared with the control, a change prevented by the combination of DOX+melatonin. Activities of GPx, SOD and CAT were higher in groups receiving DOX and/or DOX plus melatonin than in control groups. Activity of CAT and the level of GSH in the group receiving DOX plus melatonin were significantly higher than in the group intoxicated with DOX alone. The obtained results demonstrate that, when given in parallel with DOX, melatonin protects cardiomyocytes from damaging effects of the cytostatic drug (reflected by the levels of MDA + 4‐HDA). The protective effect resulted, in part from the augmented levels of GSH and from stimulation of CAT activity by melatonin in cardiomyocytes subjected to the action of DOX.
Protective effects of chronic melatonin treatment against renal injury in streptozotocin‐induced diabetic rats
Authors: Cam Meryem , Yavuz Özlem , Guven Aysel , Ercan Feriha , Bukan Neslihan , Üstündag Nil
Published: August 2003

Abstract: The aim of this study was to investigate the effects of melatonin as an antioxidant, on prevention and treatment of streptozotocin (STZ)‐induced diabetic renal injury in rats. Male Wistar rats were divided into four groups: (1) untreated, (2) melatonin‐treated, (3) untreated diabetic (UD), (4) melatonin‐treated diabetic (MD). Experimental diabetes was induced by single dose (60 mg/kg, i.p.) STZ injection. For 3 days prior to administration of STZ, melatonin was injected (200 μg/kg/day, i.p.); these injections were continued until the end of the study (4 weeks). Malondialdehyde (MDA) levels as a marker of lipid peroxidation were significantly increased in the renal homogenates of UD animals and decreased after melatonin administration. The activity of the antioxidative enzyme glutathione peroxidase (GSH‐Px) was significantly reduced in UD rats. Melatonin treatment reversed STZ‐induced reduction of GSH‐Px activity without having an effect on blood glucose. Upon histopathological examination, it was observed that the melatonin treatment prevented the renal morphological damage caused by diabetes. Upon immunohistochemical investigation, glomerular anti‐laminin β1 staining decreased in MD rats. Additionally, no tubular anti‐IGF‐1 staining was observed in melatonin‐treated rats. In conclusion, chronically administered melatonin reduced renal injury in STZ‐induced diabetic rats and thus it may provide a useful therapeutic option in humans to reduce oxidative stress and the associated renal injury in patients with diabetes mellitus.
Pharmacological rationale for the use of somatostatin and analogues in portal hypertension
Authors: Reynaert H. , Geerts A.
Published: August 2003

Somatostatin and its analogue octreotide have been used for two decades to treat oesophageal variceal haemorrhage. The drug was introduced because of its capacity to decrease portal venous pressure without major side effects. In clinical trials assessing the efficacy of somatostatin and long‐acting analogues in arresting variceal haemorrhage, conflicting results have been obtained. Furthermore, in haemodynamic studies evaluating the effects of somatostatin and analogues in patients with cirrhosis, divergent effects were observed. The main reason for these differences is probably related to different affinities of the drugs for different somatostatin receptor subtypes. The effects of somatostatin and analogues are mediated via five different G‐protein coupled receptors (somatostatin receptor subtypes 1–5), which regulate the activity of ion channels (Ca2+, K+, Na+ and Cl–) and enzymes (adenyl cyclase, phospholipase C, phospholipase A2, phosphoinositide 3‐kinase and guanylate cyclase) responsible for the synthesis or degradation of intracellular second messengers including cyclic AMP, inositol 1,4,5‐trisphosphate, diacylglycerol and cyclic GMP. Despite universal use of somatostatin, the cellular and biochemical mechanisms of its effects in portal hypertension are relatively poorly studied and remain incompletely understood. In this review, we summarize relevant signal transduction of somatostatin and analogues, the haemodynamic effects of the drugs and the possible mechanisms by which these effects are mediated.
Nutritional therapy in alcoholic liver disease
Authors: Stickel F. , Hoehn B. , Schuppan D. , Seitz H. K.
Published: August 2003

Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate‐ and protein‐derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched‐chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S‐adenosyl‐l‐methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol‐related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.
Effect of oral tacrolimus (FK 506) on steroid‐refractory moderate/severe ulcerative colitis
Authors: Högenauer C. , Wenzl H. H. , Hinterleitner T. A. , Petritsch W.
Published: August 2003

Background : Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication.

Methods : Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long‐term immunosuppression.

Results : All patients responded within 1–2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side‐effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side‐effects were common.

Conclusion : Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid‐refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side‐effects.
Response to infliximab is related to disease duration in paediatric Crohn's disease
Authors: Lionetti P. , Bronzini F. , Salvestrini C. , Bascietto C. , Canani R. Berni , Dé Angelis G. L. , Guariso G. , Martelossi S. , Papadatou B. , Barabino A.
Published: August 2003

Background : Infliximab is an effective therapy in adult patients with refractory and fistulizing Crohn's disease. Experience in children is still limited.

Aim : To evaluate the experience in 22 children and adolescents treated with infliximab with refractory and/or fistulizing Crohn's disease, and to compare duration of response in children between early Crohn's disease and late Crohn's disease.

Methods : The experience in 22 children and adolescents treated with a total of 73 infusions was evaluated retrospectively. Treatment indication was refractory Crohn's disease in 9/22 patients, fistulizing Crohn's disease in 7/22 patients and both these conditions in 6/22. All patients with refractory Crohn's disease had late Crohn's disease (> 1 year), whereas 6/13 patients with fistulas had early disease (< 1 year).

Results : Mean Paediatric Crohn's Disease Activity Index (PCDAI) decreased from 41.2 to 16.2 at 4 weeks (P < 0.01), and to 15.4 at 18 weeks (P < 0.01). Mean PCDAI at 18 weeks in children with early Crohn's disease and late Crohn's disease was 5.5 and 18.1, respectively (P < 0.05). Complete closure of fistulas was obtained in 5/6 children with early Crohn's disease and in 2/7 children with late Crohn's disease. Immediate adverse reactions were observed in two children.

Conclusions : Infliximab is a highly effective treatment in children and adolescents with both severe refractory or fistulizing Crohn's disease. Children with early Crohn's disease have a higher chance of prolonged response to infliximab than children with late Crohn's disease.
Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine
Authors: Bonaz B. , Boitard J. , Marteau P. , LÉmann M. , Coffin B. , Flourié B. , Belaiche J. , Cadiot G. , Metman E.‐H. , Cortot A. , Colombel J.‐F. ,   Getaid
Published: August 2003

Background:  Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases.

Aims : To evaluate the tolerance and efficacy of TG in patients with Crohn's disease, intolerant or resistant to AZA/MP.

Methods : An open prospective study was made on Crohn's disease patients treated with TG. Intolerance to AZA/MP was defined as a reaction occurring within 1 month after introduction of AZA/MP, including pancreatitis, abdominal pain, fever, arthralgia, myalgia, cutaneous rash, fatigue, alopecia, hepatitis and digestive intolerance. Resistance to AZA/MP was defined as the persistence of activity after at least 3 months of AZA/MP therapy.

Results : Forty‐nine Crohn's disease patients (36 women, 13 men; intolerance: n = 39; resistance: n= 10) were treated with TG (20 mg/day). Clinical pancreatitis did not recur under TG. Five patients (10%) had to stop TG due to intolerant reactions observed 13–21 days after TG was started. No haematological side‐effects were observed under TG. The probability of clinical remission without corticosteroids or infliximab at 6 and 12 months was 46% and 79%, respectively, in the 40 patients with active disease at baseline. The probability of clinical relapse during maintenance TG therapy at 6 and 12 months was 29% and 53%, respectively, in the 28 patients in remission at baseline or who had achieved remission on TG.

Conclusions : TG is a possible alternative treatment in Crohn's disease patients, intolerant (especially for pancreatitis) or resistant to AZA/MP.
Thiopurine S‐methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease
Authors: Gearry R. B. , Barclay M. L. , Burt M. J. , Collett J. A. , Chapman B. A. , Roberts R. L. , Kennedy M. A.
Published: August 2003

Background : Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype.

Aim : To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls).

Methods : Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups.

Results : Fifty‐six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic‐type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1/*3, one had *3/*3, and the rest had the wildtype genotype *1/*1. The patient with genotype *3/*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1/*3 genotype and the rest were *1/*1.

Conclusions : The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations.
High incidence of clopidogrel‐associated gastrointestinal bleeding in patients with previous peptic ulcer disease
Authors: Ng F. H. , Wong S. Y. , Chang C. M. , Chen W. H. , Kng C. , Lanas A. I. , Wong B. C. Y.
Published: August 2003

Background:  In average‐risk patients, the new anti‐platelet agent, clopidogrel, causes less upper gastrointestinal adverse events than aspirin. However, there are no safety data on the use of clopidogrel in high‐risk patients.

Aim:  To evaluate the safety of clopidogrel in patients with peptic ulcer disease in a retrospective cohort longitudinal study.

Methods:  During the period from January 2000 to May 2002, 70 patients who were prescribed clopidogrel (75 mg/day) for a previous history of non‐aspirin‐related peptic ulcer disease or a history of aspirin‐related gastrointestinal complications (dyspepsia or peptic ulcer) were recruited. The occurrence of ulcer complications (bleeding/perforation/obstruction) was the primary end‐point.

Results:  After a median follow‐up of 1 year, nine patients (12%) developed gastrointestinal bleeding and one had a perforated peptic ulcer. Clopidogrel‐associated gastrointestinal bleeding was significantly more common in patients with a history of gastrointestinal bleeding than in those without (22% vs. 0%; P = 0.007; odds ratio, 1.3; 95% confidence interval, 1.1–1.5).

Conclusions:  Clopidogrel is associated with a high incidence of upper gastrointestinal bleeding in high‐risk patients. A previous history of gastrointestinal bleeding appears to be a predictor of adverse gastrointestinal events.
Health‐related quality of life in functional dyspepsia
Authors: El‐Serag H. B. , Talley N. J.
Published: August 2003

Background : We performed a systematic review of the literature to compare the health‐related quality of life (HRQOL) of patients with functional dyspepsia with either healthy controls or those with other diseases.

Methods : Full‐length published manuscripts during 1980–2002 were included if (a) patients had functional dyspepsia, but not uninvestigated dyspepsia; and (b) HRQOL was measured using a validated generic or dyspepsia‐specific instruments, but not global assessment alone.

Results : Twelve studies were reviewed; six fulfilled the selection criteria. None examined HRQOL among samples of the general population. None used dyspepsia‐specific HRQOL instruments. Three studies contained four comparisons of HRQOL between functional dyspepsia patients and controls; two studies examined HRQOL changes in response to therapy. Two studies demonstrated a significant reduction at least in some domains of HRQOL among patients with functional dyspepsia compared to controls, while one study was negative. In general, studies that reported a decline in HRQOL Short Form‐36 (SF‐36) showed that changes in the physical domain were similar to those on mental domain of the SF‐36.

Conclusions : There is some evidence for a decrease in HRQOL in patients with moderate to severe functional dyspepsia who seek care for their symptoms; however, more studies are needed. A therapeutic response in functional dyspepsia‐related pain or discomfort might result in a corresponding improvement in HRQOL.
Essential fatty acid status in paediatric Crohn's disease: relationship with disease activity and nutritional status
Authors: Trebble T. M. , Wootton S. A. , May A. , Erlewyn‐Lajeunesse M. D. S. , Chakraborty A. , Mullee M. A. , Stroud M. A. , Beattie R. M.
Published: August 2003

Background:  Active paediatric Crohn's disease is associated with nutritional deficiencies and altered nutrient intake. The availability of essential fatty acids (linoleic and α‐linolenic acids) or their derivatives (arachidonic and eicosapentaenoic acids) may alter in plasma and cell membrane phospholipid in protein‐energy malnutrition in children and in Crohn's disease in adults.

Aim:  To investigate the relationship of fatty acid phospholipid profiles with disease activity and nutritional status in paediatric Crohn's disease.

Methods:  The fatty acid (proportionate) composition of plasma and erythrocyte phosphatidylcholine was determined in 30 patients (10.3–17.0 years) stratified into active and quiescent Crohn's disease (paediatric Crohn's disease activity index) and high and low body mass (body mass index centile).

Results:  In plasma phosphatidylcholine, active disease activity was associated with a lower level of α‐linolenic acid compared with that in quiescent disease (P < 0.05). A body mass index below the 50th centile was associated with active Crohn's disease, low linoleic and α‐linolenic acids and high arachidonic acid (P < 0.05) in plasma phosphatidylcholine, and low α‐linolenic acid in erythrocyte phosphatidylcholine. These findings could not be explained through differences in habitual dietary fat intake.

Conclusion:  In paediatric Crohn's disease, a low body mass index centile and high disease activity are associated with altered profiles of essential fatty acids and their derivatives, which may reflect altered metabolic demand.
Hydrostatic balloon dilatation of Crohn's strictures
Authors: Sabaté J.‐M. , Villarejo J. , Bouhnik Y. , Allez M. , Gornet J.‐M. , Vahedi K. , Modigliani R. , Lémann M.
Published: August 2003

Aim : To evaluate the safety and long‐term efficacy of per‐endoscopic hydrostatic balloon dilatation in a retrospective series of patients with Crohn's disease.

Methods : Thirty‐eight patients had balloon dilatation for intestinal symptomatic strictures which were located as follows: ileo‐colonic (26) or colocolic (2) anastomosis, colon (4), ileum (3), proximal jejunum (1) and ileo‐caecal valve (5); three patients had two strictures accessible to dilatation. The mean length of the strictures was 2.1 cm (s.d., 0.3 cm).

Results: Thirty‐two of the 38 patients were successfully dilated and followed for a median of 22.8 months (0.2–103 months) until surgery or last news. The probabilities of obstructive symptom recurrence were 36% at 1 year and 60% at 5 years. Twelve patients had a second dilatation, and three a third. The probabilities of surgery for stricture were 26% at 1 year and 43% at 5 years. Results were not influenced by age, sex, activity of the disease, passage of the stricture by the colonoscope or concomitant medical therapies. Complications occurred in 9.4% of the 53 dilatation sessions, with only one perforation.

Conclusions : Hydrostatic balloon dilatation is effective for Crohn's symptomatic strictures, and can avoid or postpone surgery, with an acceptable rate of complications.
Shallow‐marine sequences as the building blocks of stratigraphy: insights from numerical modelling
Authors: Storms Joep E. A. , Swift Donald J. P.
Published: August 2003

Two types of depositional sequences can be defined within the sequence stratigraphic framework: the parasequence and the high‐frequency sequence. Both sequences consist of stacked regressive and transgressive deposits. However, a parasequence forms under conditions of overall sea‐level rise, whereas a high‐frequency sequence forms as the sea level oscillates which results in typical forced regressive deposits during sea‐level fall. Both depositional sequences may develop over comparable temporal (10–100 kyr) and spatial (1–20 km wide and 1–40 m thick) scales. Numerical modelling is used to compare the architecture, preservation potential, internal volumes, bounding surfaces, condensed and expanded sections and facies assemblages of parasequences and high‐frequency sequences. Deposits originating from transgression are less pronounced than their regressive counterparts and consist of either preserved backbarrier deposits or shelf deposits. Shoreface deposits are not preserved during transgression. The second half of the paper evaluates in detail the preservation potential of backbarrier deposits and proposes a mechanism that explains the occurrence of both continuous and discontinuous barrier retreat in terms of varying rates of sea‐level rise and sediment supply. The key to this mechanism is the maximum washover capacity, which plays a part in both barrier shoreline retreat and backbarrier‐lagoonal shoreline retreat. If these two shorelines are not balanced, then the retreat of the coastal system as a whole is discontinuous and in time barrier overstep may take place.
Provenance patterns in a neotectonic basin: Pliocene and Quaternary sediment supply to the South Caspian
Authors: Morton Andrew , Allen Mark , Simmons Mike , Spathopoulos Fivos , Still John , Hinds David , Ismail‐Zadeh Arif , Kroonenberg Salomon
Published: August 2003

The South Caspian Basin has accumulated a sedimentary succession ∼20 km thick. Roughly half of this was deposited in the last 5.5 Ma, mainly in the largely lower Pliocene, fluvio‐lacustrine Productive Series, which is also the principal hydrocarbon reservoir succession in the basin. Heavy mineral data identify different sediment sources for both Productive Series sandstones and modern river sands. Lesser Caucasus sediment was supplied by the Palaeo‐Kura into the western part of the South Caspian Basin. Productive Series strata in the north of the basin were supplied by the Palaeo‐Volga, and represent a mixture of sediment from the Greater Caucasus and Russian Platform/Urals. Greater Caucasus sand input to the Palaeo‐Volga increased at the start of deposition of the Pereriva Suite, which is an important reservoir subunit of the Productive Series. We interpret this provenance shift as indicating enhanced uplift and exhumation of the Greater Caucasus within the Pliocene, during regional re‐organization of the Arabia–Eurasia collision, although late Cenozoic climate changes may have played a role.
Effects of biogenic silica on sediment compaction and slope stability on the Pacific margin of the Antarctic Peninsula
Authors: Volpi V. , Camerlenghi A. , Hillenbrand C.‐D. , Rebesco M. , Ivaldi R.
Published: August 2003

Analysis of physical properties measured on cores and on discrete samples collected by the Ocean Drilling Programme (ODP) Leg 178 on the Pacific margin of the Antarctic Peninsula reveals anomalous down‐hole curves of porosity, density, water content, and P‐wave velocity. These indicate an overall trend of increasing porosity with depth and suggest that the drifts are mostly undercompacted. In one of the two boreholes analysed, a sharp decrease in porosity, matching increasing bulk sediment density and increasing compressional velocity occurs towards the base of the hole, which corresponds to a bottom‐simulating reflector in the seismic section. Analysis of seismic reflection, down‐hole logging, geotechnical and mineralogical data from two drilling sites indicates that the observed anomalous consolidation trends are a consequence of the presence of biogenic silica (diatom and radiolarian skeletons) even with a small to moderate amount. Above the bottom‐simulating reflector, intergranular contacts among whole or broken siliceous microfossils prevent normal sediment consolidation. Diagenetic alteration of biogenic opal‐A to opal‐CT causes a dramatic reduction of intra‐ and interskeletal porosity allowing sediments to consolidate at depth. This results in overpressuring and a decrease in the effective stress. Excess fluids are expelled towards the sediment surface through near vertical, small throw normal faults extending from the diagenetic front to the seafloor and affecting the stability of the submarine slope in the form of gravitational creep along a weakened surface.

This work shows how physical properties of shallow fine‐grained marine sediments can be analysed as basin‐wide indicators of biogenic silica abundance. The diagenetic alteration of siliceous microfossils is a possible cause of slope instability along world continental margins where bottom‐simulating reflectors related to silica diagenesis are present at a regional scale.
Modelling detrital cooling‐age populations: insights from two Himalayan catchments
Authors: Brewer I. D. , Burbank D. W. , Hodges K. V.
Published: August 2003

The distribution of detrital mineral cooling ages in river sediment provides a proxy record for the erosional history of mountain ranges. We have developed a numerical model that predicts detrital mineral age distributions for individual catchments in which particle paths move vertically toward the surface. Despite a restrictive set of assumptions, the model permits theoretical exploration of the effects of thermal structure, erosion rate, and topography on cooling ages. Hypsometry of the source‐area catchment is shown to exert a fundamental control on the frequency distribution of bedrock and detrital ages. We illustrate this approach by generating synthetic 40Ar/39Ar muscovite age distributions for two catchments with contrasting erosion rates in central Nepal and then by comparing actual measured cooling‐age distributions with the synthetic ones. Monte Carlo sampling is used to assess the mismatch between observed and synthetic age distributions and to explore the dependence of that mismatch on the complexity of the synthetic age signal and on the number of grains analysed. Observed detrital cooling ages are well matched by predicted ages for a more slowly eroding Himalayan catchment. A poorer match for a rapidly eroding catchment may result from some combination of large analytical uncertainties in the detrital ages and inhomogeneous erosion rates within the basin. Such mismatches emphasize the need for more accurate thermal and kinematic models and for sampling strategies that are adapted to catchment‐specific geologic and geomorphic conditions.
T‐cell receptor excision circles: a novel prognostic parameter for the outcome of transplantation in multiple myeloma patients
Authors: Svaldi Mirija , Lanthaler Andrea Judith , Dugas Martin , Lohse Peter , Pescosta Norbert , Straka Christian , Mitterer Manfred
Published: August 2003

Summary. This study investigated whether T‐cell receptor excision circles (TRECs) are a prognostic marker for the outcome of myeloma patients undergoing a tandem autologous peripheral blood stem cell transplantation (PBSCT). Twenty‐five patients were enrolled. Samples were obtained at study enrolment, after conventional therapy, between first and second transplantation and 3, 6, 12 and 24 months after the second PBSCT. TRECs were quantified using real‐time polymerase chain reaction. A high variation in TREC levels was found at diagnosis (median TREC level 136/105 peripheral blood mononuclear cells (PBMCs); range 1–1729), suggesting individual differences in thymic output of naive T cells. Patients with more than 136 TRECs/105 P BMCs at diagnosis had a statistically significant better overall survival (P = 0·05) and event‐free survival (P = 0·045), whereas low TREC levels correlated with a higher incidence of infectious complications. Median TREC values were lowest after the first PBSCT (52/105 PBMCs) and reached the baseline 12 months after the second transplantation. Patients with high TREC levels after the second PBSCT had a significantly higher probability of being in complete or partial remission 30 months after the second PBSCT. TREC levels were not correlated with β2‐microglobulin and C‐reactive protein levels at diagnosis. These data suggest that TRECs could be a relevant prognostic factor for patients who receive high‐dose chemotherapy and autologous PBSCT.
Acquired Pseudoxanthoma elasticum‐like syndrome in β‐thalassaemia patients
Authors: Hamlin Naomi , Beck Konstanze , Bacchelli Barbara , Cianciulli Paolo , Pasquali‐Ronchetti Ivonne , Le Saux Olivier
Published: August 2003

Summary. A significant number of patients diagnosed with β‐thalassaemia develop clinical and histopathological manifestations similar to those of an inherited disorder called Pseudoxanthoma elasticum (PXE). The inherited PXE is caused by mutations in the ATP‐binding cassette, subfamily C (CFTR/MRP), member 6 (ABCC6) gene and is characterized by mineralized elastic fibres in dermal, vascular and ocular tissues. As no disease‐causing variant was found in the ABCC6 gene of 10 β‐thalassaemia patients with a PXE‐like phenotype, the present study suggests that the PXE‐like symptoms in these β‐thalassaemic patients are not related to ABCC6 mutations.
Cold storage of ‘cryohydrocytosis’ red cells: the osmotic susceptibility of the cold‐stored erythrocyte
Authors: Jarvis Helen G. , Gore Daniel M. , Briggs Carol , Chetty Margaret C. , Stewart Gordon W.
Published: August 2003

Summary. ‘Cryohydrocytosis’ is an unusual human haemolytic anaemia of the ‘hereditary stomatocytosis’ group, in which the red cell membrane is abnormally permeable to Na and K+ at both body and (even more prominently) refrigerator temperatures. If whole cryohydrocytosis blood is anticoagulated in heparin or EDTA and stored on ice overnight, about 50% of the cells will lyse. Citrate phosphate dextrose adenine (CPDa) anticoagulant, empirically verified as an optimal anticoagulant for storage of normal blood before transfusion, very markedly ameliorated this overnight lysis, suggesting that these cells might form an informative model in which cold storage of the red cell could be studied in a short time scale. Accordingly, we conducted studies of ion flux, cell swelling and lysis in different media used historically for blood preservation and compared the experimental data with an ‘integrated red cell model’, which seeks mathematically to model the osmotic behaviour of red cells under different conditions. Upon experiment, lysis in these cells was reduced by additives that could be regarded as impermeant extracellular solutes (citrate, mannitol) and by low pH, but not by those agents that are regarded as protecting the cell against energy depletion or oxidation (adenine, glucose, nicotinic acid). The protective effects of these extracellular additives were all reproduced by the computer simulation, confirming the validity of this model, although the effect of pH could be simulated only semi‐quantitatively, possibly because Na+ permeability itself depends on pH.
Three‐dimensional analysis of CD34 sialomucin distribution on cord blood and bone marrow
Authors: Whiting Karen A. , McGuckin Colin P. , Wertheim David , Pearce Daniel , Pettengell Ruth
Published: August 2003

Summary. Determining the cellular distribution of key adhesion molecules may aid in understanding haematopoietic progenitor/stem cell (HPSC) homing to bone marrow (BM). CD34, a well‐characterized marker for blast‐like HPSC, is widely used for the isolation and enumeration of HPSC. Functional studies have yet to identify a ligand for CD34. However, growing evidence suggests that CD34 may aid the regulation of HPSC differentiation and modulate the expression of other HPSC adhesion molecules necessary for homing. This study aimed to determine CD34 distribution on umbilical cord blood (CB) and BM. CD34‐selected cells were adhered to positively charged gold slides at room temperature, before indirect fluorescent antibody labelling with fluorescein isothiocyanate. Fluorescent distribution was determined by 1‐µm interval, confocal laser scanning microscope Z‐sections. Initial analysis showed CD34 distributed within peripheral halos and dense pocket regions. The development of three‐dimensional imaging software enabled spatial visualization of CD34 distribution on CB and BM in association with differential interference contrast cell image. This showed that CD34 was distributed within peripheral halos, with magnupodia‐associated ‘meridian‐shaped crescents’, extending from points of cell–slide adhesion towards the top of the cell. True CD34 distribution, not previously discernible by confocal laser scanning microscopy alone, suggests a possible role in cell adhesion/homing revealed by three‐dimensional imaging.
All‐trans retinoic acid skews monocyte differentiationinto interleukin‐12‐secreting dendritic‐like cells
Authors: Mohty Mohamad , Morbelli Silvia , Isnardon Daniel , Sainty Danielle , Arnoulet Christine , Gaugler Béatrice , Olive Daniel
Published: August 2003

Summary. All‐trans retinoic acid (ATRA) and retinoid derivatives are essential agents for multiple biological processes. Numerous immune system dysfunctions can occur in the case of retinoid deficiency. Because of the central role of dendritic cells (DCs) in controlling immunity and the wide effects of retinoids on the immune system homeostasis, we investigated the ability of ATRA to influence the differentiation of DCs from circulating peripheral blood monocytes. Human peripheral blood monocytes were cultured with granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and various concentrations of ATRA. Differentiated cells were assayed for their morphology, phenotype, antigen uptake, allostimulatory capacity and cytokine secretion profile. ATRA (10−12 mol/l) and GM‐CSF drove the differentiation of monocytes into dendritic‐like cells (ATRA‐DC). ATRA‐DCs exhibited DC morphology, had a phenotype of immature DCs, with the expression of CD1a, and upregulation of adhesion and co‐stimulatory molecules. ATRA‐DCs could induce a proliferative response in naive CD4+ T cells. Although ATRA‐DCs retained their antigen‐capture capacity, they secreted interleukin (IL)‐12p70 without the need for any maturation agent. In addition, ATRA‐DCs could drive T cells towards an IL‐12‐dependent T‐helper cell type 1 response with secretion of interferon‐γ. DCs appear to be potential targets for ATRA, giving new insights into the immunomodulatory function of retinoids, with implications potentially related to immunotherapy.
Analysis of 18 novel mutations in the factor VIII gene
Authors: Bicocchi Maria P. , Pasino Mirella , Lanza Tiziana , Bottini Federico , Boeri Elio , Mori Pier G. , Molinari Angelo C. , Rosano Camillo , Acquila Maura
Published: August 2003

Summary. We describe 18 novel mutations, unreported in the Haemophilia A mutation Databases, that have been identified in a cohort of unrelated, Italian patients affected with haemophilia A (HA). Screening of the factor VIII gene (FVIII) was performed using denaturing high‐performance liquid chromatography (DHPLC) and direct sequencing. Eight mutations were characterized as non‐missense alterations, and the remaining 10 were missense mutations. Heterozygosity for the identified mutations was observed in the female relatives of patients belonging to eight families with sporadic cases. In an attempt to understand better the causative effect of the mutations and the clinical variability of the patients, missense mutation consequences were investigated for: (1) the nature of the new amino acid; (2) the location of the substituted amino acid within crystallographic and theoretical models; and (3) the degree of conservation of the native residue in factor VIII (FVIII) protein and FVIII‐related protein family aligned sequences. These research tools have provided evidence that the mutations we describe involve residues that were conserved, at least in FVIII proteins, in all the species we compared.
Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukaemia
Authors: Uzunel Mehmet , Jaksch Marie , Mattsson Jonas , Ringdén Olle
Published: August 2003

Summary. Minimal residual disease (MRD) assessments were performed retrospectively after allogeneic stem cell transplantation (SCT) in 32 patients (23 children and nine adults) with acute lymphoblastic leukaemia (ALL). Using immunoglobulin and T‐cell receptor rearrangements as clonal markers, MRD was detected after SCT in nine patients, eight of whom have relapsed. The median time between first MRD detection and relapse was 5·5 (range 0·5–30) months. In 23 patients without MRD, six have relapsed to date: lower sensitivity, central nervous system relapse and clonal exchange of the leukaemic clone were factors that may explain the failure to detect MRD before relapse in these patients. In univariate analysis, factors associated with decreased risk of relapse were transplantation in first remission (P = 0·02), the combination of acute and chronic graft‐versus‐host disease (P = 0·03) and absence of MRD after SCT (P = 0·005). In multivariate analysis, only MRD detection after SCT was significantly associated with increased risk of relapse (P = 0·05). In conclusion, MRD detection after SCT is correlated with relapse and provides the opportunity for initiating immunotherapeutic intervention at an early stage when the tumour cell burden is still low.
Varicella‐zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan
Authors: Tomonari Akira , Iseki Tohru , Takahashi Satoshi , Ooi Jun , Takasugi Kashiya , Shimohakamada Yoko , Ohno Nobuhiro , Nagamura Fumitaka , Uchimaru Kaoru , Tani Kenzaburo , Tojo Arinobu , Asano Shigetaka
Published: August 2003

Summary. Varicella‐zoster virus (VZV) infection was studied in 40 adult patients who underwent cord blood transplantation (CBT) from unrelated donors. Twenty‐five patients developed VZV reactivation at a median of 5 months after CBT (range 1·7–26 months). The cumulative incidence of VZV reactivation after CBT was 80% at 30 months. Twenty‐two patients developed localized herpes zoster. The remaining three patients developed atypical non‐localized herpes zoster, which was associated with visceral dissemination in one patient. All the patients responded well to antiviral therapy. Unexpectedly, the absence of grade II–IV acute graft‐versus‐host disease (GVHD) was associated with a higher rate of VZV reactivation after CBT (100% versus 55%, P = 0·01). These results suggest that recovery of VZV‐specific immune responses after CBT is delayed even in patients without severe acute GVHD.
Thrombopoietin is a major limiting factor for selective outgrowth of human umbilical cord blood cells in non‐obese diabetic/severe combined immunodeficient recipient mice
Authors: Verstegen Monique M. A. , Wognum Albertus W. , Wagemaker Gerard
Published: August 2003

Summary. A single dose (0·3 µg) of recombinant human thrombopoietin (TPO) was injected into sublethal irradiated non‐obese diabetic/severe combined immunodeficient (NOD/SCID) mice immediately after transplantation of 1·5 × 105 purified CD34+ umbilical cord blood (UCB) cells. Bone marrow (BM) was analysed for human cells by immunophenotyping and colony culture at d 35. TPO treatment produced a two‐ to sixfold increase in the frequency and number of human CD45+ cells. The lineage distributions among the human cells were similar irrespective of TPO treatment; however, a prominent increase was observed in CD71+GpA– cells, reflecting the proliferative stimulus provided by TPO. The frequency of immature CD34+ cells and human granulocyte–macrophage colony‐forming units and erythroid burst‐forming units in TPO‐treated mice was similar to that of untreated mice, but their absolute numbers had increased proportionally to the increase in human cells. The results demonstrate that human TPO is a major limiting factor for multilineage outgrowth of human UCB cells in NOD/SCID mice and can be conveniently supplemented by single‐dose treatment immediately after transplantation. TPO did not affect the survival of mice after transplantation and did not significantly increase the number of immature CD34+CD38– cells; secondary transplantation revealed that TPO administration also had no significant effect on long‐term repopulation. The findings demonstrate that human TPO is required for proper outgrowth of human haematopoietic stem cells after transplantation. In addition, a single administration of TPO may improve the efficiency and reproducibility of the NOD/SCID mouse assay for human immature transplantable progenitor cells.
Multicolour fluorescence in situ hybridization analysis of t(14;18)‐positive follicular lymphoma and correlation with gene expression data and clinical outcome
Authors: Lestou Valia S. , Gascoyne Randy D. , Sehn Laurie , Ludkovski Olga , Chhanabhai Mukesh , Klasa Richard J. , Husson Hervé , Freedman Arnold S. , Connors Joseph M. , Horsman Douglas E.
Published: August 2003

Summary. In order fully to identify secondary chromosomal alterations, such as duplications, additions and marker chromosomes that remained unresolved by G banding, 60 cases of t(14;18)‐positive follicular lymphoma (FL) were analysed by multicolour karyotyping techniques [multicolour fluorescence in situ hybridization (MFISH)/multicolour banding for chromosome 1 (MBAND1)]. A total of 165 additional structural chromosomal aberrations were delineated. An increased frequency of chromosomal gains involving X, 1q, 2, 3q27‐q29, 5, 6p11‐p21, 7, 8, 11, 12, 14q32, 17q, 18 and 21 and deletions of 1p36, 3q28‐q29, 6q, 10q22‐q24 and 17p11‐p13 was revealed by the MFISH/MBAND1 analysis. Balanced translocations other than t(14;18) were uncommon, whereas unbalanced translocations were numerous. Deletion of 1p36 and duplication of 1p33‐p35, 1p12‐p21 and 1q21‐q41 were regularly involved in chromosome 1 alterations, seen in 53% of the cases. A strong correlation was demonstrated between gains of individual chromosomal bands and increased gene expression, including 1q22/MNDA, 6p21/CDKN1A, 12q13‐q14/SAS, 17q23/ZNF161, 18q21/BCL2 and Xq13/IL2RG. Unfavourable overall survival was associated with del(1)(p36) and dup(18q). These data support the notion that translocation events are primarily responsible for FL disease initiation, whereas the unbalanced chromosomal gains and losses that mirror the gene expression patterns characterize clonal evolution and disease progression, and thus provide further insights into the biology of FL.
Effective graft‐versus‐leukaemia effect after allogeneic stem cell transplantation using reduced‐intensity preparative regimens in Fanconi anaemia patients with myelodysplastic syndrome or acute myeloid leukaemia
Authors: Guardiola Philippe , Kurre Peter , Vlad Amalia , Cayuela Jean‐Michel , Espérou Hélène , Devergie Agnès , Ribaud Patricia , Socié Gérard , Richard Patrice , Traineau Richard , Storb Rainer , Gluckman Eliane
Published: August 2003

Summary. Allogeneic transplantation is the only curative treatment for Fanconi anaemia (FA) patients who develop myeloid malignancies. Dose‐intensive preparative regimens, to decrease disease recurrence, lead to unacceptable transplant‐related toxicity in FA. We report the outcome of three FA patients with such malignancies who underwent transplantation with reduced‐intensity preparative regimens. This approach was well tolerated, even as second transplantations, and resulted in complete leukaemic remissions. However, the graft‐versus‐leukaemia effect was associated with fatal graft‐versus‐host disease. Even after transplantation, myeloid malignancies remain associated with a poor outcome in FA, and this argues in favour of early intervention when suitable donors are available.
Cutaneous reactions in hairy cell leukaemia treated with 2‐chlorodeoxyadenosine and allopurinol
Authors: Chubar Yevgene , Bennett Michael
Published: August 2003

Summary. The purine nucleoside analogue 2‐chlorodeoxyadenosine (2‐CdA) is currently considered by many as first‐line therapy for hairy cell leukaemia. Cutaneous reactions have occasionally been reported with this drug, particularly if used with allopurinol. We report a high frequency of skin reactions in 15 consecutive patients with hairy cell leukaemia treated with 17 courses of 2‐CdA. These reactions occurred only in those receiving allopurinol and, in two patients, were severe enough to warrant steroid therapy. The routine concomitant use of allopurinol is therefore not recommended in this setting.