bluuebunny/crossref_metadata_2025 huggingface dataset:
CD4+ T‐cell memory: generation and multi‐faceted roles for CD4+ T cells in protective immunity to influenza
Authors: Swain Susan L. , Agrewala Javed N. , Brown Deborah M. , Jelley‐Gibbs Dawn M. , Golech Susanne , Huston Gail , Jones Stephen C. , Kamperschroer Cris , Lee Won‐Ha , McKinstry K. Kai , Román Eulogia , Strutt Tara , Weng Nan‐ping
Published: June 2006

Summary:  We have outlined the carefully orchestrated process of CD4+ T‐cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T‐cell interaction with antigen‐presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4+ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4+ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4+ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.
CD8+ T‐cell memory in tumor immunology and immunotherapy
Authors: Klebanoff Christopher A. , Gattinoni Luca , Restifo Nicholas P.
Published: June 2006

Summary:  The cellular and molecular mechanisms underlying the formation of distinct central, effector, and exhausted CD8+ T‐cell memory subsets were first described in the setting of acute and chronic viral diseases. The role of these T‐cell memory subsets are now being illuminated as relevant to the tumor‐bearing state. The generation and persistence of productive CD8+ T‐cell memory subsets is determined, in part, by antigen clearance, costimulation, responsiveness to homeostatic cytokines, and CD4+ T‐helper cells. By contrast, chronic exposure to antigen, negative costimulation, and immunomodulation by CD4+ T regulatory cells corrupt productive CD8+ T memory formation. It has become clear from human and mouse studies that the mere generation of CD8+ T‐cell memory is not a ‘surrogate marker’ for cancer vaccine efficacy. Some current cancer vaccine strategies may fail because they amplify, rather than correct or reset, the corrupted CD8+ memory population. Thus, much of the present effort in the development of vaccines for cancer and chronic infectious diseases is aimed at creating effective memory responses. Therapeutic vaccines for cancer and chronic infectious diseases may achieve consistent efficacy by ablation of the dysfunctional immune state and the provision of newly generated, non‐corrupted memory cells by adoptive cell transfer.
Development, trafficking, and function of memory T‐cell subsets
Authors: Lefrançois Leo
Published: June 2006

Summary:  The precise mechanisms that govern memory T‐cell lineage commitment during an immune response continue to be the subject of intense scrutiny. The existence of memory T‐cell subsets defined by location, function, and phenotype adds an additional layer of complexity to the overall memory T‐cell population. In this review, the integration of memory subset development and migration and the functional consequences of specific tissue localization are discussed.
Not‐so‐great expectations: re‐assessing the essence of T‐cell memory
Authors: Intlekofer Andrew M. , John Wherry E. , Reiner Steven L.
Published: June 2006

Summary:  We are often taught that secondary, or memory, responses by lymphocytes are more vigorous than primary responses. An expectation commonly associated with this notion is that the initial encounter with a pathogen should result in immunity to re‐infection. Although this outcome is sometimes the case, it is not universally true. In this review, we propose a unified model of T‐cell memory to explain the apparent successes and failures of eliciting vaccine‐like protection from prior encounters with pathogens. We speculate that memory T cells arise as an invariant consequence of clonal selection during an immune response. The quality of memory T cells, however, seems to vary in the degree to which they have acquired effector characteristics and, thus, their ability to confer immunity to re‐infection. Although not all memory T cells possess the embellished attributes of fully developed effector cells, they all seem to share the rudimentary quality of preserving an antigen specificity that has proven itself useful. We suggest that the ability to maintain the integrity of the T‐cell repertoire, more than establishing immunity to re‐infection, may represent the fundamental form of memory for the adaptive immune system.
Checkpoints in memory B‐cell evolution
Authors: McHeyzer‐Williams Louise J. , Malherbe Laurent P. , McHeyzer‐Williams Michael G.
Published: June 2006

Summary:  We consider four sequential phases in the evolution and consolidation of high affinity B‐cell memory as it is regulated in a cognate manner by antigen‐specific T‐helper (Th) cells. Sequential developmental checkpoints control cell fate in each phase of the pathway in ways that still remain poorly understood. The cellular composition and molecular attributes of each checkpoint are of great interest, but they may vary substantially depending on the nature of the immune stimulus. How this stimulus cascades through the innate and then the adaptive immune responses defines initial effector mechanisms in both Th and B‐cell compartments. The germinal center reaction controls memory B‐cell development with roles for antigen presentation and cognate Th cell regulation in the establishment of the memory B‐cell compartment. Antigen re‐challenge rapidly promotes effector responses from the memory compartments of both Th and B cells. Importantly, re‐challenge also expands and consolidates immune memory at the serological and cellular levels. We review recent advances in our understanding of memory B‐cell evolution with emphasis on the regulatory checkpoints that control lymphocyte fate at each developmental juncture.
Intrinsic properties of human and murine memory B cells
Authors: Anderson Shannon M. , Tomayko Mary M. , Shlomchik Mark J.
Published: June 2006

Summary:  The central question of how the immune system responds in a qualitatively and quantitatively better way upon re‐exposure to a pathogen is largely unanswered. Both the increased frequency of antigen‐specific memory cells and the intrinsic properties that memory cells acquire after antigen experience could contribute to the faster and more robust responses seen after repeated exposure to antigen. In the case of the memory B‐cell response, it has been difficult to discern the individual contributions of these two effects. However, because of recent advances in identifying memory B cells, there is an increasing understanding of the intrinsic properties of these cells. The current insights into the unique properties of memory B cells and the progress that has been made in understanding how these affect secondary responses in both the human and the mouse systems are discussed. In addition, we compare the various advantages and disadvantages inherent in each of these systems, in terms of studying the intrinsic properties of memory B cells, and introduce the details of the system that we have developed using conventional heavy chain transgenic (Tgic) mice, which addresses some of the drawbacks of traditional memory models.
Th1 memory: implications for vaccine development
Authors: Foulds Kathryn E. , Wu Chang‐you , Seder Robert A.
Published: June 2006

Summary:  T‐helper 1 (Th1) cells play a critical role, via interferon‐γ (IFN‐γ) production, in mediating intracellular killing against a variety of infectious pathogens. Thus, understanding the regulation of Th1 responses could provide better insight into vaccine design for infections requiring Th1 immunity. The cellular and molecular mechanisms that control the induction of Th1 effector cells have been well characterized. More recently, there has been substantial progress in furthering our understanding of the factors that regulate the development of Th1 memory cells. It is clear that Th1 responses are functionally heterogeneous, as defined by their ability to produce IFN‐γ. Furthermore, this heterogeneity has profound implications for the capacity of distinct lineages of Th1 cells to develop into memory cells. This review emphasizes the mechanisms controlling the differentiation of naïve CD4+ T cells into effector and then memory cells in a progressive manner. It highlights the importance of IFN‐γ as a positive regulator for inducing Th1 responses but a negative regulator for sustaining Th1 effector cells. In conclusion, we discuss how this current understanding of Th1 differentiation will inform vaccine design and better define immune correlates of protection.
Homeostasis of memory T cells
Authors: Surh Charles D. , Boyman Onur , Purton Jared F. , Sprent Jonathan
Published: June 2006

Summary:  The pool of memory T cells is regulated by homeostatic mechanisms to persist for prolonged periods at a relatively steady overall size. Recent work has shown that two members of the common γ chain (γc) family of cytokines, interleukin‐7 (IL‐7) and IL‐15, govern homeostasis of memory T cells. These two cytokines work in conjunction to support memory T‐cell survival and intermittent background proliferation. Normal animals contain significant numbers of spontaneously arising memory‐phenotype (MP) cells, though whether these cells are representative of true antigen‐specific memory T cells is unclear. Nevertheless, it appears that the two types of memory cells do not display identical homeostatic requirements. For antigen‐specific memory CD8+ T cells, IL‐7 is primarily important for survival while IL‐15 is crucial for their background proliferation. For memory CD4+ T cells, IL‐7 has an important role, whereas the influence of IL‐15 is still unclear.
Protective ‘immunity’ by pre‐existent neutralizing antibody titers and preactivated T cells but not by so‐called ‘immunological memory’
Authors: Zinkernagel Rolf M. , Hengartner Hans
Published: June 2006

Summary:  The idea of immunological memory originally arose from the observation that survivors of infections were subsequently resistant to disease caused by the same infection. While most immunologists accept a special ‘remembering’ memory quality, we have argued previously and document here that increased resistance against re‐infection, i.e. immunity, reflects low‐level antigen‐driven T‐ and B‐cell responses, resulting in elevated serum or mucosal titers of protective antibodies or of activated T cells, respectively. Periodic antigen re‐exposure is from within, by persisting infection (long‐term) or by immune complexes (short‐term), or from without, by low‐level re‐infections. This simple concept is supported by clinical evidence and model experiments but is often ignored, although this concept, but not so‐called ‘immunological memory’, as defined in textbooks (i.e. earlier and better responses of a primed host), is compatible with evolutionary maternal antibody transfer of protection as well as immunity against existing infections. The concept of ‘immunity without immunological remembering memory’ explains why it is easy to generate vaccines against acute cytopathic infections, particularly those of early childhood, where neutralizing antibodies are the key to protection, because it has been validated by adoptive transfer of maternal antibodies. It also explains why we have not succeeded (yet?) to generate truly protective vaccines against persisting infections, because we cannot imitate ‘infection immunity’ that is long‐lasting, generating protective T‐ and B‐cell stimulation against variable infections without causing disease by either immunopathology or tolerance.
Understanding and making use of human memory B cells
Authors: Lanzavecchia Antonio , Bernasconi Nadia , Traggiai Elisabetta , Ruprecht Claudia R. , Corti Davide , Sallusto Federica
Published: June 2006

Summary:  The work of our laboratory has focused on the study of human memory B cells. Using an in vitro approach we dissected the triggering requirements of B cells and unveiled a distinct role for TLRs in the activation of naive versus memory B cells. Using an ex vivo approach we analyzed the dynamics of memory B cells and ASCs and the kinetics of serum antibodies during secondary immune responses and in steady state conditions and used these quantitative data to build up a model of serological memory. According to this model memory B cells behave as `stem cells' capable of generating plasma cells and antibodies in an antigen‐dependent as well as in an antigen‐independent fashion. Finally we developed an efficient method to interrogate human memory B cells and to isolate human monoclonal antibodies. This method can be exploited for the production of neutralizing antibodies for serotherapy and for “analytic vaccinology”.
Two‐dose basiliximab compared with two‐dose daclizumab in renal transplantation: a clinical study
Authors: Lin Minzhuan , Ming Aimin , Zhao Ming
Published: June 2006

Abstract:  Background:  Addition of the interleukin‐2 receptor (IL‐2R) antagonists basiliximab or daclizumab to a calcineurin inhibitor‐based regimen significantly reduces risk of acute rejection with a tolerability profile similar to a placebo. Use of a truncated two‐dose regimen of daclizumab has been reported, but till date, there has been no controlled study of two‐dose daclizumab vs. two‐dose basiliximab.

Methods:  Deceased‐donor renal transplant recipients were randomized to basiliximab (20 mg on days 0 and 4) or daclizumab (50 mg on days 1 and 14) with cyclosporine, mycophenolate mofetil and corticosteroids. Flow cytometry was used to calculate the proportion of CD25+ T cells in peripheral blood.

Results:  Thirty patients were randomized to basiliximab and 28 to daclizumab. There was one patient death in each group, with no other graft losses. By six months, the incidence of biopsy‐proven acute rejection was 0% with basiliximab vs. 21.4% with daclizumab (p<0.05). Three patients in the daclizumab group required OKT3 for steroid‐resistant rejection. There were no between‐group differences in the incidence of infection. The proportion of CD25+ T cells declined markedly during the first two wk in both groups, but was significantly lower in the basiliximab group during weeks six to eight.

Conclusion:  Two doses of basiliximab are more effective than two 1 mg/kg doses of daclizumab in preventing acute rejection in de novo renal transplant patients receiving cyclosporine, mycophenolate mofetil and corticosteroid maintenance therapy. In patients receiving relatively low‐level immunosuppression in order to minimize toxicity, basiliximab may be preferable to a truncated daclizumab regimen.
Reactivation of hepatitis and lamivudine therapy in 11 HBsAg‐positive renal allograft recipients: a single centre experience
Authors: Murakami Reiichi , Amada Noritoshi , Sato Takaomi , Orii Takashi , Kikuchi Hiroyuki , Haga Izumi , Ohashi Yoichi , Okazaki Hajime
Published: June 2006

Abstract:  Background:  In hepatitis B virus (HBV) surface antigen (HBsAg) (+) renal allograft recipients, the mortality associated with liver disease reaches 37–78%. An antiviral agent, lamivudine, has recently been reported to be safe and effective for preventing hepatic damage in these patients, although either resurgence of HBV‐DNA levels after discontinuation or emerging resistant HBV mutants caused by long‐term administration are still unsettled.

Methods:  Between July 1976 and December 2003, 555 renal transplantations were performed in our centre. Of these, 11 patients who were HBsAg (+) at the time of transplantation (2.0%) were selected for this study. We investigated the incidence of hepatitis reactivation for three yr after transplantation and their clinical courses, including the efficacy of lamivudine therapy in seven of the 11 patients.

Results:  Six episodes of hepatitis reactivation developed in five of the 11 patients (45.5%) within three yr after transplantation. Five episodes of six occurred within four months after transplantation. The patient who underwent the most severe reactivation needed intensive care including lamivudine administration and plasma exchange. Lamivudine caused no severe adverse effects and HBV‐DNA levels dropped to under measurable levels within four months after lamivudine administration in all patients. Resistant HBV mutant emerged in only one patient, who had the longest lamivudine administration of 49 months.

Conclusions:  For HBsAg (+) renal allograft recipients, careful monitoring of HBV‐DNA levels and timely administration of lamivudine could prevent hepatic damage caused by reactivation of hepatitis.
Living or deceased donor kidney transplants for candidates with significant extrarenal morbidity
Authors: Kandaswamy Raja , Kasiske Bertram , Ibrahim Hassan , Matas Arthur J.
Published: June 2006

Abstract: Background: Individuals with end‐stage renal disease (ESRD) must weigh the benefits and risks of dialysis vs. a transplant. However, if the patient has extrarenal morbidity, survival may be limited. We have recommended that, when possible, recipients have a living donor (LD) transplant. However, it could be argued that for recipients with extrarenal morbidity, the potential benefit does not justify the donor risks and that, therefore, recipients with increased risks should be denied an LD transplant.

Materials and methods: We studied the outcome of LD vs. deceased donor (DD) transplants in recipients with extrarenal morbidity. For recipients with extrarenal morbidity, patient survival (p<0.01) and graft survival (p<0.01) rates were significantly better for LD (vs. DD) transplant recipients. We found no difference in death‐censored graft survival rates.

Conclusion: Kidney transplant recipients with extrarenal morbidity benefit from an LD transplant. Both donor and recipient informed consent is important.
Supporting medication adherence in renal transplantation (SMART): a pilot RCT to improve adherence to immunosuppressive regimens
Authors: De Geest Sabina , Schäfer‐Keller Petra , Denhaerynck Kris , Thannberger Nicole , Köfer Susanne , Bock Andreas , Surber Christian , Steiger Jürg
Published: June 2006

Abstract:  Background:  Although non‐adherence to an immunosuppressive regimen (NAH) is a major risk factor for poor outcome after renal transplantation (RTx), very few studies have examined non‐adherence intervention in this context. This pilot randomized controlled trial (RCT) tested the efficacy of an educational–behavioural intervention to increase adherence in non‐adherent RTx patients. We also assessed how NAH evolves over time.

Methods:  Eighteen RTx non‐adherent patients (age: 45.6±1.2 yr; 78.6% male) were randomly assigned to either an intervention group (IG) (n=6) or an enhanced usual care group (EUCG) (n=12), the latter receiving the usual clinical care. The IG received one home visit and three telephone interviews. We assessed NAH through electronic monitoring (EM) of medication intake during a nine‐month period (three months intervention, six months follow‐up).

Results:  Five of 18 patients withdrew. Inclusion in the study resulted in a remarkable decrease in NAH in both groups over the first three months (IG χ2=3.97, df=1, p=0.04; EUCG χ2=3.40, df=1, p=0.06). The IG showed the greatest decrease in NAH after three months, although this did not reach statistical significance (at 90 d, χ2=1.05, df=1, p=0.31). Thereafter, NAH increased gradually in both groups, reaching comparable levels at the end of the six‐month follow‐up (i.e. at nine months).

Conclusion:  Our findings suggest an inclusion effect. Although the intervention in this pilot RCT appeared to add further benefit in medication compliance, a lack of statistical power prevented us from making a strong statistical statement.
Primary endoluminal stenting of transplant renal artery stenosis from cadaver and non‐heart‐beating donor kidneys
Authors: Ridgway D. , White S. A. , Nixon M. , Carr S. , Blanchard K. , Nicholson M. L.
Published: June 2006

Abstract:  This study evaluated the efficacy of primary endovascular stenting in cases of transplant renal artery stenosis (TRAS) from cadaver and non‐heart‐beating donor kidneys. Patients with TRAS (n = 13) from a single‐centre transplant population (n = 476) were treated by primary percutaneous angioplasty and endovascular stenting. The short‐term efficacy of this intervention is demonstrated in terms of serum creatinine, glomerular filtration rate (GFR) biochemical, anti‐hypertensive medications and mean arterial blood pressure control. Stenting for TRAS was performed in male (n = 10) and female (n = 3) recipients. The median age at transplantation was 55 yr (range 10–67 yr). Stenting occurred at a median duration of 410 d post‐transplantation (range 84–5799 d). Mean serum creatinine (pre, 247 μmol/L; post, 214 μmol/L; p = 0.002), GFR (pre, 82.6 mL/min; post, 100.9 mL/min; p<0.001), arterial blood pressure (pre, 104 mmHg; post, 97 mmHg; p = 0.036) and the number of anti‐hypertensive medications required (pre, 3.4; post, 3.0; p = 0.002) showed significant improvement after post‐endovascular therapy. There were no serious complications encountered. Primary endovascular stenting of TRAS produces a significant improvement in biochemical parameters of renal graft function and in blood pressure stability, with the benefit of low patient morbidity and single arterial puncture. Primary endoluminal stenting of TRAS is a safe and effective procedure for the treatment of TRAS.
Tacrolimus and quality of life after kidney transplantation – a multicenter study
Authors: Bohlke Maristela , Rocha Marcos , Gomes Rafael Hissé , Marini Stela Scaglioni , Terhorst Lisoneide , Barcellos Franklin Correa , Hallal Pedro Curi , Casarini Dulce , Irigoyen Maria Claudia
Published: June 2006

Abstract:  Kidney transplantation is currently the treatment of choice for end‐stage renal disease. Although new immunosuppressive drugs have been introduced into clinical practice, the effect of such medication on quality of life (QoL) in transplant recipients is still unclear. The present study analyzes the impact of tacrolimus‐based immunosuppression on QoL in a representative sample of adult kidney transplant recipients from Rio Grande do Sul, a Brazilian southern state. This was a cross‐sectional multicenter study which used the SF‐36 Health Survey for measuring QoL. The effect of tacrolimus on QoL was adjusted for possible confounders using multiple linear regression. A total of 272 patients (from 11 different centers) were evaluated, 48 of them were treated with tacrolimus. Transplant patients in use of tacrolimus presented significant higher scores in the physical component summary of SF‐36 than non‐users (49.1 ± 8.3 vs. 46.1 ± 8.7; p = 0.03), and such difference was noted in the physical functioning and general health subscales (81.5 ± 17.1 and 74.7 ± 21.8; 74.6 ± 22.3 and 67.1 ± 22.3 for users and non‐users of tacrolimus, respectively, p < 0.05). The effect of tacrolimus remained significant after adjustment for age, gender, skin color and time since transplantation (coeff.: 2.83; 95% CI: 0.05–5.6, p = 0.045). The association between tacrolimus‐based immunosuppression and better perception of physical functioning and general health for renal transplant patients represents a significant finding as it may influence therapeutical decisions and contribute to maximize kidney transplantation benefits.
The transmission of donor‐derived malignant melanoma to a renal allograft recipient
Authors: Milton C.A. , Barbara J. , Cooper J. , Rao M. , Russell C. , Russ G.
Published: June 2006

Abstract:  The transmission to organ transplant recipients of donor origin malignancy in the allograft has been described. Here we report the transmission of malignant melanoma in a renal allograft transplanted from a multiorgan donor. The lung transplant recipient presented with an allograft lesion that was proven to be melanoma and of donor‐origin based on human leukocyte antigen (HLA)‐DR typing. One renal allograft recipient was undergoing his second deceased donor renal transplant, having lost his first graft from recurrent IgA nephropathy. He was unsensitized and immunosuppression consisted of tacrolimus, mycophenolate and prednisolone. He achieved stable graft function and there were no episodes of rejection. Four and a half months post‐transplant a diagnosis of donor origin melanoma in the lung recipient was made and his immunosuppression was stopped. He presented with clinical rejection two wk later and a transplant nephrectomy was undertaken. Histology demonstrated vascular and cellular rejection and there was a 3‐mm melanoma deposit with no evidence of tumour infiltrating lymphocytes. Three years post‐transplant he remained clinically well with no evidence of melanoma and received his third deceased donor renal transplant. This was complicated by cellular rejection in the first week treated with methylprednisolone and vascular rejection at day 10 treated with anti‐thymocyte globulin. Three months post‐transplant he has achieved good allograft function and remains well with no evidence clinically or on imaging of metastatic melanoma. The other renal allograft recipient was receiving his first deceased donor transplant, having end‐stage renal failure of uncertain aetiology. His immunosuppression was not stopped until melanoma was proven in the renal allograft pair six months post‐transplant and he then presented with clinical rejection six wk later. Transplant nephrectomy was undertaken and histology did not demonstrate melanoma, but severe vascular and cellular rejection was evident. At three‐yr post‐transplant he remains disease free clinically and on imaging. At present, the cardiac allograft recipient has no evidence of transmitted melanoma. The highest risk of transmission of donor origin melanoma appears to be from donors who are older and have died from an intracerebral haemorrhage. It is likely these donors have metastatic melanoma and their intracerebral haemorrhage is not primary but has occurred in an unrecognized metastatic cerebral deposit. While the occurrence of donor‐transmitted malignancy is not common, the outcome is often fatal.
Infectious complications after kidney transplantation: current epidemiology and associated risk factors
Authors: Alangaden George J , Thyagarajan Rama , Gruber Scott A. , Morawski Katherina , Garnick James , El‐Amm Jose M. , West Miguel S. , Sillix Dale H. , Chandrasekar Pranatharthi H. , Haririan Abdolreza
Published: June 2006

Abstract: Background: The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied.

Methods: This is an observational study in 127 adult recipients transplanted from 2001 to 2004. Patients received thymoglobulin (ATG) (50%) or basiliximab (50%) for induction and were maintained on mycophenolate mofetil, either tacrolimus (73%) or sirolimus (SRL) (27%), and prednisone (79%). Antimicrobial prophylaxis included perioperative cefazolin, trimethoprim/sulfamethaxazole for six months, valganciclovir for three months and nystatin for two months. Regression models were used to examine the association of various factors with infections.

Results: We observed 127 infections in 65 patients, consisting of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%) and surgical wound infections (7%). UTI was the most common infection in all post‐transplant periods.Enterococcusspp. (33%) andEscherichia coli(21%) were the most prevalent uropathogens. Of six patients with cytomegalovirus infection, none had tissue‐invasive disease. There were no cases of pneumocystis pneumonia or BK nephropathy. Six patients developed fungal infections. Two deaths due to disseminatedRhizopusandCandida albicansaccounted for a 1.5% infection‐related mortality. Retransplantation and ureteral stents were independently associated with UTI (OR = 4.5 and 2.9, p = 0.06 and 0.03, respectively), as were ATG and SRL with bacterial infections (OR = 3.3 and 2.5, p = 0.009 and 0.047, respectively).

Conclusion: This study suggests that the use of newer immunosuppressive agents in recent years is associated with some changes in the epidemiology of post‐transplant infections. Enterococci have become the predominant uropathogen. Invasive fungal infections, although rare, are often fatal.
Body mass index as a predictive factor for long‐term renal transplant outcomes in Asians
Authors: Chow Kai Ming , Szeto Cheuk Chun , Leung Chi Bon , Lui Siu Fai , Tong Yuen Fan , Li Philip Kam‐Tao
Published: June 2006

Abstract:  Background:  There is substantial evidence that renal transplant recipients with obesity or body mass index >30 kg/m2 have increased risk of graft loss. However, few data exist for Asian population; clinicians have to rely upon indirect evidence by extrapolating the results from Caucasians to Asian recipients.

Study:  Using data from a study population of 150 consecutive cadaveric or living related Chinese renal transplant recipients at our center between 1985 and 2002, we examined the effect of baseline body mass index cut‐off 25 kg/m2 on the transplant outcomes using Kaplan–Meier analysis and Cox proportional hazards analysis. Primary study end point was overall graft survival.

Results:  The mean body mass index was 22.9 ± 4.0 kg/m2. Thirty‐seven (25%) patients were classified as overweight and 113 patients as non‐overweight, using the cut‐off of 25 kg/m2. After median follow up period of nine yr, 15 graft losses (41%) occurred in the overweight group, as compared with 14 graft losses (12%) in the non‐overweight group. Kaplan–Meier estimates of cumulative graft survival at five yr were significantly worse for the overweight group than non‐overweight group (83.6% versus 92.7%, p = 0.0041). By multivariate Cox proportional hazards analysis, baseline body mass index ≥25 kg/m2 conferred a significantly higher risk of graft loss (with relative risk of 4.78, 95% CI = 1.52–15.2) and doubling of serum creatinine (relative risk 3.19, 95% CI = 1.22–8.40). Death with a functioning graft occurred in 11% of overweight recipients, compared with 3% among the non‐overweight group (p = 0.041).

Conclusion:  Our results draw attention to a recipient body mass index cut‐off value ≥25 kg/m2, which might confer an increased risk of graft loss in Asian kidney transplant populations.
Revival of effective and safe high‐dose mizoribine for the kidney transplantation*
Authors: Sugitani Atsushi , Kitada Hidehisa , Ota Morihito , Yoshida Junichi , Doi Atsushi , Hirakata Hideki , Tanaka Masao
Published: June 2006

Abstract:  We investigated whether high‐dose Mizoribine (MIZ: a water‐soluble anti‐metabolite), 4–6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24‐male and 16‐female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas–kidney transplantation four examples. Of these, 33 patients were on Tacrolimus‐based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post‐transplant lymphoproliferative disorder in one case (2.5%). We initiated 4–6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient.

There was no big difference in the sCr value before and after MIZ administration in each individual patient, 1.79 ± 1.37 and 1.65 ± 1.30 mg/dL, respectively. A 12 h pharmaco‐kinetic study of MIZ revealed that a peak value reached 2.87 μg/mL on average at three h (C3) followed by a slow decrease afterward. Acute rejection occurred in two cases and adverse effects were seen in five cases. The results of analysis of 349 points divided into three groups by renal function were as follows; poor renal function Group A revealed a trough level of 2.21 ± 0.99 μg/mL and dosage 2.20 ± 1.06 mg/kg, good renal function Group B had a trough level of 1.06 ± 0.82 μg/mL and dosage 4.40 ± 1.72 mg/kg, and excellent function Group C had a trough level of 0.92 ± 0.55 μg/mL and dosage of 4.36 ± 1.08 mg/kg.

High‐dose MIZ 4–6 mg/kg/d is an anti‐metabolite having an equivalent immunosuppressive effect, fewer serious adverse events and good cost‐effectiveness as MMF even for patients with prolonged hemodialysis period and declined digestive function in Japan.
End‐to‐side caval anastomosis in adult piggyback liver transplantation
Authors: Polak Wojciech G. , Nemes Balazs A. , Miyamoto Shungo , Peeters Paul M.J.G , De Jong Koert P. , Porte Robert J , Slooff Maarten J.H.
Published: June 2006

Abstract:  No consensus exists regarding the optimal reconstruction of the cavo‐caval anastomosis in piggyback orthotopic liver transplantation (PB‐LT). The aim of this study was to analyze our experience with end‐to‐side (ES) cavo‐cavostomy. Outcome parameters were patient and graft survival and surgical complications. During the period 1995–2002 146 full‐size PB‐LT in 137 adult patients were performed with ES cavo‐cavostomy without the routine use of temporary portocaval shunt (TPCS). In 12 patients (8%) this technique was used for implantation of second or third grafts. Veno‐venous bypass was not used in any case and TPCS was performed only in eight patients (6%). One‐, three‐ and five‐yr patient and graft survival were 84%, 79% and 75%, and 81%, 74% and 69%, respectively. The median number of intraoperative transfusion of packed red blood cells (RBC) was 2.0 (range 0–33) and 30% of the patients (n = 43) did not require any RBC transfusion. Surgical complications of various types were observed after 49 LT (34%) and none of the complications was specifically related to the technique of ES cavo‐cavostomy. Our experience indicates that PB‐LT with ES cavo‐cavostomy is a safe procedure, can safely be performed without the routine use of a TPCS, has a very low risk of venous outflow obstruction and can also be used effectively during retransplantations.
Effect of concurrent elemental diet on infliximab treatment for Crohn’s disease
Authors: Tanaka Torao , Takahama Kazuya , Kimura Tomomi , Mizuno Tamaki , Nagasaka Mitsuo , Iwata Katsumi , Nakano Hiroshi , Muramatsu Masaaki , Takazoe Masakazu
Published: June 2006

Background:  Infliximab and elemental diet (ED) have been shown to be effective in the management of Crohn’s disease. However, few experiences have been reported regarding their combination therapy. The aim of the present study was to investigate the efficacy and safety of infliximab in Japanese patients, the first such study in Asia, as well as the effect of concomitant ED.

Methods:  One hundred and ten consecutive patients receiving infliximab were followed up to week 16 after the last infusion, and clinical response and primary outcome were collected. A response was defined as a reduction in Harvey–Bradshaw Index for inflammatory disease and closure of fistula in fistulizing disease.

Results:  Out of 75 inflammatory and 35 fistulizing disease patients, 68 (90.7%) and 25 (71.4%) responded at week 4, and 38 (50.7%) and 14 (40.0%) continued to respond until week 16, respectively. Interestingly, inflammatory disease patients with concurrent ED had a significantly higher response rate at week 16 (68.4%) than those without ED (32.4%, P = 0.0026). The effects of ED were independent of the usage of azathioprine and smoking habit.

Conclusions:  Infliximab was clinically useful in the treatment of Crohn’s disease in Japanese patients as well as in those in Western countries. The efficacy of concurrent ED was suggestive and should be confirmed in a randomized controlled study.
Mutation of keratin 8 in patients with liver disease
Authors: Schöniger‐Hekele Maximilian , Petermann Dagmar , Müller Christian
Published: June 2006

Background:  Epithelial tissues of the gastrointestinal tract and the liver express predominantly cytokeratin 8 and cytokeratin 18. In vitro experiments and animal studies have demonstrated a protective influence of keratin 8 and keratin 18 against toxic damage of hepatocytes. A specific mutation of keratin 8 (G61C) was found to be a genetic risk factor for the development of cryptogenic liver cirrhosis. The purpose of the present paper was therefore to determine the prevalence of cytokeratin 8 (G61C) and cytokeratin 18 mutations (Y53H) in patients with liver disease.

Methods:  Overall 152 patients (male, n = 93, 61%; female, n = 59, 39%) were included in the present study. The 152 patients consisted of 107 patients with liver disease (70.4%; male, n = 71, 66.4%; female, n = 36, 33.6%) and 45 control patients (29.6%; male, n = 22, 48,9%; female, n = 23, 51,1%) without liver disease. Of the patients with liver disease 46 had alcoholic liver disease; 25, chronic hepatitis C; 15, cryptogenic liver disease; and 21, other liver diseases of various etiologies. Cytokeratin 8 and 18 genotypes were specified by polymerase chain reaction (PCR) amplification and direct sequence analysis was used to detect the previously described mutations in cytokeratin 8 (G61C) and in cytokeratin 18 (Y53H).

Results:  Four out of 152 patients (male n = 2, female n = 2) with a mutation (G61C) in cytokeratin 8 were found. The etiology was alcoholic liver disease (n = 1), cryptogenic liver disease (n = 1) and idiopathic liver disease with minimal changes in liver biopsy (n = 1). Also, one out 45 disease control patients with an adenoma of the colon but without liver disease was found to carry the mutation G61C of cytokeratin 8. Therefore, the mutation G61C in cytokeratin 8 was found in 2.8% of patients with liver disease and in 2.2% of control patients without liver disease. Two of 15 patients (13.3%) with cryptogenic liver disease had the mutation G61C in cytokeratin 8 (P = 0.069 vs patients with non‐cryptogenic liver disease). In the 152 patients studied, no mutation in cytokeratin 18 was found.

Discussion:  The mutation G61C in the cytokeratin 8 gene was found in one patient with alcoholic liver disease and in two patients with liver disease of unknown etiology. Also, one patient without liver disease had the cytokeratin 8 G61C mutation. In summary, the cytokeratin 8 mutation G61C, which has been found to be associated with cryptogenic liver cirrhosis, was also found in the present patient population. However, the clinical relevance is yet to be determined in further investigations.
Colonic amoebiasis and spirochetosis: Morphological, ultrastructural and microbiological evaluation
Authors: Calderaro Adriana , Villanacci Vincenzo , Bommezzadri Simona , Gorrini Chiara , Piccolo Giovanna , Aquilano Maria Costanza , Incaprera Marina , Viviani Giovanni , Dettori Giuseppe , Chezzi Carlo
Published: June 2006

Background:  The present study reports on a prompt diagnosis of colonic amoebiasis with colonic spirochetosis by Brachyspira aalborgi and B. pilosicoli; such diagnosis allowed exclusion of other diseases and resolution of the case after specific treatment.

Methods and Results:  A 37‐year‐old Italian man with a history of several months’ mucosal diarrhea travelled to Greece, Romania and Tunisia. After his last trip he presented with an increase of up to 3–5 discharges daily, associated with bloody diarrhea, supporting the clinical suspect of inflammatory bowel disease. Colonoscopy revealed erosions from the cecum to the rectum, and ulcers both in the descending and sigmoid colon. Structures resembling amoebic trophozoites and sinusoidal microorganisms were observed in the colonic biopsies at histopathology and electron microscopy. Entamoeba histolytica DNA was detected by small‐subunit rDNA polymerase chain reaction (PCR) from feces, rectal biopsies and isolated trophozoites. Spirochetes were identified from feces, colonic biopsies and cultures using a 16S rDNA restriction fragment length polymorphism‐PCR specific for the detection of B. aalborgi and B. pilosicoli. After therapy, the patient was restored to health.

Conclusions:  The rapid identification of E. histolytica, B. aalborgi and B. pilosicoli using traditional and specific and sensitive molecular methods permitted an accurate diagnosis and a specific therapy. It is suggested that mixed infection by parasites and spirochetes might occur more frequently than expected: it would be of extreme interest and importance to intensify clinical findings, and one infection should not prompt the pathologist/clinician to stop looking.
What are the risk factors for aggravation of esophageal varices in patients with hepatocellular carcinoma?
Authors: Kadouchi Kaori , Higuchi Kazuhide , Shiba Masatsugu , Okazaki Hirotoshi , Yamamori Kazuki , Sasaki Eiji , Tominaga Kazunari , Watanabe Toshio , Fujiwara Yasuhiro , Oshitani Nobuhide , Arakawa Tetsuo
Published: June 2006

Background and Aim:  The risk factors for aggravation of esophageal varices (EV) in patients with hepatocellular carcinoma (HCC) are poorly understood. The aim of this study was to evaluate the effects of HCC on the appearance of the red color (RC) sign on EV and also investigate whether risk factors for the appearance of the RC sign differed between patients with and without HCC.

Methods:  A total of 243 patients with cirrhosis (127 with HCC, 116 without HCC) without the RC sign, with no previous variceal hemorrhage, and not on prophylactic treatment for EV were enrolled. The endpoint was defined as being either when the RC sign was first noted, or when variceal bleeding occurred. In patients without HCC, follow‐up was discontinued if HCC was discovered. The risk factors were analyzed by Cox proportional hazards regression.

Results:  In patients with HCC, portal vein tumor thrombus was a statistically independent risk factor (risk ratio [RR] 4.58, 95% confidence interval [CI] 1.32–15.86), although the presence of HCC was not. A large HCC (≥50 mm) tended to be a risk factor, but this was not statistically significant (RR 2.50, 95%CI 0.98–6.39). Child–Pugh classification and low platelet count were common risk factors regardless of whether HCC was present or not.

Conclusions:  Portal vein tumor thrombus, but not the presence of HCC, was a significant risk factor for aggravation of EV in patients with HCC. Cirrhotic patients with portal vein tumor thrombus should receive more aggressive management of portal hypertension to prevent aggravation of EV.
Cytochrome P450 2C19 polymorphism influences the preventive effect of lansoprazole on the recurrence of erosive reflux esophagitis
Authors: Kawamura Masashi , Ohara Shuichi , Koike Tomoyuki , Iijima Katsunori , Suzuki Hitoshi , Kayaba Shoichi , Noguchi Kenji , Abe Shinya , Noguchi Mitsunori , Shimosegawa Toru
Published: June 2006

Background:  The efficacy of lansoprazole (LPZ) at inhibiting gastric acid secretion is influenced by cytochrome P450 2C19 (CYP2C19) polymorphism. The purpose of the present study was to investigate whether CYP2C19 polymorphism had an influence on the remission of erosive reflux esophagitis (RE) during maintenance therapy with LPZ.

Methods:  Eighty‐two Japanese patients with initial healing of erosive RE by 8 weeks of LPZ therapy were enrolled. As maintenance therapy, the patients were treated with LPZ (15 mg/day) for 6 months. The CYP2C19 genotype, Helicobacter pylori infection status, and serum pepsinogen (PG) I/II ratio were assessed before treatment. The patients were investigated for relapse by endoscopy at 6 months or when symptoms recurred.

Results:  The proportion of patients in remission after 6 months was 61.5%, 78.0%, and 100% among homozygous extensive metabolizers (homo‐EM), heterozygous EM (hetero‐EM), and poor metabolizers (PM), respectively. The percentage of PM patients who remained in remission was significantly higher than that of homo‐EM or hetero‐EM.

Conclusions:  The efficacy of LPZ (15 mg/day) as maintenance therapy for erosive RE is influenced by CYP2C19 polymorphism.
Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease
Authors: Kaneda Hiroyuki , Hashimoto Etsuko , Yatsuji Satoru , Tokushige Katsutoshi , Shiratori Keiko
Published: June 2006

Background and Aim:  Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver disease from simple steatosis to cirrhosis. Therefore, markers for predicting NAFLD with advanced fibrosis are needed. The aim of this study was to establish non‐invasive predictive markers of liver fibrosis in NAFLD.

Methods:  One hundred and forty‐eight patients were diagnosed as having biopsy‐proven NAFLD. In order to separately identify severe fibrosis (bridging fibrosis plus cirrhosis) and cirrhosis, the patients were analyzed twice: first, as mild fibrosis versus severe fibrosis; and second, as non‐cirrhosis versus cirrhosis. Univariate and multivariate analyses were conducted. The diagnostic ability to detect severe fibrosis and cirrhosis was assessed by the area under the receiver operating characteristic curve. The cut‐off values of serum markers to detect severe fibrosis and cirrhosis were determined.

Results:  Hyaluronic acid was selected as a predictive marker for severe fibrosis. A cut‐off value of 42 ng/mL of hyaluronic acid had a 100% predictive value for patients free of severe fibrosis and was associated with an optimal combination of sensitivity (100%, 95% confidence interval [CI] 90–100%) and specificity (89%, 95%CI 80–94%). The platelet count was found to be an independent predictor of cirrhosis. A cut‐off value of 16 × 104/µL for the platelet count was associated with an optimal combination of sensitivity (100%, 95%CI 82–100%) and specificity (95%, 95%CI 90–98%).

Conclusions:  Hyaluronic acid levels can accurately identify NAFLD patients with severe fibrosis, and the platelet count can identify NAFLD patients with cirrhosis. Thus, these markers offer a good guideline for the assessment of hepatic fibrosis in the many patients with NAFLD.