bluuebunny/crossref_metadata_2025 huggingface dataset:
Market Power, Multinationality and Intra‐Eu Industry Exports in the 90s
Authors: Egger Peter
Published: October 2004

This paper assesses the impact of market power and multinationality in EU12 manufacturing industries on EU integration in goods trade in the 90s. An increase in the market concentration exhibits a positive impact on bilateral exports, while an increase in multinationality works in the opposite direction. Both effects are in accordance with the theoretical hypotheses. As a result, goods trade between the member countries waspolarisedin terms of a relative disintegration of southern Europe.
Wage Flexibility and Unemployment: The Keynesian Perspective Revisited
Authors: Amendola Mario , Gaffard Jean‐Luc , Saraceno Francesco
Published: October 2004

Keynes' main concern in the General Theory is about the capacity of an economy to return to full employment equilibrium when subject to a (negative) demand shock. He maintains that money wages cuts may not help reabsorb unemployment, as they do not necessarily imply a fall in real wages. On the contrary, wage rigidity may be necessary for avoiding that a cumulative process propels the economy far away the full employment equilibrium. Co‐ordination failures in the investment‐saving market are behind this conclusion. However, the analysis is carried out within a static equilibrium framework. This paper is an attempt to focus on the problems of intertemporal co‐ordination arising within the context of a sequential economy. Our analysis of the out‐of‐equilibrium process of adjustment stirred by a shock allows to generalize the original Keynesian intuition. Unemployment emerges as the result of a lack of co‐ordination due to irreversibly constrained choices, and not only nominal but also real wage flexibility does not necessarily help to restore equilibrium. As a matter of fact, it may even be harmful, by triggering processes that make the economy diverge from equilibrium. Our analysis has important analytical implications as regards the role of market imperfections and the interpretation of the effects of monetary policy.
Pricing Personal Services: An Empirical Study of Earnings in the UK Prostitution Industry
Authors: Moffatt Peter G. , Peters Simon A.
Published: October 2004

The hedonic pricing method is used to investigate the way in which the prices of prostitutes' services are determined. The data used in the analysis are extracted from an internet site, each observation being based on a report submitted by a client. The factors affecting price are identified in a regression framework, and combined with other information to provide estimates of the earnings, both aggregate and individual, for a sub‐sector of this underground service industry in the United Kingdom. Comparison of these earnings' estimates with data on earnings from alternative employment then allows us to estimate the compensating wage differential, and also to verify the theoretical prediction that prostitutes' earnings are positively related to earnings from alternative employment.
Clinical value of immunological monitoring of minimal residual disease in acute lymphoblastic leukaemia after allogeneic transplantation
Authors: Sánchez Joaquín , Serrano Josefina , Gómez Pedro , Martínez Francisco , Martín Carmen , Madero Luis , Herrera Concepción , García J Manuel , Casaño Javier , Torres Antonio
Published: October 2004

Summary. In this study, we used multiparameter flow cytometry to quantify minimal residual disease (MRD) in 165 serial bone marrow samples from 40 patients diagnosed with acute lymphoblastic leukaemia (ALL) who underwent allogeneic stem cell transplantation (allo‐SCT) from siblings (n = 34) or unrelated donors (n = 6). Samples were prospectively taken from 24 patients before starting the conditioning regimen, at days +30, +60 and +90 and subsequently every 2–3 months. Samples from 16 patients in complete remission (CR) after allo‐SCT were taken at least twice. Six of 24 patients harboured MRD (0·2–10% of mononuclear cells) at transplant and 18 were negative. Estimated disease‐free survival for the MRD+ and MRD– groups at transplant was 33·3% and 73·5% respectively (P = 0·03). During follow‐up, increasing MRD levels were detected in nine patients, a finding that preceded marrow relapse by 1–6 months. Two patients with stable low MRD levels remained in CR. When we used flow cytometry to test the effect of donor leucocyte infusions (DLI) in six patients, we observed that the only sustained remission was achieved when DLI was applied prior to overt relapse. We conclude that MRD by flow cytometry can rapidly assess tumoral burden before transplant to predict outcome, and can be clinically useful for the timing of DLI for increasing levels of leukaemia after transplant.
Influence of retrograde flushing via the caval vein on the post‐reperfusion syndrome in liver transplantation
Authors: Daniela Kniepeiss , Michael Zink , Florian Iberer , Silvia Schaffellner , Estrella Jakoby , Doris Duller , Karl‐Heinz Tscheliessnigg
Published: October 2004

Abstract:  Introduction:  The reperfusion phase during orthotopic liver transplantation (LTX) is a critical event with sometimes profound hemodynamic and cardiac changes. We present the influence of retrograde reperfusion in LTX on the post‐reperfusion syndrome (PRS).

Methods:  Fifty‐six LTXs in 53 patients were performed with the piggy‐back technique with retrograde reperfusion via the caval vein and antegrade reperfusion via the portal vein. The incidence of PRS was evaluated.

Results:  We observed a PRS in two patients (3.6%), four patients (7.1%) had a decrease in mean arterial pressure (MAP) of 20–29%, 18 patients (32.2%) of 10–19%, 27 patients (48.2%) of 1–9% and five patients (8.9%) had a small increase in MAP.

Discussion:  Our retrospective study showed that retrograde reperfusion seems to maintain stability during the reperfusion phase. Hemodynamic disturbances during LTX were uncommon, leading us to suppose that the incidence of PRS could be diminished with retrograde reperfusion.
Accelerated rejection following offspring‐to‐mother and husband‐to‐wife transplants
Authors: Rosenberg Jerry C. , Jones Bruce , Oh Henry
Published: October 2004

Abstract:  It has been demonstrated that graft survival rates of offspring‐to‐mother and husband‐to‐wife renal transplants are equivalent to those of other living donors. Although the vast majority of these transplants proceed without incident, we have encountered several instances of delayed accelerated rejections that are not predicted by a positive cross‐match. The accelerated rejection can result from an anamnestic reaction subsequent to the in utero exposure of the mother to human leukocyte antigen (HLA) antigens of the fetus with sensitization developing during the pregnancy.
Management of biliary tract complications after orthotopic liver transplantation
Authors: Thethy Sanjeet , Thomson Benjamin NJ , Pleass Henry , Wigmore Stephen J , Madhavan Krishnakumar , Akyol Murat , Forsythe John LR , James Garden O
Published: October 2004

Abstract: Introduction: Despite improved survival, biliary complications remain a significant cause of morbidity following orthotopic liver transplantation. The aim of this study was to review the incidence, treatment and optimum management pathway of biliary complications at the Scottish Liver Transplant Unit.

Materials and methods: All patient data were collected prospectively onto a database at the Scottish Liver Transplant Unit with review of hospital records for validation.

Results: A total of 379 consecutive orthotopic liver transplants were performed in 333 adult patients between November 1992 and September 2001. Biliary complications occurred in 55 grafts (51 patients) (14.6%) and their incidence decreased with time. Biliary complications occurred in 29 (10.9%) of the 265 choledocho‐choledochostomies compared with 14 (25%) of the 56 with T‐tubes. Twenty‐eight biliary leaks occurred, 22 of which were anastomotic. Seventeen anastomotic leaks were successfully treated non‐operatively. Eight patients with biliary leaks subsequently developed an anastomotic stricture. Of the 30 anastomotic strictures, stent insertion was successful in resolving six of 14 (42%) early anastomotic strictures compared with one of 12 (8%) late anastomotic strictures (p = 0.0479). Six (38%) of the 16 early anastomotic strictures required surgery for complete resolution, compared with 12 (86%) of the 14 late anastomotic strictures (p = 0.0106).

Conclusion: The incidence of biliary complications has decreased with time. The abandonment of choledocho‐choledochostomy over a T‐tube has been justified. A combination of conservative, endoscopic, and radiological management has been effective in treating biliary leaks and early anastomotic stricture. However endoscopic or radiological stenting was ineffective in the management of late anastomotic strictures, which were best treated by surgical intervention.
Cyclosporine pharmacokinetics in anti‐HCV+ patients
Authors: Wolffenbüttel Luciano , Poli Débora D , Manfro Roberto C , Gonçalves Luiz Felipe S
Published: October 2004

Abstract: Background: Cyclosporine (CsA) is a widely used immunosuppressive agent in kidney transplant patients. In Brazil, around 30% of patients awaiting kidney transplantation carry anti‐HCV antibodies. Previous observations suggest altered CsA pharmacokinetics in these patients.

Methods: We conducted two pharmacokinetic studies. In the pre‐transplant (pre‐Tx) study, we examined 22 dialysis patients on chronic hemodialysis awaiting transplantation, 11 anti‐HCV+ [seven polymerase chain reaction (PCR)‐positive] matched against 11 controls. In the post‐transplant (post‐Tx) study, we enrolled 24 kidney allograft recipients – 10 anti‐HCV+ (six PCR‐positive), and 14 controls. In the first study, all patients received an 8‐mg/kg dose of CsA microemulsion (ME). Secondly, the dosage was indicated by the patient's medical team. Pharmacokinetic parameters were calculated from 13 blood samples (0–12 h postdose) by fluorescence polarization immunoassay with specific monoclonal antibodies.

Results: In both studies, maximum concentration (Cmax), minimum concentration (Cmin) and area under the CsA time–concentration curve from 0 to 12 h (AUC0−12) were higher for anti‐HCV+ patients than for controls, but significantly so only forAUC0−12in the pre‐Tx study (42%; p < 0.05). When PCR‐positive patients were compared with controls, differences were amplified. In the pre‐Tx study, differences were 58%, 69%, and 91% higher in PCR‐positive patients forCmax(p = 0.05),AUC0−12(p < 0.01), andCmin(p < 0.01), respectively. In the post‐Tx study, results were 50% (p < 0.01) and 32% (p < 0.01) higher in PCR‐positive patients forCmaxandAUC0−12, respectively. In the pre‐Tx study, the impact of viremia was significantly higher in female patients. CsA trough levels remained higher along the first year post‐transplantation in viremic patients.

Conclusions: Anti‐HCV+ patients, especially those with viremia, present altered CsA pharmacokinetics, with higher peak levels and drug exposure than controls.
Hepatic artery pseudoaneurysm – duodenal fistula after living donor liver transplant
Authors: Slater Kellee , Ludkowski Michael , Mehling Jason , Forman Lisa , Pieramici Erik , Wachs Michael , Kam Igal , Bak Thomas
Published: October 2004

Abstract:  A 38‐yr‐old woman who underwent living donor liver transplant for alcoholic cirrhosis presented 2 months after transplant with gastrointestinal bleeding from an hepatic artery pseudoaneurysm eroding into the duodenum. She underwent endovascular hepatic artery stenting, resulting in cessation of hemorrhage and salvage of the graft.
Tuberculous infection in southern Chinese renal transplant recipients
Authors: Lui Sing Leung , Tang Sydney , Li Fu Keung , Choy Bo Ying , Chan Tak Mao , Lo Wai Kei , Lai Kar Neng
Published: October 2004

Abstract: A retrospective study of the prevalence and pattern of tuberculosis among renal transplant patients in a single centre in southern China was performed. Twenty‐three cases of tuberculosis were diagnosed among 440 patients between January 1991 and December 2002. There were 18 men and five women. The mean age of the patients was 39.3 ± 13.4 yr. There were 13 living‐related and 10 cadaveric renal transplants. The interval between renal transplantation and the development of tuberculosis ranged from 3 to 127 months with a median of 46 months. There were 18 cases of pulmonary tuberculosis, two cases of pulmonary plus laryngeal tuberculosis, two cases of disseminated tuberculosis, and one case of tuberculosis involving the urinary tract. Diagnosis was established by positive culture forMycobacterium tuberculosisin 21 patients and response to empirical anti‐tuberculosis treatment in two patients. The duration of symptoms before the diagnosis of tuberculosis was 27 ± 12 d. The patients were treated with standard anti‐tuberculosis drugs for 11 ± 3 months. The anti‐tuberculosis treatment was in general well‐tolerated. Five patients developed transient hepatitis, three patients developed thrombocytopenia and five patients developed gouty arthritis. One patient died 2 months after initiation of anti‐tuberculosis therapy. All other patients completed anti‐tuberculosis treatment. No recurrence of tuberculosis was observed after a median follow‐up of 90 months. We concluded that (i) tuberculosis is prevalent among southern Chinese renal transplant recipients; (ii) high index of suspicion for tuberculosis among renal transplant recipients is warranted to ensure early diagnosis and prompt initiation of treatment; and (iii) treatment with standard anti‐tuberculosis drugs for an extended period of time is well‐tolerated and is associated with favourable outcome.
Optimal prophylactic dosage and disposition of micafungin in living donor liver recipients
Authors: Kishino Satoshi , Ohno Keiko , Shimamura Tsuyoshi , Furukawa Todo Hiroyuki, Satoru
Published: October 2004

Abstract:  Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean Cmax and Cmin (trough) values of micafungin in plasma were 6.31 ± 1.08 and 1.65 ± 0.54 μg/mL, respectively. The mean elimination half‐life (t1/2) and mean area under the curve up to 12 h post‐dosing (AUC 0–12 h) were 13.63 ± 2.77 h and 50.04 ± 6.48 μg·h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (±SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 ± 0.04 and 0.054 ± 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40–50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH.
Living with a functioning kidney transplant at 74 yr or older: a national epidemiological study
Authors: Büchler Matthias , Halimi Jean‐Michel , Najjar Azmi Al , Giral Magalie , Hiesse Christian , Giraudeau Bruno , Jacquelinet Christian , Nivet Hubert , Lebranchu Yvon
Published: October 2004

Abstract:  The number of older patients living with a functioning kidney graft is increasing. However the safety of the immunosuppressive treatment and quality of life in this population have not yet been determined. All patients grafted in France since 1969, born before the January 1 1926 and living with a functioning graft on January 1 2000 were included in this national study including all 34 French transplant centers. Renal function, immunosuppressive treatment, comorbid conditions and quality of life were assessed. From the initial population of 446 patients, 113 (26.2%) were still alive in 2000 (study population). Mean age was 76 yr (range: 74–80) with a mean post‐transplant follow‐up of 9.9 yr (0.1–28.7). Average serum creatinine level was 129 μmol/L (55–286). Immunosuppression was heterogeneous and included triple therapy (18.6%), dual therapy (41.6%) and monotherapy (40.8%). A history of cancer was noted in 36 of the 113 patients (32.1%) whereas hypertension was the most frequent co‐morbid condition (80.3%). Estimated quality of life using the Karnofsky scale was between 80 and 100 in 78.4% of the patients. The immunosuppressive regimen in older renal transplant recipients living with a functioning graft varied widely among the 34 French transplant centers. Renal function in this group of patients was good and quality of life seemed excellent. Cardiovascular disease and malignancies were the main co‐morbid conditions.
Rhodococcus equi pneumonia in a renal transplant patient: a case report and review of literature
Authors: Arya Basant , Hussian Syed , Hariharan Sundaram
Published: October 2004

Abstract:  Immunocompromised patients are susceptible to many pathogens, including those that are predominantly problems in veterinary medicine. We report a case of a 42‐yr‐old white male who presented 19 months post‐cadaveric renal transplant (for IgA nephropathy) with a 5 d history of nausea, vomiting, abdominal cramping and diarrhea. Admission chest X‐ray revealed a suspicious mass lesion in the left lower lobe. Computed tomography (CT) guided biopsy of the lesion showed a large zone of CD68 +ve histiocytes in a non‐caseating granuloma. Gram stain revealed multiple gram‐positive rods within the histiocytes, which were eventually identified as R. equi. After 4 months of therapy with fluoroquinolones (Avelox) and Azithromycin a repeat CT showed complete resolution of the lesion. We reviewed the literature with special focus on the clinical features, challenges in diagnosis, and treatment of this rare infection (especially in the transplant patients who are also on immunosuppressive therapy).
Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults
Authors: Miyamoto Shungo , Polak Wojciech G. , Geuken Erwin , Peeters Paul M.J.G. , de Jong Koert P. , Porte Robert J. , van den Berg Aad P. , Hendriks Herman G. , Slooff Maarten J. H.
Published: October 2004

Abstract: The aim of this study is to analyse a single centre's experience with two techniques of liver transplantation (OLT), conventional (CON‐OLT) and piggyback (PB‐ES), and to compare outcome in terms of survival, morbidity, mortality and post‐operative liver function as well as operative characteristics. A consecutive series (1994–2000) of 167 adult primary OLT were analysed. Ninety‐six patients had CON‐OLT and 71 patients had PB‐ES. In PB‐ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB‐seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB‐sim). One‐, 3‐ and 5‐yr patient survival in the CON‐OLT and PB‐ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p = ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p = ns). Apart from the higher number of patients with cholangitis and sepsis in CON‐OLT group, morbidity, retransplantation rate and post‐operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB‐ES vs. 10.0 h in CON‐OLT), but in PB‐ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs. 10.7 h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p < 0.05). RBC use in the PB‐ES group was lower compared to the CON‐OLT group (4.0 min vs. 10.0 units, p < 0.05). Except for WIT and REVT there were no differences in operative characteristics between PB‐Sim and PB‐Seq groups. The WIT was significantly longer in PB‐Sim group compared with PB‐Seq group (64 min vs. 50 min, p < 0.05); however REVT was significantly shorter in PB‐Sim group (64 min vs. 97 min, p < 0.05). Results of this study show that both techniques are comparable in survival and morbidity; however PB‐ES results in shorter AAHP, FAHP, REVT and WIT as well as less RBC use. In the PB‐ES group there seems to be no adavantage for any of the revascularization protocols.
Impact of late conversion from C0 to C2 monitoring of microemulsified cyclosporine in pediatric living donor liver transplant recipients
Authors: Takatsuki Mitsuhisa , Chen Chao‐Long , Chen Yaw‐Sen , Wang Chih‐Chi , Lin Chih‐Che , Yang Chin‐Hsiang , Yong Chee‐Chien , Liu Yueh‐Wei
Published: October 2004

Abstract:  The efficacy and feasibility of 2‐h post‐dose level (C2) monitoring of cyclosporine in long‐term living donor liver transplantation (LDLT) is not clear. The aim of this study was to investigate the impact of late conversion from conventional trough‐level (C0) monitoring to C2 monitoring of a microemulsion form of cyclosporine (Neoral) in pediatric LDLT recipients. From June 1994 to August 2002, we performed 116 LDLTs in 115 patients. Initially, we adapted conventional C0 monitoring of Neoral, which was converted to C2 monitoring starting in January 2002. The 60 patients who were enrolled in the study had the following characteristics: they were younger than or equal to 15 yr at transplantation, and they had survived LDLT, and they had received a Neoral‐based immunosuppression regimen, and they underwent conversion to C2 more than 1 month after transplantation. We evaluated the impact of conversion on doses, blood levels, rejection, adverse effects, and patient/graft outcome. In the long‐term patients, the mean C2 levels immediately after conversion were higher than the target levels at any time point selected after transplantation; thus, 34 patients (57%) finally required a dose reduction of Neoral. The current mean C2 level was significantly lower than that observed immediately after conversion (584.6 ± 262.8 ng/ml vs. 893.1 ± 260.2 ng/ml, mean ± SD, p < 0.0001) with a mean follow‐up period of 7.4 ± 0.6 months (range: 5–8 months) after conversion. Only one patient encountered rejection after conversion (1.7%), and no de novo infection or adverse effects were observed. Traditional C0 monitoring of Neoral was safely replaced by C2 monitoring without an increase in the rejection rate or any adverse effects in pediatric LDLT patients. C2 monitoring contributed to the dose reduction of Neoral, which may lead to the avoidance of long‐term complications due to immunosuppression.
A report on the activity and clinical outcomes of renal non‐heart beating donor transplantation in the United Kingdom
Authors: Brook Nicholas R , Waller Julian R , Richardson Amanda C , Andrew Bradley J , Andrews Peter A , Koffman Geoff , Gok Mohammed , Talbot David , Nicholson Michael L
Published: October 2004

Abstract:  The use of kidneys from non‐heart beating donors (NHBDs) presents a paradox; whilst they provide more organs for transplantation, there is an increased risk of poor graft outcome, particularly in the short term. This study has highlighted the difference in early graft function and late graft survival between NHBD kidneys with short (controlled) and long (uncontrolled) warm ischaemic times. Whilst it would seem that it is preferable to use controlled donors only, their numbers are small. By employing a rational approach to the use of each of these types of kidney, such as structured viability assessment and risk analysis, it may be that the results of uncontrolled NHBD can be improved.
Spinal epidural lipomatosis following haploidentical allogeneic bone marrow transplantation for non‐Hodgkin lymphoma
Authors: Resnick Igor B , Gomori John M , Kiselgoff David , Lossos Alex , Zilberman Irina , Miron Svetlana , Bitan Menachem , Or Reuven , Slavin Shimon , Shapira Michael Y
Published: October 2004

Abstract:  Objectives:  Spinal epidural lipomatosis, is a very rare condition, usually seen as an uncommon complication of Cushing's syndrome secondary to chronic steroid therapy leading to increased fat deposits in the epidural space.

Case report:  We report the first documented case of acute symptomatic spinal epidural lipomatosis in a patient with relapsed non‐Hodgkin lymphoma. The patient underwent an allogeneic bone marrow transplantation (BMT) and a month of steroid treatment for acute graft vs. host disease (GvHD). He presented with a mild to moderate Cushing's syndrome and minimal obesity. He progressed rapidly to paraparesis, sensory deficit, urinary incontinence and finally respiratory arrest complicated with staphylococcal sepsis.

Conclusion:  Epidural lipomatosis, with subacute thecal sac compression, is a possible life‐threatening complication of relatively short‐term systemic glucocorticoid therapy for GvHD in BMT setting.
Alternative substrates for wild‐type and L109A E. coli CTP synthases
Authors: Lunn Faylene A. , Bearne Stephen L.
Published: October 2004

Cytidine 5′‐triphosphate (CTP) synthase catalyses the ATP‐dependent formation of CTP from uridine 5′‐triphosphate using either NH3 or l‐glutamine as the nitrogen source. The hydrolysis of glutamine is catalysed in the C‐terminal glutamine amide transfer domain and the nascent NH3 that is generated is transferred via an NH3 tunnel [Endrizzi, J.A., Kim, H., Anderson, P.M. & Baldwin, E.P. (2004) Biochemistry43, 6447–6463] to the active site of the N‐terminal synthase domain where the amination reaction occurs. Replacement of Leu109 by alanine in Escherichia coli CTP synthase causes an uncoupling of glutamine hydrolysis and glutamine‐dependent CTP formation [Iyengar, A. & Bearne, S.L. (2003) Biochem. J.369, 497–507]. To test our hypothesis that L109A CTP synthase has a constricted or a leaky NH3 tunnel, we examined the ability of wild‐type and L109A CTP synthases to utilize NH3, NH2OH, and NH2NH2 as exogenous substrates, and as nascent substrates generated via the hydrolysis of glutamine, γ‐glutamyl hydroxamate, and γ‐glutamyl hydrazide, respectively. We show that the uncoupling of the hydrolysis of γ‐glutamyl hydroxamate and nascent NH2OH production from N4‐hydroxy‐CTP formation is more pronounced with the L109A enzyme, relative to the wild‐type CTP synthase. These results suggest that the NH3 tunnel of L109A, in the presence of bound allosteric effector guanosine 5′‐triphosphate, is not leaky but contains a constriction that discriminates between NH3 and NH2OH on the basis of size.
Solution structure of Cu6 metallothionein from the fungus Neurospora crassa
Authors: Cobine Paul A. , McKay Ryan T. , Zangger Klaus , Dameron Charles T. , Armitage Ian M.
Published: October 2004

The 3D‐solution structure of Neurospora crassa Cu6‐metallothionein (NcMT) polypeptide backbone was determined using homonuclear, multidimensional 1H‐NMR spectroscopy. It represents a new metallothionein (MT) fold with a protein chain where the N‐terminal half is left‐handed and the C‐terminal half right‐handedly folded around a copper(I)‐sulfur cluster. As seen with other MTs, the protein lacks definable secondary structural elements; however, the polypeptide fold is unique. The metal coordination and the cysteine spacing defines this unique fold. NcMT is only the second MT in the copper‐bound form to be structurally characterized and the first containing the ‐CxCxxxxxCxC‐ motif. This motif is found in a variety of mammalian MTs and metalloregulatory proteins. The in vitro formation of the Cu6NcMT identical to the native Cu6NcMT was dependent upon the prior formation of the Zn3NcMT and its titration with Cu(I). The enhanced sensitivity and resolution of the 800 MHz 1H‐NMR spectral data permitted the 3D structure determination of the polypeptide backbone without the substitution and utilization of the NMR active spin 1/2 metals such as 113Cd and 109Ag. These restraints have been necessary to establish specific metal to cysteine restraints in 3D structural studies on this family of proteins when using lower field, less sensitive 1H‐NMR spectral data. The accuracy of the structure calculated without these constraints is, however, supported by the similarities of the 800 MHz structures of the α‐domain of mouse MT1 compared to the one recalculated without metal–cysteine connectivities.
IFN‐γ enhances TRAIL‐induced apoptosis through IRF‐1
Authors: Park Sang‐Youel , Seol Jae‐Won , Lee You‐Jin , Cho Jong‐Hoo , Kang Hyung‐Sub , Kim In‐Shik , Park Soo‐Hyun , Kim Tae‐Hyoung , Yim John H. , Kim Moonil , Billiar Timothy R. , Seol Dai‐Wu
Published: October 2004

Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF family and a potent inducer of apoptosis. TRAIL has been shown to effectively limit tumor growth in vivo without detectable cytotoxic side‐effects. Interferon (IFN)‐γ often modulates the anticancer activities of TNF family members including TRAIL. However, little is known about the mechanism. To explore the mechanism, A549, HeLa, LNCaP, Hep3B and HepG2 cells were pretreated with IFN‐γ, and then exposed to TRAIL. IFN‐γ pretreatment augmented TRAIL‐induced apoptosis in all these cell lines. A549 cells were selected and further characterized for IFN‐γ action in TRAIL‐induced apoptosis. Western blotting analyses revealed that IFN‐γ dramatically increased the protein levels of interferon regulatory factor (IRF)‐1, but not TRAIL receptors (DR4 and DR5) and pro‐apoptotic (FADD and Bax) and anti‐apoptotic factors (Bcl‐2, Bcl‐XL, cIAP‐1, cIAP‐2 and XIAP). To elucidate the functional role of IRF‐1 in IFN‐γ‐enhanced TRAIL‐induced apoptosis, IRF‐1 was first overexpressed by using an adenoviral vector AdIRF‐1. IRF‐1 overexpression minimally increased apoptotic cell death, but significantly enhanced apoptotic cell death induced by TRAIL when infected cells were treated with TRAIL. In further experiments using an antisense oligonucleotide, a specific repression of IRF‐1 expression abolished enhancer activity of IFN‐γ for TRAIL‐induced apoptosis. Therefore, our data indicate that IFN‐γ enhances TRAIL‐induced apoptosis through IRF‐1.
Trehalose synthase of Mycobacterium smegmatis
Authors: Pan Yuan T. , Koroth Edavana Vineetha , Jourdian William J. , Edmondson Rick , Carroll J. David , Pastuszak Irena , Elbein Alan D.
Published: October 2004

Trehalose synthase (TreS) catalyzes the reversible interconversion of trehalose (glucosyl‐α,α‐1,1‐glucose) and maltose (glucosyl‐α1‐4‐glucose). TreS was purified from the cytosol of Mycobacterium smegmatis to give a single protein band on SDS gels with a molecular mass of ≈ 68 kDa. However, active enzyme exhibited a molecular mass of ≈ 390 kDa by gel filtration suggesting that TreS is a hexamer of six identical subunits. Based on amino acid compositions of several peptides, the treS gene was identified in the M. smegmatis genome sequence, and was cloned and expressed in active form in Escherichia coli. The recombinant protein was synthesized with a (His)6 tag at the amino terminus. The interconversion of trehalose and maltose by the purified TreS was studied at various concentrations of maltose or trehalose. At a maltose concentration of 0.5 mm, an equilibrium mixture containing equal amounts of trehalose and maltose (42–45% of each) was reached during an incubation of about 6 h, whereas at 2 mm maltose, it took about 22 h to reach the same equilibrium. However, when trehalose was the substrate at either 0.5 or 2 mm, only about 30% of the trehalose was converted to maltose in ≥ 12 h, indicating that maltose is the preferred substrate. These incubations also produced up to 8–10% free glucose. The Km for maltose was ≈ 10 mm, whereas for trehalose it was ≈ 90 mm. While β,β‐trehalose, isomaltose (α1,6‐glucose disaccharide), kojibiose (α1,2) or cellobiose (β1,4) were not substrates for TreS, nigerose (α1,3‐glucose disaccharide) and α,β‐trehalose were utilized at 20 and 15%, respectively, as compared to maltose. The enzyme has a pH optimum of about 7 and is inhibited in a competitive manner by Tris buffer. [3H]Trehalose is converted to [3H]maltose even in the presence of a 100‐fold or more excess of unlabeled maltose, and [14C]maltose produces [14C]trehalose in excess unlabeled trehalose, suggesting the possibility of separate binding sites for maltose and trehalose. The catalytic mechanism may involve scission of the incoming disaccharide and transfer of a glucose to an enzyme‐bound glucose, as [3H]glucose incubated with TreS and either unlabeled maltose or trehalose results in formation of [3H]disaccharide. TreS also catalyzes production of a glucosamine disaccharide from maltose and glucosamine, suggesting that this enzyme may be valuable in carbohydrate synthetic chemistry.
Salt‐inducible kinase‐1 represses cAMP response element‐binding protein activity both in the nucleus and in the cytoplasm
Authors: Katoh Yoshiko , Takemori Hiroshi , Min Li , Muraoka Masaaki , Doi Junko , Horike Nanao , Okamoto Mitsuhiro
Published: October 2004

Salt‐inducible kinase‐1 (SIK1) is phosphorylated at Ser577 by protein kinase A in adrenocorticotropic hormone‐stimulated Y1 cells, and the phospho‐SIK1 translocates from the nucleus to the cytoplasm. The phospho‐SIK1 is dephosphorylated in the cytoplasm and re‐enters the nucleus several hours later. By using green‐fluorescent protein‐tagged SIK1 fragments, we found that a peptide region (586–612) was responsible for the nuclear localization of SIK1. The region was named the ‘RK‐rich region’ because of its Arg‐ and Lys‐rich nature. SIK1s mutated in the RK‐rich region were localized mainly in the cytoplasm. Because SIK1 represses cAMP‐response element (CRE)‐mediated transcription of steroidogenic genes, the mutants were examined for their effect on transcription. To our surprise, the cytoplasmic mutants strongly repressed the CRE‐binding protein (CREB) activity, the extent of repression being similar to that of SIK1(S577A), a mutant localized exclusively in the nucleus. Several chimeras were constructed from SIK1 and from its isoform SIK2, which was localized mainly in the cytoplasm, and they were examined for intracellular localization as well as CREB‐repression activity. A SIK1‐derived chimera, where the RK‐rich region had been replaced with the corresponding region of SIK2, was found in the cytoplasm, its CREB‐modulating activity being similar to that of wild‐type SIK1. On the other hand, a SIK2‐derived chimera with the RK‐rich region of SIK1 was localized in both the nucleus and the cytoplasm, and had a CREB‐repressing activity similar to that of the wild‐type SIK2. Green fluorescent protein‐fused transducer of regulated CREB activity 2 (TORC2), a CREB‐specific co‐activator, was localized in the cytoplasm and nucleus of Y1 cells, and, after treatment with adrenocorticotropic hormone, cytoplasmic TORC2 entered the nucleus, activating CREB. The SIK1 mutants, having a strong CRE‐repressing activity, completely inhibited the adrenocorticotropic hormone‐induced nuclear entry of green fluorescent protein‐fused TORC2. This suggests that SIK1 may regulate the intracellular movement of TORC2, and as a result modulates the CREB‐dependent transcription activity. Together, these results indicate that the RK‐rich region of SIK1 is important for determining the nuclear localization and attenuating CREB‐repressing activity, but the degree of the nuclear localization of SIK1 itself does not necessarily reflect the degree of SIK1‐mediated CREB repression.
Cloning of two melanocortin (MC) receptors in spiny dogfish
Authors: Klovins Janis , Haitina Tatjana , Ringholm Aneta , Löwgren Maja , Fridmanis Davids , Slaidina Maija , Stier Susanne , Schiöth Helgi B.
Published: October 2004

We report the cloning and characterization of two melanocortin receptors (MCRs) from the spiny dogfish (Squalus acanthias) (Sac). Phylogenetic analysis shows that these shark receptors are orthologues of the MC3R and MC5R subtypes, sharing 65% and 70% overall amino acid identity with the human counterparts, respectively. The SacMC3R was expressed and pharmacologically characterized in HEK293 cells. The radioligand binding results show that this receptor has high affinity for adrenocorticotropic hormone (ACTH)‐derived peptides while it has comparable affinity for α‐ and β‐melanocyte stimulating hormone (MSH), and slightly lower affinity for γ‐MSH when compared with the human orthologue. ACTH(1–24) has high potency in a second‐messenger cAMP assay while α‐ and γ‐MSH had slightly lower potency in cells expressing the SacMC3R. We used receptor–enhanced green fluorescence protein (EGFP) fusion to show the presence of SacMC3R in plasma membrane of Chinese hamster ovary and HEK293 cells but the SacMC5R was retained in intracellular compartments of these cells hindering pharmacological characterization. The anatomical distribution of the receptors were determined using reverse transcription PCR. The results showed that the SacMC3R is expressed in the hypothalamus, brain stem and telencephalon, optic tectum and olfactory bulbs, but not in the cerebellum of the spiny dogfish while the SacMC5R was found only in the same central regions. This report describes the first molecular characterization of a MC3R in fish. The study indicates that many of the important elements of the MC system existed before radiation of gnathostomes, early in vertebrate evolution, at least 450 million years ago.
Platelet aggregation is significantly associated with cardiovascular mortality in elderly patients
Authors: Kin Kyoko , Iwamoto Toshihiko , Kanaya Kiyoshi , Takasaki Masaru
Published: October 2004

Background:  The relationship between cardiovascular mortality and platelet function in elderly patients remains unclear.

Methods:  The outcomes for 347 consecutive patients aged 60 or older (mean age 77.5 years; 161 men and 186 women) who were treated without antiplatelet drugs on registration, were retrospectively studied after platelet aggregatability tests. The grading curve (GC) type, as an index of platelet aggregatability, was determined with an aggregometer and adenosine‐5′‐diphosphate as an agonist. Patients were classified into three groups according to GC type: Group I with suppressed aggregation (n = 40); Group II, normal aggregation (n = 208); and Group III, increased aggregation (n = 99). The mean follow‐up was 3.9 years.

Results:  There were three deaths in Group I, 33 in Group II, and 30 in Group III. The mean annual mortality rate was 2.1% in Group I, 4.0% in Group II and 7.5% in Group III. Although the most common cause of death was pneumonia in all three groups, the annual mortality rates due to vascular events were 0.7% in Group I, 0.6% in Group II and 4.2% in Group III. Cox proportional hazards models for vascular death yielded a hazard ratio of 1.5 in the increased GC type.

Conclusion:  These findings indicated that elderly patients with accelerated aggregation had higher mortality rates due to vascular events. Therefore, accelerated aggregation in the elderly suggested not only the progress of arteriosclerosis, but indications of antiplatelet therapy to prevent vascular events.
White matter changes in early‐onset Alzheimer's disease brains
Authors: Umahara Takahiko , Tsuchiya Kuniaki , Kiuchi Akihiro , Kanaya Kiyoshi , Iwamoto Toshihiko , Takasaki Masaru
Published: October 2004

Background:  The pathogenesis of white matter changes in Alzheimer's disease (AD) is not completely clear.

Methods:  We histologically and immunohistochemically examined white matter lesions in 11 brains with early onset Alzheimer's disease.

Results:  All 11 early onset AD brains had subcortical white‐matter pale lesions, but corpus callosum and optic radiation fibers were relatively well preserved. Some cases had severe white matter atrophy in the temporal lobe, and this is one cause of lateral ventricle inferior horn enlargement. Five of the 11 cases had white‐matter lesions without vascular changes, causing ischemic changes. It was difficult to clarify whether or not white‐matter changes were caused by secondary degeneration due to neuronal loss (Wallerian degeneration), because we could not explain why secondary degeneration occurred only in subcortical white matter excluding communicating fibers. Subcortical white‐matter beta protein deposits may not be associated with white‐matter lesions, because those beta deposits are located at marginal zones, while the myelin sheaths of those zones were relatively preserved.

Conclusion:  We believe that some AD brains had definite white‐matter lesions without ischemic changes.
Multiple myeloma with infiltration into skeletal muscle after injections of granulocyte‐colony stimulating factors
Authors: Kikuchi Motoo , Inagaki Toshiaki , Ueda Ryuzo
Published: October 2004

Multiple myelomas often occur in elderly people with age‐related complications as they age further. A 54‐year‐old man was first admitted with cerebral infarction and multiple myeloma (IgG kappa, stage IIIA) in November 1989. There was partial remission following chemotherapy. The karyotype of the marrow cells was 46, XY, and no p53 gene mutations were detected by polymerase chain reaction and single‐strand conformation polymorphism analysis. In February 1999, chemotherapy (melphalan, vindesine, ranimustine, prednisolone) was administered as a result of aggravation of the myeloma. Later, after daily subcutaneous injection of 50 µg of nartograstim for 6 days to treat febrile neutropenia, the soft tissues around the right eye swelled gradually, but without redness accompanied by an elevation of the serum creatine‐kinase concentration. When nartograstim was discontinued, however, the swelling disappeared and the creatine‐kinase level normalized. Then in July, on the sixth day of daily subcutaneous injections of 75 µg of filgrastim following the same chemotherapy regimen, similar swelling of the soft tissues occurred around the left eye, and was again reversed by withdrawal of the drug. In July 2000, infusion of dexamethasone was conducted, and following daily subcutaneous‐injection of 75 µg of filgrastim for 5 days, the right subclavicular soft tissue became swollen. The patient later died of myocardial infarction and an autopsy revealed an infiltration of myeloma cells into the right subclavicular muscle and bone marrow that was packed with myeloma cells. This case suggests that exposure to granulocyte‐colony stimulating factors enables myeloma cells to proliferate and infiltrate into soft tissues.
Imaging the large bowel in the elderly
Authors: Abdulla Aza , Thomas Adrian , Jenkins Anthony
Published: October 2004

Diseases of the large bowel are common in older patients and many of these, notably polyps, cancer, diverticular disease and ischemia, increase in incidence with age. A variety of imaging modalities are available in clinical practice but the choice of investigation should take into consideration not only its diagnostic yield but also the ability of the older patient to undergo the procedure with minimal discomfort. Perhaps more important is whether that investigation is likely to have an effect on the overall management of the patient.
Apathetic hyperthyroidism associated with thyroid storm
Authors: Yi‐Sun Yang , Chong‐Jen Yu , Fen‐Yu Tseng
Published: October 2004

We report the case of an 89‐year‐old man with fever and consciousness change who was found to be in thyroid storm. The patient was apathetic before this admission. The patient's general condition and mental status improved after prompt treatment for his thyrotoxicosis and he was discharged 4 weeks later with good mental and physical activity. Apathetic hyperthyroidism is a less common occult presentation of thyrotoxicosis when apathy, inactivity and depression replace the readily recognizable manifestations of hyperthyroidism. Although it can occur at any age, it is more commonly encountered in elderly patients. The apathetic presentation may enhance the difficulty in diagnosing thyroid crisis. A high index of clinical suspicion is needed in general practice.
Association of a single‐nucleotide polymorphism in the promoter region of leukemia inhibitory factor receptor gene with low bone mineral density in adult women
Authors: Sudo Yoshihiro , Ezura Yoichi , Ishida Ryota , Kajita Mitsuko , Yoshida Hideyo , Suzuki Takao , Hosoi Takayuki , Inoue Satoshi , Shiraki Masataka , Orimo Hajime , Ito Hiromoto , Emi Mitsuru
Published: October 2004

Background:  Osteoporosis is believed to result from the interaction among multiple environmental and genetic determinants that regulate bone‐mineral density (BMD).

Methods:  To investigate a potentially predisposing genetic factor in the onset of osteoporosis, we looked for a possible association between BMD in adult Japanese women and known polymorphisms in the leukemia inhibitory factor receptor gene (LIFR).

Results:  An association analysis of chromosomes from 384 volunteer subjects revealed significant correlation between the −603T > C variant of LIFR and radial BMD (r = 0.11, P = 0.032) in this test population. Comparisons of mean values of adjusted radial BMD among separate genotypic groups implied an allelic dosage effect, because homozygous carriers of T alleles of that SNP had the highest adjusted BMDs (0.403 ± 0.054 g/cm2); women homozygous for the C‐allele had the lowest (0.373 ± 0.042 g/cm2), and heterozygous individuals had intermediate scores (0.394 ± 0.056 g/cm2).

Conclusion:  This polymorphism in LIFR may be an important determinant of predisposition to postmenopausal osteoporosis.
Emotions, Personality, and Health: Introduction to the Special Issue
Authors: Zautra Alex J. , Davis Mary C. , Smith Bruce W.
Published: October 2004

AbstractOur intent in this introduction to the special issue onEmotions, Personality, and Healthis to alert readers to the logic underlying the editors' choices of topics for the issue and to provide a brief summary of its contents. We discuss how the 10 articles fit together to provide a mosaic of diverse approaches to the study of emotion. Collectively, these articles show ways that emotion research may be integrated with personality theory to inform us about the psychological dimensions of health and illness.
Healthy and Unhealthy Emotion Regulation: Personality Processes, Individual Differences, and Life Span Development
Authors: John Oliver P. , Gross James J.
Published: October 2004

AbstractIndividuals regulate their emotions in a wide variety of ways. Are some forms of emotion regulation healthier than others? We focus on two commonly used emotion regulation strategies:reappraisal(changing the way one thinks about a potentially emotion‐eliciting event) andsuppression(changing the way one responds behaviorally to an emotion‐eliciting event). In the first section, we review experimental findings showing that reappraisal has a healthier profile of short‐term affective, cognitive, and social consequences than suppression. In the second section, we review individual‐difference findings, which show that using reappraisal to regulate emotions is associated with healthier patterns of affect, social functioning, and well‐being than is using suppression. In the third section, we consider issues in the development of reappraisal and suppression and provide new evidence for a normative shift toward an increasingly healthy emotion regulation profile during adulthood (i.e., increases in the use of reappraisal and decreases in the use of suppression).