bluuebunny/crossref_metadata_2025 huggingface dataset:
The Economic Effects of Road Safety Improvements: An Insurance Claims Analysis
Authors: Feber David J. , Feldmeier Judith M. , Crocker Keith J.
Published: November 2003

Abstract

This article demonstrates the feasibility of exploiting insurance claims data to estimate the marginal benefits to society of highway infrastructure improvements. We construct a unique database linking claims expenditures for a major auto insurer in Michigan to infrastructure investments at 62 intersections in the City of Detroit, and conclude that the addition of a left‐turn lane, or left‐turn phase in the signal, decreases the insurer's average monthly claims costs at a representative intersection by $944 or $1,062, respectively. The evidence also indicates that these cost savings are a result of reductions in accident severity, rather than being a consequence of fewer accidents.
Do Property‐Casualty Insurance Underwriting Margins Have Unit Roots?
Authors: Harrington Scott E. , Yu Tong
Published: November 2003

Abstract

A growing literature analyzes determinants of insurance prices using time series data on insurer underwriting margins. If the variables analyzed are stationary, conventional regression models may be appropriately used to test hypotheses. Based on pretests for a unit root, several studies have instead used co‐integration analysis to analyze the long‐run relationship between purportedly nonstationary underwriting margins and macroeconomic variables. We apply a battery of unit root tests to investigate whether underwriting margins are stationary under different assumptions concerning deterministic components in the data generating process (DGP). When linear and/or quadratic trends are included in the assumed DGPs, the tests reject the null hypothesis of a unit root for loss ratios, expense ratios, combined ratios, and economic loss ratios from 1953 through 1998 for many of the individual lines examined and for all lines combined. Consistent with prior work on whether macroeconomic variables have unit roots, a simulation of test power for underwriting margins during the sample period demonstrates that nonrejections of the null hypothesis of a unit root could easily reflect low power. The overall findings suggest that conventional regression methods can be used appropriately to analyze underwriting margins after controlling for deterministic influences and transforming any nonstationary regressors.
Claiming Behavior in Workers' Compensation
Authors: Biddle Jeff , Roberts Karen
Published: November 2003

Abstract

Using administrative data on workers' compensation claims in Michigan combined with data collected from a sample of workers identified by physicians as having work‐related pain in their backs, wrists, hands, or shoulders, this article provides evidence that a substantial number of potentially eligible workers do not file workers' compensation claims. Multivariate analysis identifies the effects of various factors on the probability of filing a workers' compensation claim, conditional on having a work‐related health problem. We find that the severity of the worker's condition and the worker's general health are the most important determinants of the decision to file, and that the generosity of wage loss benefits also affects the decision of an eligible worker to file. Finally, claims propensities vary considerably across workplaces, holding all other measured factors constant.
Kultuur Reclaimed: Afrikaner Nationalist Politics and the Stellenbosch District (South Africa), 1934–1939
Authors: Duffy Joanne
Published: November 2003

Abstract  This article challenges the notion that Afrikaner nationalism was underpinned by Afrikaner Unity. Focusing on the University town of Stellenbosch between 1934 and 1939 it explores the extreme fluidity of Afrikaner nationalist politics during this period, demonstrating the multiplicity of identities, and conflicting and co‐existing ideologies, which these politics comprised. The contested nature of Afrikaner nationalism in the period after the formation of Malan's “Purified” National Party in 1934 is illuminated through an examination of the debates within the Stellenbosch constituency over the true nature of the Afrikaner. Contestations over Afrikaans Kultuur (culture) were a key element of politics in Stellenbosch during this period, as Nationalist politicians and their supporters sought to “reclaim” control over “their” cultural icons.
Effect of atrial natriuretic factor and fate of cyclic‐guanosine‐monophosphate in the rat kidney
Authors: SYRÉN M.‐L.
Published: November 2003

The mechanisms whereby atrial natriuretic factor (ANF) induces natriuresis are not clarified. Here, the effects of ANF and the cGMP analogue, 8‐bromo‐cGMP, on Na+, K+‐ATPase activity in microdissected segments from rat medullary thick ascending limb of Henle (TAL) were evaluated. ANF‐induced cGMP accumulation and the cellular handling of intracellularly produced cGMP were also investigated, by measuring the accumulation of extracellular cGMP in suspensions of tubules from outer medulla, enriched in TAL, and of isolated glomeruli.

ANF dose‐dependently inhibited Na+, K+‐ATPase activity in isolated TAL in a parallel fashion with increasing cGMP accumulation in OM tubules. For both parameters, pharmacological concentrations (≥ 10−6 m) of ANF were needed to induce a significant effect. 8‐Bromo‐cGMP mimicked the inhibitory effect of ANF. The increase in the intracellular cGMP level in response to ANF was dose‐dependently reflected in the extracellular level. This finding contrasted with that in the glomerular preparation, where cGMP in response to ANF accumulated entirely intracellularly. Also in glomeruli, high (≥ 10−6 m) concentrations of ANF were needed to induce a significant effect on cGMP accumulation.

In conclusion, ANF inhibited Na+, K+‐ATPase activity in TAL and the effect was mimicked by 8‐bromo‐cGMP. cGMP, produced in response to ANF, was extruded from the tubular epithelial cells, but not from glomeruli.
Leptin and thermogenesis in humans
Authors: TUOMINEN J. A. , EBELING P. , HEIMAN M. L. , STEPHENS T. , KOIVISTO V. A.
Published: November 2003

We examined changes in serum leptin concentrations and thermogenesis in 12 healthy men (39 ± 2 years, BMI 22.8 ± 0.3 kg m−2) during a 4 h euglycaemic hyperinsulinaemia performed on a control day and after a day of a competitive marathon run. As compared with the control day, after the marathon, baseline FFA concentration (543 ± 0.73 vs. 955 ± 96 μmol L−1, P < 0.05), lipid oxidation rate (0.8 ± 0.1 vs. 1.2 ± 0.1 mg kg−1 min−1}, P < 0.01) and energy expenditure (5.2 ± 0.1 vs. 5.5 ± 0.1 kJ min−1}, P < 0.01) were elevated. Baseline serum leptin concentrations were similar on the control and postexercise days and increased during insulin infusion by 35–45% on both days (P ≤ 0.01). Baseline serum leptin concentration correlated directly with serum insulin ( r = 0.65, P < 0.05) and cortisol ( r = 0.64, P < 0.05), and inversely with serum growth hormone concentration ( r = −0.66, P < 0.05). In the postexercise study, the rise in energy expenditure during insulin clamp correlated with serum leptin concentration as determined before ( r = 0.61, P < 0.05) or at the end of insulin infusion ( r = 0.55, P < 0.05). Thus, in healthy individuals with normal body weight: (1) hyperinsulinaemia increases serum leptin concentrations; (2) a rise in energy expenditure correlates with serum leptin concentration. These data suggest that leptin is involved in the regulation of energy expenditure in humans.
Cardiovascular regulation by endogenous nitric oxide is essential for survival after acute haemorrhage
Authors: MELLANDER S. , BJÖRNBERG J. , EKELUND U. , ALM P.
Published: November 2003

Our previous studies have indicated that endogenous nitric oxide serves as a physiologically important inhibitor of vascular tone during acute haemorrhage. This vasodilator action attenuates the concomitant reflex adrenergic constriction and thereby prevents critical reduction of tissue blood flow. The present study aimed to evaluate the overall importance of this nitric oxide regulation for survival after acute haemorrhage. This was done by comparative observations of survival time and circulatory. metabolic and histopathological changes after an acute standardized lethal blood loss (45%) in cats exposed to nitric oxide synthase (NOS) inhibition and in matched control animals with intact nitric oxide regulation. NOS inhibition was instituted by intravenously administered N‐nitro‐L‐arginine methyl ester. The survival time averaged 2 h 49 min in the NOS‐blocked animals and 10 h 14 min in the control animals (P  0.001). NOS inhibition thus reduced the posthaemorrhagic survival time to  30% of that in the control cats. Haemorrhage in the NOS‐blocked animals led to rapidly developing arterial hypotension. increased anaerobic metabolism. metabolic lactacidosis. hyperkalaemia. and morphological tissue damage especially in heart and liver. in spite of maintained arterial normoxia, which signifies tissue hypoxia caused by seriously impaired nutritional blood supply. At the time of death of the NOS‐blocked cats. the control animals still exhibited a virtually normal circulatory/metabolic state. A much later. and more slowly developing circulatory/metabolic deterioration was observed in the control animals. These differences between the two groups of animals indicate that nitric oxide release. by its vasodilator action. to a significant extent helps to maintain an adequate nutritional blood supply to the tissues in acute haemorrhage.
The involvement of nurses in reporting suspected adverse drug reactions: experience with the meningococcal vaccination scheme
Authors: Ranganathan S. Sri , Houghton J. E. , Davies D. P. , Routledge P. A.
Published: November 2003

Aims  In order to aid the monitoring of the new Meningococcal serogroup C Conjugate (Men C) vaccine, the Yellow Card Scheme was extended to allow nurses for the first time to report any suspected adverse reactions associated with these vaccines. We have analysed the Yellow Cards received by the Committee on Safety of Medicines (CSM) Wales from nurses reporting a suspected reaction in association with these vaccines during the first 16 months of the programme.

Methods  CSM Wales receives Yellow Cards from healthcare professionals in Wales. Details of Yellow Cards reporting a suspected adverse reaction associated with Men C vaccines during the study period were extracted from the CSM Wales database and analysed according to health professional category [nurses, General Practitioners (GP), hospital doctors or pharmacists].

Results  During the study period 534 117 doses of Men C vaccines were administered in Wales; in the same period CSM Wales received 1095 Yellow Cards containing 1952 suspected reactions. Nurses completed 529 [48.3%, 95% confidence interval (CI) 43.6, 53.1] Yellow Cards compared with 294 (26.8%, 95% CI 22.7, 30.8) from GPs, 262 (23.9%, 95% CI 20.1, 27.6) from hospital doctors and 10 (0.91%, 95% CI 0.43, 1.73) from others, which include hospital pharmacists, community pharmacists and health visitors. The proportion of Yellow Cards sent by nurses was significantly higher than those sent by GPs and hospital doctors. Ninety‐five percent CIs for differences in proportions (CI diff prop) were (0.175, 0.254) and (0.204, 0.282), respectively. The majority (90.9%, 95% CI 88.7, 93.5) of the Yellow Cards from nurses reported suspected reactions children in over the age of 5 (95% CI diff prop 0.861, 0.917). The spectrum of suspected adverse drug reactions (ADRs) involved the skin and subcutaneous tissue, central nervous system, general reactions, and the gastrointestinal tract. Of the suspected reactions reported by nurses, GPs and hospital doctors, 13.4% (95% CI 10.5, 15.8), 12.9% (95% CI 9.6, 16.8) and 9.1% (95% CI 6.5, 11.8), respectively, were of serious reactions. Nurses reported 52.5% (95% CI 45.4, 60.6) of all the suspected serious reactions, which was statistically more significant than hospital doctors [χ2 = 5.864, degree of freedom (DF) = 1, P < 0.05] but not GPs (χ2 = 0.066, DF = 1, P > 0.05).

Conclusions  Nurses were the health professionals who provided the largest proportion of reports of suspected ADRs and almost half of all reports during the Men C vaccination campaign. Their reports contained an equal proportion of serious suspected ADRs and the reports were documented as completely as those from GPs and hospital doctors.
Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity
Authors: Härtter Sebastian , Nordmark Anna , Rose Dirk‐Matthias , Bertilsson Leif , Tybring Gunnel , Laine Kari
Published: November 2003

Aims  The aim of this study was to assess the influence of concomitant caffeine intake on the pharmacokinetics of oral melatonin, a probe drug for CYP1A2 activity.

Methods  Twelve healthy subjects, six smokers and six nonsmokers, were given melatonin (6 mg) either alone or in combination with caffeine (3 × 200 mg). Blood samples for the analysis of melatonin or caffeine and paraxanthine were taken from 1 h before until 6 h after intake of melatonin. Subjects were genotyped with respect to the CYP1A2*1F (C734A) polymorphism.

Results  When caffeine was coadministered the Cmax and AUC of melatonin were increased on average by 142% (P = 0.001, confidence interval on the difference 44, 80%) and 120% (P < 0.001, confidence interval on the difference 63, 178%), respectively. The inhibitory effect of caffeine was more pronounced in nonsmokers and in individuals with the *1F/*1F genotype.

Conclusion  The results of this study revealed a pronounced effect of caffeine on the bioavailability of orally given melatonin, most probably due to inhibition of CYP1A2 activity.
Effect of food on the pharmacokinetics of multiple‐dose oral voriconazole
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Greenhalgh Katie , Nichols Don
Published: November 2003

Aims Voriconazole is a new triazole antifungal agent with activity against a range of clinically important and emerging pathogens. This study determined the effect of food on the pharmacokinetics of voriconazole in healthy volunteers.

Methods This was an open, randomized, two‐way crossover, multiple‐dose study in male volunteers. Twelve subjects received voriconazole 200 mg twice daily for 6.5 days. Each dose was administered either with food or in the fasted state, i.e. not within 2 h of food. Treatment periods were separated by a minimum 7‐day washout period. Plasma samples were taken for the estimation of voriconazole plasma concentrations on days 1 and 7. Safety and toleration were assessed by monitoring of both laboratory safety tests and adverse events.

Results Administering voriconazole with food significantly decreased both day 7 AUCτandCmaxby approximately 35% (9598–7520 ng·h  ml−1;P = 0.003) and 22% (2038–1332 ng ml−1;P = 0.008), respectively. Administering voriconazole with food statistically significantly delayed absorption, evident fromtmaxvalues; the mean difference fortmaxon day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase half‐life was 7.3 h compared with 6.6 h for the fed state. Visual inspection ofCminvalues suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios ofCmaxand AUCτon days 1 and 7, was statistically significantly greater when administered with food (Cmax,P = 0.010, AUCτ,P = 0.006). MeanCmaxaccumulation in the fasted state was 2.1‐fold compared with 3.5‐fold in the fed state. AUCτaccumulation in the fasted state was 3.1‐fold compared with 4.2‐fold in the fed state. There were no discontinuations due to adverse events or laboratory abnormalities. Treatment‐related mild‐to‐moderate visual disturbances were experienced by six out of 12 subjects.

Conclusions The bioavailability of twice‐daily 200 mg voriconazole is reduced by approximately 22% as measured by AUCτafter multiple dosing when taken with food, compared with fasting.
The production of tissue inhibitors of metalloproteinases (TIMPs) in megakaryopoiesis: possible role of platelet‐ and megakaryocyte‐derived TIMPs in bone marrow fibrosis
Authors: Murate Takashi , Yamashita Kyoko , Isogai Chiho , Suzuki Hitoshi , Ichihara Masatoshi , Hatano Sonoko , Nakahara Yosuke , Kinoshita Tomohiro , Nagasaka Tetsuro , Yoshida Shonen , Komatsu Norio , Miura Yasusada , Hotta Tomomitsu , Fujimoto Noboru , Saito Hidehiko , Hayakawa Taro
Published: November 2003

We quantified tissue inhibitor of metalloproteinase (TIMP)‐1 and TIMP‐2 in serum and plasma in normal control subjects and patients with a low or high platelet count, using one‐step sandwich enzyme immunoassays. The serum levels of TIMP‐1 and TIMP‐2 were 101.1 ± 13.3 ng/ml, and 82.7 ± 26.3 ng/ml, respectively, in normal subjects. In patients with an elevated platelet count, such as in essential thrombocytosis, polycythaemia vera, and myelofibrosis, serum levels of TIMP‐1 and TIMP‐2 were 351.6 ± 200.9 ng/ml and 148.9 ± 84.0 ng/ml, respectively. Serum levels of TIMP‐1 and TIMP‐2 in patients with a low platelet count, such as in aplastic anaemia and idiopathic thrombocytopenic purpura, were 57.2 ± 25.8 ng/ml and 19.7 ± 7.68 ng/ml, respectively. The serum level of TIMP‐1 was significantly correlated with the platelet count in all subjects. The correlation between the serum level of TIMP‐2 and the platelet count was not as strong. The level of TIMP‐1 in platelet‐depleted plasma was not correlated with the platelet count.

Immunohistochemical staining using monoclonal antibodies against TIMP‐1 and TIMP‐2 showed that megakaryocytes and platelets were positive for both TIMP‐1 and TIMP‐2, confirming that they are rich sources of TIMPs. TIMP‐1 and TIMP‐2 stimulated the proliferation of bone marrow fibroblasts, although their effect was less potent than that of TGF‐β and PDGF.

Erythroleukaemia and megakaryoblastic cell lines showed the highest secretion of TIMP‐1 among the leukaemia cell lines examined. There was no lineage specificity for TIMP‐2 secretion. These results suggest that TIMPs released from megakaryocytes or from local platelet coagulation may be important in the development of bone marrow fibrosis.
Separation of G‐CSF‐mobilized PBSC transplants by counterflow centrifugal elutriation: modest enrichment of CD34+ cells but no loss of primitive haemopoietic progenitors
Authors: Kwekkeboom Jaap , Buurman Dennis E. P. , Van Hennik Paula B. , Ploemacher Rob E. , Loos Hans A. , Slaper‐Cortenbach Ineke C. M.
Published: November 2003

The suitability of counterflow centrifugal elutriation (CCE) for reduction of the number of non‐stem cells in autologous G‐CSF‐mobilized peripheral blood stem cell (PBSC) transplants was investigated. By cell size‐monitored CCE, small cells could be rapidly separated from the haemopoietic progenitor cells present in leukapheresis product (LP) samples. The large cell fraction contained an average 86 ± 25% of the CD34+ cells and 76 ± 20% of the granulocyte‐macrophage progenitors (CFU‐GM) loaded into the separation chamber, and was depleted of 75 ± 18% of the lymphocytes, 89 ± 7% of the erythrocytes and 98 ± 2% of the platelets (n = 21). Due to the presence of high numbers of large immature myeloid cells, which co‐elutriated with progenitor cells, enrichment of CD34+ cells in the large cell fraction was only modest (average 1.8 times). No indication of preferential co‐elutriation of primitive stem cells with the small cells was obtained. There was no difference in expression of CD38 or Thy‐1 on CD34+ cells between the two elutriation fractions. Frequencies of cobblestone‐area‐forming cells (CAFC) week 6, which are considered to represent cells with long‐term repopulating ability, were reduced in the small cell fractions as compared to those in the unseparated samples and the large cell fractions. On average, 100% of CAFC week 6 were recovered in the large cell fractions (n = 5). In conclusion erythrocytes, platelets and 40–50% of leucocytes can be depleted from G‐CSF‐mobilized PBSC samples by CCE with an almost complete recovery of both clonogenic and primitive stem cells.
MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia
Authors: Van Den Heuvel‐Eibrink Marry M. , Van Der Holt Bronno , Te Boekhorst Peter A. W. , Pieters Rob , Schoester Martijn , Löwenberg Bob , Sonneveld Pieter
Published: November 2003

The Multidrug Resistance gene (MDR 1) is frequently expressed in acute myeloid leukaemia (AML). MDR 1 is associated with resistance to chemotherapy in vitro and with a poor response rate in AML. We have investigated the prognostic value of MDR 1 expression in relation to other patient characteristics with respect to response and survival.

One hundred and thirty patients aged 0–88 years were treated for de novo AML with standard induction and consolidation chemotherapy. MDR 1 expression was determined by immunocytochemistry. Univariate and multivariate analyses were conducted to identify prognostic factors for reaching complete remission (CR) and for overall survival from diagnosis, in order to compare MDR 1 with known prognostic factors. Univariate analysis showed that higher MDR 1 expression was an adverse prognostic factor for CR (P < 0.001), as was higher age (P < 0.001) and unfavourable karyotype (P < 0.01). These factors were also negative prognostic factors for overall survival (P < 0.001, P < 0.05 and P < 0.005, respectively). In the multivariate analysis MDR 1 (P < 0.001), higher age (P < 0.001) and karyotype (P < 0.01) were independent adverse prognostic factors for CR as well as for overall survival (P < 0.001, P < 0.005, P < 0.001, respectively). Our data indicate that MDR 1 expression is a disease‐related unfavourable prognostic factor which has a significant impact on complete remission and overall survival in AML. Analysis of MDR 1 may be used to determine prognosis in individual patients.
Disparate lympho‐erythroid donor to recipient chimaerism in a β°‐thalassaemia bone marrow transplant recipient with red cell indices indicative of apparent full engraftment
Authors: Weinberg R. S. , Vlachos A. , Najfeld V. , Galperin Y. , Scalise A. , Fruchtman S. , Lipton J. M.
Published: November 2003

A 4‐year‐old girl with transfusion‐dependent β°‐thalassaemia received an HLA‐identical bone marrow transplant (BMT) from her β°‐thalassaemia trait sister. Prior to BMT, chromosomal analysis revealed the recipient to have 46,XX,9qh+, a polymorphic variant of the heterochromatin region of chromosome 9, which her donor did not have. Within 1 month post‐BMT, 89% of nucleated bone marrow cells were of donor origin. One year later, donor engraftment had decreased to 44% and 34% in nucleated bone marrow cells and blood lymphocytes, respectively. By 2 years, donor lymphocyte engraftment fell to 5%, raising concern of possible graft rejection. To examine erythroid chimaerism, globin synthesis by individual erythroid progenitor cell derived colonies (BFU‐E) was analysed. On days 1000 and 1130 post‐BMT, 79% and 77% of colonies, respectively, synthesized β‐globin and therefore were of donor origin.
Quantification of CMV viraemia in a case of transfusion‐related graft‐versus‐host disease associated with purine analogue treatment
Authors: DEANE MIRIAM , GOR DEHILA , MACMAHON M. EITHNE , EMERY VINCE , GRIFFITH PAUL D. , CUMMINS MICHELLE , PRENTICE H. GRANT
Published: November 2003

We report a patient who developed transfusion‐associated graft‐versus‐host‐disease (GvHD) and concurrent cytomegalovirus (CMV) infection, both complications thought to be related to severe T lymphocyte depletion induced by treatment with a purine analogue drug, fludarabine. CMV viraemia was detected by qualitative PCR and the viral load in positive samples was measured using a fully quantitative PCR assay. This quantitative assay enabled the evaluation of the efficacy of antiviral interventions based on the qualitative PCR result. The case illustrates the risks associated with the use of purine analogue drugs, as well as the value of quantitative CMV PCR assays for monitoring CMV infection in immunocompromised patients.
Prevalence of hepatitis G virus RNA in a monocentric population of French haemophiliacs
Authors: Gerolami V. , Halfon P. , Chambost H. , Sicardi F. , Thuret I. , Planells R. , Halimi G. , Fossat C. , Michel G. , Cartouzou G.
Published: November 2003

Hepatitis G virus (HGV) and hepatitis GB virus (GBV‐C) have been reported as possible causes of non‐A–E transfusional hepatitis. To assess the prevalence of hepatitis G virus infection in haemophiliacs we retrospectively investigated the presence of viral RNA in 92 patients with and without HCV infection. HGV/GBV‐C RNA was reverse transcribed and amplified with primers from the 5′ non‐coding region of the genome. RNA was detected in 16/92 patients (17.4%). Restriction enzyme analysis revealed that the 16 patients belonged to the HGV‐like genotype. Serology with E2‐specific antibodies demonstrated that HGV viraemia underestimates previous infection by HGV. 33 patients were positive for HGV; all but two have cleared HGV RNA. 47/92 patients had a marker of prior infection by HGV.

No difference between HGV RNA positive and negative patients was observed concerning age, diagnosis, HIV and HCV status. Previous HBV infection correlated with the frequency of HGV infection. There was no difference in alanine aminotransferase levels between HGV positive and negative patients. All 18 patients exposed to only virally inactivated plasma‐derived concentrates were negative for both HGV RNA and anti E2 antibodies.

Prior exposure to untreated concentrates correlated with HGV viraemia (P=0.03), HGV seropositivity (P=0.0002), and markers of HGV infection (P<0.0001).

In haemophiliacs with a past exposure to non‐inactivated concentrates, persistence of HCV RNA (53/74 patients) was more frequent than HGV RNA persistence (16/74 patients) although HGV viraemia is more frequent than HCV viraemia in blood donors. This may be related to a greater ability of individuals to clear HGV infection and suggests that hepatitis G virus infection in multi‐transfused patients has a better outcome than infection with other blood‐borne viruses.
Treatment of hairy cell leukaemia (HCL) with 2‐chlorodeoxyadenosine (2‐CdA): identification of parameters predictive of adverse effects
Authors: Legrand Ollivier , Vekhoff Anne , Marie Jean‐Pierre , Zittoun Robert , Delmer Alain
Published: November 2003

2‐chlorodeoxyadenosine (2‐CdA) induces high complete remission (CR) rates in hairy cell leukaemia (HCL), but is associated with serious toxicities. Therefore we reviewed our experience with 2‐CdA in 16 HCL patients, with special attention to adverse effects. One‐third of patients presented severe neutropenic infections and/or required prolonged blood support. Patients with low tumour mass and moderate cytopenias were more likely to achieve CR, whereas those with high tumour burden and severe bone marrow impairment were at increased risk of severe infection and blood product requirements. All these unfavourable parameters may be corrected by short‐term alpha‐interferon (IFN) therapy. Therefore we suggest that patients with unfavourable presenting features might benefit from IFN therapy before 2‐CdA.
Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X
Authors: Chessells J. M. , Swansbury G. J. , Reeves B. , Bailey C. C. , Richards S. M. ,   on behalf of the Medical Research Council Working Party in Childhood Leukaemia
Published: November 2003

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically‐defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event‐free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph‐positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event‐free survival of 87.5% at 5 years. A number of other non‐random abnormalities were identified with no clear prognostic significance.

We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined.
The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakaryopoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukaemia
Authors: Adams J. A. , Liu Yin J. A. , Brereton M. L. , Briggs M. , Burgess R. , Hyde K.
Published: November 2003

Mpl ligand is a recently cloned haemopoietic growth factor that stimulates megakaryopoiesis in vitro and in vivo. We describe the in vitro effect of a truncated form of Mpl ligand, recombinant human megakaryocyte growth and development factor (rHuMGDF), on megakaryopoiesis in bone marrow from normal subjects and patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We used both semi‐solid and suspension culture techniques to assess the effect of pegylated (PEG) rHuMGDF on megakaryocyte colony growth (CFU‐Mk) and on the production of CD61+ cells in 7 d suspension cultures. PEG rHuMGDF increased CFU‐Mk growth and CD61+ cell production in a dose‐dependent fashion in all normal marrows tested. Normal CFU‐Mk growth was increased threefold with the addition of 10 ng/ml PEG rHuMGDF to cultures and CD61+ cells were increased 8–10‐fold by the same dose. Although increased CFU‐Mk growth was only seen in 1/10 AML and 6/16 MDS marrows, CD61+ cell numbers in suspension culture were increased in 9/13 AML and 12/15 MDS samples, responses ranged from very limited to normal magnitude. There was no correlation between platelet count and CFU‐Mk number, CD61+ cell number or response to PEG rHuMGDF. We did not find any increased CFU‐GM colony or cluster growth in response to PEG rHuMGDF and the CD61+ cells produced in suspension culture had features of megakaryocytic differentiation. These data suggest that PEG rHuMGDF can enhance megakaryocyte proliferation in some patients with MDS and AML, and may have a role in the treatment of thrombocytopenia in these patients.
Autologous peripheral blood stem cell transplantation in a patient with chronic autoimmune thrombocytopenia
Authors: Skoda R. C. , Tichelli A. , Tyndall A. , Hoffmann T. , Gillessen S. , Gratwohl A.
Published: November 2003

Immunoablation by high‐dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) is one approach currently under discussion for the treatment and possible cure of patients with severe autoimmune diseases. Chronic immune thrombocytopenic purpura (ITP) can be refractory to current therapies and in severe cases may constitute a life‐threatening condition. We performed autologous PBSCT with T‐cell depletion in a patient with severe chronic ITP but observed no effect on platelet levels. This contrasts with a recent report where complete remission was induced by a similar regimen in two patients with ITP. Further studies will be necessary to identify subgroups of patients who might benefit from this form of therapy.
Point mutations of the BCL‐6 gene in Burkitt's lymphoma
Authors: Capello Daniela , Carbone Antonino , Pastore Cristina , Gloghini Annunziata , Saglio Giuseppe , Gaidano Gianluca
Published: November 2003

BCL‐6 codes for a transcription factor implicated in chromosomal translocations of diffuse large cell lymphomas. Recent evidence indicates that BCL‐6 may also be altered by mutations of its 5′ non‐coding regions. In this study we have investigated the distribution of BCL‐6 5′ mutations among 35 Burkitt's lymphoma cases representative of the epidemiologic variants of the disease. Mutations were detected in 6/21 (28.6%) sporadic Burkitt's lymphomas and 7/14 (50%) endemic Burkitt's lymphomas. These data expand the spectrum of B‐cell non‐Hodgkin's lymphomas associated with BCL‐6 5′ mutations and have implications for the pathogenesis, histogenesis and clinical monitoring of Burkitt's lymphoma.
Signal transduction involved in the platelet adenylate cyclase sensitization associated with PGH2/TxA2 receptor desensitization
Authors: Elalamy Ismail , Emadi Sharareh , Boris Vargaftig B. , Hatmi Mohamed
Published: November 2003

The exposure of human platelets to prostaglandin H2 analogue (PGH2, U46619) induces homologous desensitization and a concomitant adenylate cyclase (AC) sensitization.

We demonstrate the involvement of phospholipase C (PLC) in this enzyme sensitization. Pre‐incubation of platelets with neomycin, a PLC activity inhibitor, prevented AC sensitization but not PGH2/thromboxane (Tx)A2 receptor desensitization. PGH2/TxA2 receptor desensitization, although necessary, is not sufficient to induce AC sensitization, since neomycin, which prevents AC sensitization, failed to prevent receptor desensitization. Inositol phosphate formation, determined in parallel, was also inhibited. Interestingly, no guanylate cyclase sensitization was noted, suggesting a specific relationship between PGH2/TxA2 receptor desensitization and AC sensitization. In addition, using alkaline phosphatase, a dephosphorylating enzyme, and the tyrosine kinase inhibitor erbstatin, we examined the role of phosphorylation–dephosphorylation on AC sensitization. Effectively, alkaline phosphatase, which has no effect by itself, enhances the cAMP production triggered by prostacyclin in control but not in desensitized platelets. In contrast, erbstatin failed to modify this synthesis, indicating the non‐involvement of tyrosine kinase pathway in this process.

Our results indicate that the AC sensitization was mediated by PLC and also suggest the participation of other mechanisms, including phosphorylation–dephosphorylation processes. This specific enzyme sensitization may be relevant for the in vivo modulation of platelet activation, in different thrombotic diseases with an increased TxA2 generation.
Home treatment as an alternative to inpatient admission: characteristics of those treated and factors predicting hospitalization
Authors: BRIMBLECOMBE N. , O'SULLIVAN G. , PARKINSON B.
Published: November 2003

In response to the NHS Plan, crisis and home treatment teams will be developed across the UK in order to provide intensive home treatment as an alternative to inpatient admission for individuals with severe, acute mental health problems. This study describes aspects of the work of two teams in Hertfordshire. A total of 293 individuals were taken on for intensive home treatment in a 12‐month period. A range of social and demographic variables was recorded at the point of initial assessment regarding each individual, as well as two rating scales: the Brief Psychiatric Rating Scale and the Scale for Suicide Ideation. Sixty‐two individuals (21.1%) required admission to hospital after a median period of home treatment of 11 days. The most frequently recorded reason for admission taking place was ‘risk to self’ (n = 33, 53.2%). Two variables were identified by logistic regression analysis as being predictive of an increased risk of hospitalization: high suicidal ideation at initial assessment (P < 0.01) and previous hospital admission (P < 0.01). Although statistically significant, these variables were only weakly predictive of whether admission would actually take place.
Influence and coercion: relational and rights‐based ethical approaches to forced psychiatric treatment
Authors: OLSEN D. P.
Published: November 2003

The dominant rights‐based approach to the ethics of coercion in psychiatric treatment guides clinicians in deciding whether treatment should be compelled or the patient's autonomy respected, but provides no guidance across the remaining broad continuum of influence that clinicians exert with patients. The assumptions of the rights‐based approach lead to three dichotomous decisions: (1) ‘Is the treatment voluntary?’; (2) ‘Is the patient competent?’ and (3) ‘Are the consequence of no treatment dangerous?’. The assumptions of a relational approach lead to ethical guidance across the full range in the intensity and types of influence which may be ethically justified or required in psychiatric treatment. These assumptions are: (1) influence is inherent in the clinical relationship; (2) the relevant factors are continuous and (3) all decisions are subjective. While the rights‐approach emphasizes defining competence and developing techniques to predict future patient dangerousness, the relational approach emphasizes patient–clinician responsibilities in ethical relationships and understanding all factors which legitimately bear on the use of influence. An initial list of such factors is offered.
Incorporating psycho‐educational family and carers work into routine clinical practice
Authors: SIN J. , MOONE N. , WELLMAN N.
Published: November 2003

There is growing evidence of the benefits of family and carers interventions using a psycho‐educational model for carers of people with psychosis. In order to get this work into clinical practice, a network of interrelated services for carers and families of people with psychoses has been established in Reading, Berkshire. This paper reports the experience of the authors in establishing these services using a series of practice development initiatives including training for staff, education programmes, integration projects and collaboration across organizations. This work illustrates change processes through which evidence‐based practice has been incorporated into routine clinical care and in which research‐based assessment and evaluation tools have being used in routine clinical practice to measure outcomes.
Restoration of genetic diversity in the dry forest treeSwietenia macrophylla(Meliaceae) after pasture abandonment in Costa Rica
Authors: Céspedes M. , Gutierrez M. V. , Holbrook N. M. , J. Rocha O.
Published: November 2003

We studied the levels of genetic diversity ofSwietenia macrophylla(big leaf mahogany) in five successional plots in the Santa Rosa National Park, Guanacaste, Costa Rica. We selected sites with different lengths of time since the last major disturbance (typically fire): 6, 9, 15 and 20 years. In addition, we also included a patch of mature forest that had experienced selective logging and other human activity in the past 100 years. Genetic diversity was assessed using five polymorphic DNA microsatellite loci. We found a total of 21 alleles in the five loci examined, in which the number of alleles present varied among the five sites studied. Allelic diversity varied between sites ranging from 20 to 14 alleles, and our data revealed that earlier successional sites have more alleles than older sites. There was significant heterogeneity in allele frequencies between sites; however, genetic differentiation between populations was low (FST = 0.063) indicating that most of the variation was found within sites and extensive gene flow between sites. In addition, our analysis also showed that genetic diversity of adult trees does not solely determine the diversity of seedlings and saplings found around them, also supporting the existence of extensive gene flow. The impact of these findings for the design of conservation strategies for tropical dry forests trees is discussed.
Geographic and habitat partitioning of genetically distinct zooxanthellae (Symbiodinium) in Acropora corals on the Great Barrier Reef
Authors: Ulstrup K. E. , Van Oppen M. J. H.
Published: November 2003

Intra‐ and intercolony diversity and distribution of zooxanthellae in acroporid corals is largely uncharted. In this study, two molecular methods were applied to determine the distribution of zooxanthellae in the branching corals Acropora tenuis and A. valida at several reef locations in the central section of the Great Barrier Reef. Sun‐exposed and shaded parts of all colonies were examined. Single‐stranded conformational polymorphism analysis showed that individual colonies of A. tenuis at two locations harbour two strains of Symbiodinium belonging to clade C (C1 and C2), whereas conspecific colonies at two other reefs harboured a single zooxanthella strain. A. valida was found to simultaneously harbour strains belonging to two distinct phylogenetic clades (C and D) at all locations sampled. A novel method with improved sensitivity (quantitative polymerase chain reaction using Taqman™ fluorogenic probes) was used to map the relative abundance distribution of the two zooxanthella clades. At two of the five sampling locations both coral species were collected. At these two locations, composition of the zooxanthella communities showed the same pattern in both coral species, i.e. correlation with ambient light in Pioneer Bay and an absence thereof in Nelly Bay. The results show that the distribution of genetically distinct zooxanthellae is correlated with light regime and possibly temperature in some (but not all) colonies of A. tenuis and A. valida and at some reef locations, which we interpret as acclimation to local environmental conditions.
Long‐term population isolation in the endangered tropical tree species Caesalpinia echinata Lam. revealed by chloroplast microsatellites
Authors: Lira C. F. , Cardoso S. R. S. , Ferreira P. C. G. , Cardoso M. A. , Provan J.
Published: November 2003

Habitat fragmentation represents the single most serious threat to the survival of tropical ecosystems. In formulating strategies to counteract the detrimental effects of fragmentation, knowledge of the levels and patterns of genetic diversity within and between natural populations is vital to the establishment of any conservation programme. We utilized polymorphic chloroplast microsatellite markers to analyse genetic diversity in populations of the endangered tropical tree Caesalpinia echinata Lam. representing the entire extant range of the species. Levels of within‐population diversity were low, with only two of seven populations studied displaying any variation. The vast majority of the genetic variation was partitioned between geographical regions (36%) and between populations within regions (55%). These levels of genetic structuring, coupled with a calculated pollen‐to‐seed flow ratio of ≈ 6.7:1, suggest that there has been little gene flow between the three major geographical regions over an extended period. Thus, the current tripartite distribution of the species is more consistent with the existence of separate glacial refugia, rather than reflecting any anthropogenic effects.
Selection‐induced variation at the pantophysin locus (PanI) in a Norwegian fjord population of cod (Gadus morhuaL.)
Authors: Karlsson S. , Mork J.
Published: November 2003

A total of 1290 cod (Gadus morhuaL.), sampled between 1985 and 1999 from a spawning area in the Trondheimsfjord, Norway, were assayed for the nuclear‐encoded locusPanI(pantophysin). The majority of samples were taken during the spawning season at two nearby sampling locations at depths of 100 and 60 m, respectively. Genetic analysis revealed significant effects of cohort, sex and sampling location on allele frequencies atPanI. The contribution of each of these three factors to the total among‐sample diversity (FST) of 8.01% atPanI was estimated to be 3.78, 2.55 and 1.68%, respectively. Sign tests revealed a significant excess of heterozygotes at both sampling locations in females; a significant excess of heterozygotes in males was observed at one of the localities. Mutation, genetic drift and immigration do not appear to contribute significantly to the observed genetic heterogeneity atPanI, leaving natural selection as the main explanatory factor for the Hardy–Weinberg imbalance. The dynamics of the selection atPanI appear to be complex. Analysis of age, sex and cohort proved crucial to disentangle putative explanatory factors from their secondary effects.
Phylogeography of the fungal pathogenHistoplasma capsulatum
Authors: Kasuga Takao , White Thomas J. , Koenig Gina , Mcewen Juan , Restrepo Angela , Castañeda Elizabetha , Da Silva Lacaz Carlos , Heins‐Vaccari Elisabeth M. , De Freitas Roseli S. , Zancopé‐Oliveira Rosely M. , Qin Zhenyu , Negroni Ricardo , Carter Deidre A. , Mikami Yuzuru , Tamura Miki , Taylor María Lucía , Miller Georgina F. , Poonwan Natteewan , Taylor John W.
Published: November 2003

Until recently,Histoplasma capsulatumwas believed to harbour three varieties, var.capsulatum(chiefly a New World human pathogen), var.duboisii(an African human pathogen) and var.farciminosum(an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein‐coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny.Histoplasma capsulatumvar.capsulatumindividuals were found in all eight clades. The African clade included all of theH. capsulatumvar.duboisiiindividuals as well as individuals of the other two varieties. The 13 individuals of var.farciminosumwere distributed among three phylogenetic species. These findings suggest that the three varieties ofHistoplasmaare phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein‐coding genes with the phylogeny suggests that the radiation ofHistoplasmastarted between 3 and 13 million years ago in Latin America.