bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients
Authors: Vasquez EM , Sifontis NM , Pollak R , Benedetti E
Published: March 2003

Purpose: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long‐term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation.  Methods: Forty‐four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1–2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti‐rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone±azathioprine. Anti‐rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy.  Results: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF‐associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One‐yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One‐year patient survival was 93 and 100%, respectively (p>0.05).  Conclusions: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow‐up year.
A randomized prospective trial of OKT3 induction in the current immunosuppression era
Authors: Henry Mitchell L , Pelletier Ronald P , Elkhammas Elmahdi A , Bumgardner Ginny L , Davies Elizabeth A , Ferguson Ronald M
Published: March 2003

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri‐transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral®, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty‐four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3‐treated group, but were not significantly different. The low incidence of rejection in the OKT3‐treated group was intriguing and validates the use of antibody therapy in the early post‐operative periods even in the era of improved baseline immunosuppression.
A multicenter, open‐label, comparative trial of two daclizumab dosing strategies vs. no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids for the prevention of acute rejection in simultaneous kidney–pancreas transplant recipients: interim analysis
Authors: Stratta Robert J , Alloway Rita R , Hodge Ernest , Lo Agnes ,   for the Pancreas Investigators Vital Outcomes Trial (PIVOT) Study Group
Published: March 2003

Introduction: The safety and efficacy of daclizumab (1 mg/kg/dose every 14 d for five doses) has been established in kidney and heart transplant recipients. Alternative dosing regimens based on pharmacokinetic simulation and limited clinical trials are being investigated. The purpose of this ongoing multicenter study is to determine the safety and efficacy of two dosing regimens of daclizumab as an adjunctive immunosuppressive agent compared with no antibody induction in simultaneous kidney–pancreas transplant (SKPT) recipients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and steroids as primary immunosuppression.

Methods: This is an interim report of a multicenter, prospective, open‐label, randomized study with a target enrolment of 290 patients. Eligible SKPT patients were randomized to one of three groups: daclizumab 1 mg/kg/dose every 14 d for five doses (Group I), daclizumab 2 mg/kg/dose every 14 d for two doses (Group II), and no antibody induction (Group III). The primary endpoint of the study is a composite of the incidence of presumed or biopsy‐proven kidney or pancreas rejection, graft loss, or death within the first 6 months post‐transplantation.

Results: A total of 166 patients were randomized into the three groups [Group I (n=70), Group II (n=74), Group III (n=22)]. Demographic and transplant characteristics were similar among the groups. At a minimum follow‐up of 3 months, patient, kidney and pancreas graft survival rates were similar among the three groups. However, the rates of acute renal allograft rejection were 18% (Group I), 8% (Group II), and 36% (Group III), p < 0.05. The probabilities of either kidney or pancreas allograft rejection were 22% (Group I), 8% (Group II), and 38% (Group III). At 3 months, the actuarial event‐free survival (no acute rejection, allograft loss, or death) rates were 67, 81 and 50% in Groups I, II, and III, respectively. There were no differences in the incidence of infectious complications among the groups and no serious adverse events associated with daclizumab were observed.

Conclusions: The two‐dose regimen (Group II) appears to be as effective as the five‐dose regimen (Group I) in preventing acute rejection after SKPT and is associated with the lowest acute rejection rates and the highest rate of event‐free survival (no rejection or graft loss). However, the benefits of daclizumab compared with no antibody induction await larger sample size accrual.
The effect of angiotensin converting enzyme gene polymorphism on chronic allograft dysfunction in living donor renal transplant recipients
Authors: Yildiz Alaattin , Yazici Halil , Çine Naci , Akkaya Vakur , Kayacan S Mehmet , Sever Mehmet Sükrü , Erginel‐Ünaltuna Nihan
Published: March 2003

Background. Chronic allograft dysfunction (CAD), the major cause of the failure of kidney allografts, may be caused by immunological and non‐immunological haemodynamic factors. Renin–angiotensin system has been implicated in the development of intraglomerular hypertension and has a central role on progression in chronic renal disease. Polymorphism in 16th intron of the ACE gene has been reported to predict the circulating angiotensin II levels. The aim of this study was to investigate the effect of the both recipient and donor angiotensin converting enzyme (ACE) genotype on the development of CAD in renal allograft recipients.

Patients and methods. A total of 143 renal transplant recipients (95 male, 48 female, mean age 32 ± 10 yr) were included. In order to exclude the effect of cold ischaemia, only patients transplanted from living donors were selected. Factors analysed in the development of CAD were donor and recipient age, past history of acute rejection, presence of hypertension and hypercholesterolaemia, serum uric acid level and ACE gene polymorphism.

Results. Forty of the patients (28%) had CAD. Homozygous deletion type ACE gene polymorphism was detected in 59 renal transplant recipients (42%) and in 31 donors of the patients (37%). On comparing patients with and without CAD, donor age, rate of acute rejection and hypertension and serum uric acid levels were significantly higher in CAD (+) groups. Neither recipient nor donor ACE genotype was associated with time to CAD. Cox regression analysis revealed donor age (p < 0.001), presence of hypertension (p=0.002) and serum uric acid levels (p=0.009), but neither donor nor recipient ACE genotype as independent factors for predicting development of CAD.

Conclusion. Donor age, presence of hypertension and serum uric acid levels was independent factors. Donor and recipient ACE genotype seemed to have no influence on the development of CAD in living donor transplanted patients.
The oxidative metabolism of polymorphonuclear neutrophils in pediatric liver graft recipients
Authors: Ganschow R , Albani J , Rogiers X , Burdelski M
Published: March 2003

Background: Data on the oxidative metabolism of polymorphonuclear neutrophils (PMN) after solid organ transplantation are very limited. We hypothesized that immunosuppressive agents reduce the capacity of PMN to produce reactive oxygen species, such as O2−, H2O2, OH, and OCL−leading to an increased susceptibility to infectious complications after liver transplantation.

Methods: A lucigenin‐enhanced chemiluminescence (CL) assay was used with soluble and particulate stimuli to study the oxidative metabolism of PMN in pediatric liver graft recipients. Sixteen patients (median age: 2.4 yr) were enrolled in a prospective study and integrated CL response was compared with the CL activity of 29 healthy controls.

Results: In the second week post‐transplant, we found a significantly reduced CL activity. Pre‐operatively, and after lowering steroids and cyclosporin A (CsA) the oxidative burst was normal.

Conclusions: Our data suggest that CsA and steroids may not only influence T and B cells but also PMN, which may be a relevant factor for the incidence of infectious complications in pediatric liver graft recipients.
Calcineurin inhibitor nephrotoxicity: reduction in dose results in marked improvement in renal function in patients with coexisting chronic allograft nephropathy
Authors: Pilmore Helen L , Dittmer Ian D
Published: March 2003

Background: Calcineurin inhibitors (CNI) have significantly reduced the incidence of acute rejection. Nephrotoxicity however, may contribute to long‐term allograft dysfunction.

Methods: Forty‐six biopsies from patients who had been transplanted for more than 6 months were examined. Sixteen biopsies had evidence of chronic allograft nephropathy (CAN) alone, 21 biopsies had evidence of coexisting CAN in addition to histological evidence of calcineurin inhibitor nephrotoxicity (CNIN) while nine had neither evidence of nephrotoxicity nor CAN. Patients with evidence of nephrotoxicity underwent a reduction in dose of CNI while those with CAN alone had no change in therapy. Renal function was followed for a mean of 17.4 months after biopsy.

Results: The serum creatinine at the time of diagnostic renal biopsy was comparable between those with CAN alone (mean 0.25 ± 0.18 mmol/L) and those with coexisting CNIN (mean 0.23 ± 0.05 mmol/L, p=0.33).

The patients with CNIN however, had a rapid improvement in renal function within 1 month after dose reduction. This was sustained for the duration of follow‐up (mean serum creatinine 0.162 ± 0.038 mmol/L at 1 yr after dose reduction; p=0.001). In comparison, those with CAN alone had a gradual decline in renal function with a serum creatinine at 1 yr after biopsy of 0.31 ± 0.187, p=0.01.

Conclusion: Reduction in the dose of CNI in those with histological evidence of nephrotoxicity resulted in a sustained improvement in renal function.
Nocardiosis in tropical renal transplant recipients
Authors: John George T , Shankar Viswanathan , Abraham Abi M , Mathews Mary S , Thomas Paulose P , Jacob Chakko K
Published: March 2003

Background: The epidemiology of nocardiosis in the tropics among renal transplant recipients has not been reported.

Methods: An evaluation of nocardiosis for 30 yr in one of the large transplant centres in South Asian region.

Results: Of the 1968 patients who received primary renal allografts at Christian Medical College & Hospital, 27 patients developed nocardiosis over 30 yr. Early nocardiosis (≤ 2 yr) was associated with chronic liver disease and the use of cyclosporin (CsA) as compared with its later occurrence (>2 yr). Seventeen patients (63%) had two or more associated post‐transplant infections, of whom 10 had tuberculosis. Mortality in these patients was associated with chronic liver disease.

Conclusions: Nocardiosis manifests earlier (<2 yr) in CsA treated patients who have chronic liver disease. Among renal transplant recipients of the tropics nocardiosis is a marker of a high susceptibility to tuberculosis and other infections, the association with tuberculosis is stronger in those developing early nocardiosis (<2 yr). Chronic liver disease is a risk factor for death in patients with nocardiosis especially when associated with tuberculosis. This report constitutes the largest single centre experience among renal transplant recipients.
Role of anti‐β 2 glycoprotein 1 antibodies in ESRD patients with antiphospholipid antibody syndrome
Authors: Vaidya S , Daller J , Gugliuzza K
Published: March 2003

Vaidya S, Daller J, Gugliuzza K. Role of anti‐β 2 glycoprotein 1 antibodies in ESRD patients with antiphospholipid antibody syndrome. Clin Transplant 2002: 16: 362–367. © Blackwell Munksgaard, 2002

Introduction. End stage renal disorder (ESRD) patients with antiphospholipid antibody syndrome (APAS) are at high risk for the development of post‐transplant renal thrombosis. Positive titre of anticardiolipin antibodies (ACA) is considered a major characteristic of APAS. However, several studies have suggested that ACA in patients with APAS do not bind to phospholipids alone. Beta 2 glycoprotein 1 (β2gp1), a 40‐kD plasma protein is required. In this study, we have tested a hypothesis that significant portions of our ESRD patients with APAS have antibodies only to β2gp1.

Methods: Serum samples from each of 169 ESRD patients waiting for cadaver renal transplant in August 2000 were tested for ACA and anti‐β 2gp1 antibodies by enzyme‐linked immunoabsorbent assay (ELISA) method. Twenty‐four of these patients had clotting disorders that met the criteria established by the Eighth International Symposium on Antiphospholipid Antibodies (). They included frequent areterio–venous (a–v) shunt thrombosis, cerebrovascular thrombosis, lupus, frequent abortions and microrenal angiopathy.

Results: Thirty‐three of the patients (20%) had positive titre of either ACA or β2gp1 or both. Twenty‐eight patients had ACA antibodies, of which eight had no evidence of clotting disorder while remaining 20 patients had various clotting disorders. Fourteen of these 20 patients with APAS had the positive titre of ACA only; the remaining six patients had both the antibodies, i.e. anti‐β2gp1 as well as ACA. There were four patients with APAS that had positive titres of only β2gp1 antibodies. In total there were 11 patients with β2gp1 antibodies, 10 of which had APAS, the remaining one did not. The sensitivity and the specificity of ACA test were 83 and 94%, respectively, and the sensitivity and specificity of β2gp1 antibody test were 71 and 99%, respectively. The chi‐square analysis demonstrated that there was statistically significant correlation between positive titres of both the antibodies and the presence of APAS.

Conclusion: The APAS in the ESRD patients should be characterized by not only the positive titre of ACA but also the positive titres of anti‐β2gp1 antibodies in association with history of clotting disorder.
Fungal brain abscess in transplant recipients: epidemiologic, microbiologic, and clinical features*
Authors: Baddley John W , Salzman Donna , Pappas Peter G
Published: March 2003

Abstract:  Fungal brain abscess is an unusual but serious complication associated with solid organ and hematopoietic stem cell transplantation. To examine the epidemiology and clinical features of fungal brain abscess in transplant recipients, we reviewed retrospectively all cases of fungal brain abscess diagnosed during a 3‐yr period among 1620 adult patients who underwent allogeneic or autologous stem cell, liver, heart, lung, or renal transplantation at one institution. Seventeen cases of fungal brain abscess were identified and occurred a median of 140 d post‐transplantation. Fungal brain abscess was more common among allogeneic stem cell transplant recipients (p < 0.01). Aspergillus species were most commonly isolated, but unusual, opportunistic molds were also identified. Altered mental status was present in 65% of patients, and multiple brain lesions were commonly seen on imaging studies. Although fungal brain abscess is an uncommon disease in this population, outcome was poor, suggesting that early recognition of this disease might be helpful.
Initial report of bladder carcinoma following combined bladder‐drained pancreas and kidney transplantation
Authors: Highshaw Ralph A , Tunuguntla Hari SGR , Perez Richard V , Gandour‐Edwards Regina , Evans Christopher P
Published: March 2003

Highshaw RA, Tunuguntla HSGR, Perez RV, Gandour‐Edwards R, Evans CP. Initial report of bladder carcinoma following combined bladder‐drained pancreas and kidney transplantation. Clin Transplant 2002: 16: 383–386. © Blackwell Munksgaard, 2002

Although long‐term survival of a functional allograft requiring long‐term immunosuppressive therapy is responsible for higher incidence of non‐urothelial cancers in renal allograft recipients than in normal population, the incidence of bladder cancer is uncommon and carcinoma of the bladder in the setting of combined kidney–pancreas transplantation has not been reported to date. We herein report a case of poorly differentiated invasive adeno‐squamous cell carcinoma of the bladder following renal and bladder‐drained pancreatic transplantation in a 44‐yr‐old lady with long‐standing insulin dependent diabetes mellitus, which necessitated radical extirpation. Management implications are reviewed.
Two‐hour post‐dose cyclosporine level is a better predictor than trough level of acute rejection of renal allografts
Authors: Pescovitz Mark D , Barbeito Ralph ,   for the Simulect US01 Study Group
Published: March 2003

Pescovitz, MD, Barbeito, R for the Simulect US01 Study Group. Two‐hour post dose cyclosporin level is a better predictor than trough level of acute rejection of renal allografts. Clin Transplant 2002: 16: 378–382. © Blackwell Munksgaard, 2002

Cyclosporine (CyA) trough concentrations are poor predictors for acute rejection post‐transplant. Patients were part of a randomized trial of basiliximab (n=70) vs. anti‐thymocyte globulin (ATGAM) (n=65), both in combination with Neoral, mycophenolate mofetil, and steroids, undergoing first or second, cadaveric or live donor renal transplants. Whole blood samples were collected just before (C0) and at 2 h after CyA dosing on day 4 and at the end of weeks 1, 2, 4, and 8. The CyA was measured by florescence polarization immunoassay (TDx). Mean CyAC0andC2concentrations were calculated. Logistic regression analysis revealed that meanC2level was the only predictor of acute rejection (P ≤ 0.001). Higher meanC2levels predicted lower rejection probabilities. Linear regression analysis revealed that higher meanC2levels were not related to higher serum creatinine levels at either week 4 or 24 or to incidence of headache or tremor. The CyAC2levels predict the frequency of rejection postrenal transplant. TargetC2levels are in the range of 1500 ng/dL.
Bone marrow transfusions in cadaver renal allografts: pilot trials with concurrent controls
Authors: Light Jimmy , Salomon Daniel R , Diethelm Arnold G , Alexander J Wesley , Hunsicker Lawrence , Thistlethwaite Richard , Reinsmoen Nancy , Stablein Donald M
Published: March 2003

Abstract: Background: The safety and immune tolerance potential of donor marrow infusion with cadaveric source renal transplants was evaluated in a series of non‐randomized multicenter pilot trials by the NIH Cooperative Clinical Trials in Transplantation (CCTT) Group.

Patients and methods: Three strategies were tested: (1) immunosuppression with cyclosporin, azathioprine and prednisone with a single post‐transplant day 1 infusion of 5 × 107viable cells/kg, (2) OKT3 induction with triple drug therapy and marrow transfusion on day 1, or (3) same therapy as (2) but with an additional marrow transfusion on day 10–12.

Results: Thirty‐eight marrow recipients and 35 contemporaneous controls were entered with a mean follow‐up of over 5 yr. Graft survival was initially better in the marrow recipients than the controls but was similar after 5 yr. Microchimerism rates were similar for the marrow infusion and control groups throughout the follow‐up period, regardless of the immunosuppression strategies.

Discussion: Bone marrow infusions were well tolerated by a group of cadaver renal allograft recipients. There were no complications from the infusion(s), no episodes of graft‐vs.‐host disease (GVHD) and no increase in infections or other complications. There was a trend toward early improved graft survival in marrow recipients. Decreased rejection rates were observed in black recipients.
Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation
Authors: Breitenfeldt Marie K , Rasenack Jens , Berthold Hans , Olschewski Manfred , Schroff Joachim , Strey Christoph , Grotz Wolfgang H
Published: March 2003

Background: Mortality or graft loss after renal transplantation might be influenced by hepatitis virus infection.

Methods: Sera from time of transplantation of 927 renal transplant recipients were tested for hepatitis C (HCV) and hepatitis B virus (HBV) in order to investigate the impact of hepatitis virus infection on graft loss and mortality over an observation period of 20 yr.

Results: One hundred and twenty three of 927 patients were HCV positive, 30 patients HBV positive and seven patients HBV and HCV positive. The observation period was 9.2 ± 4.4 yr. Mortality was significantly higher in patients with hepatitis B (p=0.0005), as well as in patients with concomitant B and C hepatitis (p < 0.0001) and in those who acquired HCV infection after transplantation (n=30, p=0.0192) compared with non‐infected patients. Patients with replicating HBV infection (HBeAg positive) had the worst prognosis (p < 0.0001). In the multivariate analysis the presence of HBeAg (p < 0.0001), patients' age (p < 0.0001) and HCV infection after transplantation (p=0.0453) were predictors for death. Graft survival was significantly shorter in patients with concomitant hepatitis B and C (p=0.0087) as well as in HBeAg positive patients (p=0.002). HCV infection or HBs antigenemia did not have a significant impact on graft survival compared with non‐infected patients.

Conclusion: HCV infection after transplantation is associated with a high mortality whereas chronic HCV infection before trans plantation does not have a significant impact on mortality. Patients with replicating HBV infection or concomitant HBV and HCV infection have a high risk of graft loss and mortality.
Life satisfaction and adverse effects in renal transplant recipients: a longitudinal analysis
Authors: Matas Arthur J , Halbert RJ , Barr Mark L , Helderman J Harold , Hricik Donald E , Pirsch John D , Schenkel Felicia A , Siegal Bonita R , Liu Honghu , Ferguson Ronald M
Published: March 2003

Introduction: Previous cross‐sectional analyses have identified significant associations between quality of life (QOL), comorbidities and adverse effects in renal transplant recipients. This report examines the longitudinal relationship between adverse effects and QOL, with particular attention to the relative impact of adverse effects associated with immunosuppression.

Methods: The Transplant Learning Center (TLC) is a program designed to improve QOL and preserve graft function in transplant recipients. Self‐selected enrollees filled out questionnaires at roughly 3‐month intervals. Each questionnaire included QOL scales developed for the program. Repeated measures multiple regression analysis was used to examine the relationship between the QOL scales, comorbidities, adverse effects, adjusting for other factors.

Results: A total of 4247 TLC enrollees were included in the analysis, with a mean time since transplant of 5.1 yr. Comorbidities and adverse effects were common, with high blood pressure reported by 87% of respondents and unusual hair growth reported by 69.6%. In bivariate analysis, emotional/psychological problems and headaches had the largest impact on QOL. In multivariate analysis, emotional/psychological problems decreased sexual interest or ability, and headache had the largest adverse QOL effect.

Conclusions: We have identified QOL issues that have been previously underemphasized in transplant recipients. These findings open new areas of research to further explore and define these issues. They provide new opportunities for interventions to address factors adversely impacting QOL and to develop strategies to improve QOL in these patients. Clinicians should actively solicit information about adverse effects of medications, particularly information about sexual and relationship issues, when evaluating renal recipients. These issues should be taken into account when making therapeutic decisions.
Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review
Authors: Brown E Sherwood , Bobadilla Leonardo , Rush A John
Published: March 2003

Background:
Data from several studies suggest that medications, such as ketoconazole, which lower cortisol levels, may be effective for major depressive disorder (MDD). As with MDD, the manic, depressive, and mixed phases of bipolar disorder are frequently associated with elevated cortisol levels. The literature on the use of cortisol‐lowering strategies in mood disorders is reviewed, and a case series illustrating the use of ketoconazole in bipolar depression is presented.   Methods: For the review, the MEDLINE and PSYCHINFO databases were searched, as were the bibliographies of pertinent articles to find papers on the use of cortisol‐lowering agents in patients with mood disorders. In our open‐label case series (n=6), ketoconazole (up to 800 mg/day) as an add‐on therapy was given to patients with treatment‐resistant or intolerant bipolar I or II disorders with current symptoms of depression.   Results: Several case reports and small open studies suggest that cortisol‐lowering agents may be useful for patients with depression. Two recent placebo‐controlled trials of ketoconazole on patients with MDD report conflicting results. In our case series, all three patients who received a dose of at least 400 mg/day had substantial reductions in depressive symptoms. None had significant increases in mania. However, cortisol levels were not lowered in any of the subjects.   Conclusions: The literature suggests that cortisol‐lowering medications may be effective for a subset of depressed patients. Our preliminary findings suggest that ketoconazole may be useful in some patients with bipolar depression. Larger clinical trials are needed to confirm our observations.
Regulation of tau phosphorylation and protection against β‐amyloid‐induced neurodegeneration by lithium. Possible implications for Alzheimer's disease
Authors: Alvarez Gema , Muñoz‐Montaño Juan Ramón , Satrústegui Jorgina , Avila Jesús , Bogónez Elena , Díaz‐Nido Javier
Published: March 2003

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the β‐amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the β‐amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic β‐amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by β‐amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase‐3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase‐3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase‐3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered.
Modulation of synaptic plasticity by stress and antidepressants
Authors: Popoli Maurizio , Gennarelli Massimo , Racagni Giorgio
Published: March 2003

Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N‐methyl‐D‐aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin‐dependent protein kinase II (CaM kinase II).

Both stress and antidepressants induce alterations in long‐term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug‐induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain‐derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders.
Neuroprotective effects of lithium in cultured cells and animal models of diseases
Authors: Chuang De‐Maw , Chen Ren‐Wu , Chalecka‐Franaszek Elzbieta , Ren Ming , Hashimoto Ryota , Senatorov Vladimir , Kanai Hirohiko , Hough Christopher , Hiroi Toyoko , Leeds Peter
Published: March 2003

Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N‐methyl‐D‐aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long‐lasting, requires long‐term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mechanisms involve inactivation of NMDA receptors, decreased expression of pro‐apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl‐2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate‐induced loss of the activities of Akt, cyclic AMP‐response element binding protein (CREB), c‐Jun – N‐terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
Regulation of adult hippocampal neurogenesis – implications for novel theories of major depression1
Authors: Kempermann Gerd
Published: March 2003

Major depression, whose biological origins have been difficult to grasp for decades, might result from a disturbance in neuronal plasticity. New theories begin to consider a fundamental role of adult hippocampal neurogenesis in this loss of plasticity. Could depression and other mood disorders therefore be ‘stem cell disorders’? In this review, the potential role of adult hippocampal neurogenesis and of neuronal stem or progenitor cells in depression is discussed with regard to those aspects that are brought up by recent research on how adult hippocampal neurogenesis is regulated. What is known about this regulation today are mosaic pieces and indicates that regulation is complex and is modulated on several levels. Accordingly, emphasis is here laid on those regulatory feedback mechanisms and interdependencies that could help to explain how the pathogenic progression from a hypothesized disruptive cause can occur and lead to the complex clinical picture in mood disorders. While the ‘neurogenic theory’ of depression remains highly speculative today, it might stimulate the generation of sophisticated working hypotheses, useful animal experiments and the first step towards new therapeutic approaches.
In vitro fertilization in patients with ovarian endometriomas
Authors: TINKANEN HELENA , KUJANSUU ERKKI
Published: March 2003

Objective. The objective of the study was to establish whether operative treatment of recurrent ovarian endometriosis improves the prognosis of in vitro fertilization.

Methods and material. A retrospective analysis of one hundred endometriosis patients admitted to Tampere University Hospital for IVF treatment. Forty‐five patients had an ovarian endometrioma during IVF treatment, 36 of the cases being recurrences after a previous operation. Fifty‐five patients had ovarian endometriomas operated without recurrence. The patient groups with or without endometriosis did not differ in age, duration of infertility, sperm parameters, amount of gonadotropins required per oocyte and number of retrieved oocytes.

Results. The patients with ovarian endometriosis had more embryos (mean 3.9) than women without endometriomas (mean 2.8) (p<0.05) and the respective pregnancy rates per IVF cycle were 38% and 22%. Patients with endometriomas had a live birth rate of 27% compared with 20% in women with no endometriomas.

Conclusions. The presence of a small endometrioma does not reduce the success of IVF treatment.
The risk of premalignant and malignant pathology in endometrial polyps
Authors: BAKOUR SHAGAF H. , KHAN KHALID S. , GUPTA JANESH K.
Published: March 2003

Objective. To evaluate the risk of premalignant and malignant pathology among endometrial polyps.

Design. Prospective cohort study.

Setting. Minimal Access Surgical Training (MAST) center in a large teaching hospital.

Methods. Among 248 patients seen in outpatient hysteroscopy clinic (1996–97), 62 had endometrial polyps. All patients had endometrial sampling for histological assessment. To determine the magnitude of malignant potential among polyps, we compared the pathological findings in polyps (cases) with non‐polypoidal specimens (controls).

Results. Out of 62 polyps, histologically 53 (85.5%) were benign, seven (11.3%) had hyperplasia, and two (3.2%) were associated with malignancy. Hyperplasia was more frequent in endometrial specimens with polyps than in those without (11.3% vs 4.3%, p=0.04), but the incidence of carcinoma in the two groups was the same (3.2% vs 3.2%, p=1.0).

Conclusion. In abnormal uterine bleeding, hyperplasia was, but cancer was not, more common in women with endometrial polyps compared to those without polyps.
A prospective randomized study comparing acupuncture with physiotherapy for low‐back and pelvic pain in pregnancy
Authors: WEDENBERG KAJ , MOEN BERIT , NORLING ÅSA
Published: March 2003

Background. The aim of this study was to describe the effects of acupuncture in the treatment of low‐back and pelvic pain during pregnancy and compare it with physiotherapy.

Methods. Sixty pregnant women were allotted to acupuncture or physiotherapy. The women estimated the severity of their pain using a visual analog scale (VAS) from 0 to 10 and disability in performing twelve common daily activities using a disability‐rating index (DRI) from 0 to 10.

Results. In the acupuncture group all 30 women completed the study (two exclusions), in the physiotherapy group only 18. Before treatment the two study groups were rather similar with respect to pain and disability. After treatment the mean morning VAS had declined from 3.4 to 0.9 (p<0.01) in the acupuncture group and from 3.7 to 2.3 (NS) in the physiotherapy group. The corresponding evening values had declined from 7.4 to 1.7 (p<0.01) and 6.6 to 4.5 (p<0.01), respectively. The mean VAS values were lower after acupuncture than after physiotherapy both in the morning (p=0.02) and in the evening (p<0.01). After treatment also the mean DRI values had decreased significantly in the acupuncture group for 11 of 12 activities and the values were significantly lower for all activities than in the physiotherapy group where no significant changes had taken place. Overall satisfaction was good in both groups. There were no serious adverse events in any of the patients.

Conclusions. Acupuncture relieved pain and diminished disability in low‐back pain during pregnancy better than physiotherapy.
Relationship between histopathological changes in post partum renal biopsies and renal function tests of African women with early onset pre‐eclampsia
Authors: KHEDUN SHAUN M. , NAICKER THAJASVARIE , MOODLEY JAGDISEA
Published: March 2003

Background. To improve the diagnostic accuracy of concurrent renal disease in hypertension of pregnancy, biopsy evaluation is essential. In addition, establishing underlying renal disease is important for prognosis on future pregnancies. We therefore designed a study to determine the diagnostic yield of postpartum renal biopsy and the nature and frequency of complications associated with this procedure. Also, to determine relationships, if any, between renal function tests and ultrastructural and histopathological findings.

Methods. Fifty renal biopsies were performed in the immediate postpartum period in black African women with early onset pre‐eclampsia. Each biopsy specimen was placed in a separate container and coded so that sampling was unknown to the electron microscopist. Each biopsy specimen was divided into three parts, and processed and stained for light, fluorescent and transmission electron microscopy using conventional techniques.

Results. Renal tissue biopsies were adequate for diagnostic purposes in all cases. There were no complications in any of the 50 patients studied. Ultrastructural examination confirmed the light microscopy findings. In addition the ultrastructural findings showed intramembranous deposits, foot process fusion and mesangial deposits. In 16 patients with normal renal function tests; the biopsies evaluation from these patients showed ultrastructural changes. In the remaining 34 patients with abnormal renal function tests of varying severity; biopsy evaluation from these patients showed both ultrastructural and histopathological changes.

Conclusion. Renal biopsy procedure is safe, and ultrastructural and histological findings obtained from postpartum renal biopsies are more informative than the routine renal function tests.
Effectiveness of ultrasonographic parameters for documenting the severity of anatomic stress incontinence
Authors: YALCIN OMER T. , HASSA HIKMET , OZALP SINAN
Published: March 2003

Background. To assess the correlation between the severity of incontinence and some ultrasonographic parameters used to document the mobility of bladder neck.

Methods. The severity of the incontinence and mobility the bladder neck were evaluated by pad test and perineal ultrasonography respectively in 74 patients with pure anatomic stress incontinence. During perineal ultrasonography, distances from the bladder neck to the lower tip (A) and to the posterior midpoint of symphysis pubis (B) were measured at rest and during stress. The first bladder neck mobility was obtained by two caliper method (Mu). After superimposing the symphysis pubis of the frozen images, the bladder neck positions at rest and during stress were plotted on an x‐y coordinate system by using computer programs and the corresponding X and Y values were calculated. The second bladder neck mobility was measured on this x‐y coordinate system (Mc). Paired t‐test and correlation analysis were used for statistical analysis of the data.

Results. The mean Mc was significantly higher than the mean Mu (p<0.01). Compared to the values at rest, the mean distance A did not change significantly; however, the mean distance B increased, and X and Y values decreased significantly during stress (p<0.01). The amount of urine leaked per hour had significant positive correlation with distance B‐stress and Mc and significant negative correlation with Y‐rest, X‐stress and Y‐stress (p<0.05–0.001).

Conclusion. These data suggested that the bladder neck mobility was underestimated when it was measured by two caliper method and the absolute positions or mobility of the bladder neck measured by computer on an x‐y coordinate system could effectively document the severity of the decreased support of bladder neck.
Maternal smoking and birthweight: effect modification of period, maternal age and paternal smoking
Authors: HAUG KJELL , IRGENS LORENTZ M. , SKJÆRVEN ROLV , MARKESTAD TROND , BASTE VALBORG , SCHREUDER PATRICIA
Published: March 2003

Objective. To study the effect on birthweight of maternal smoking, and its modification by study period, maternal age and paternal smoking.

Design. A retrospective questionnaire based national survey comprising a random sample (n=34,799) of all mothers giving birth in Norway 1970–91. Variables studied were parental smoking during pregnancy, birthweight, maternal age and infant's year of birth.

Results. The overall difference in mean birthweight between non‐smoking and smoking mothers was 197 g. The difference in birthweight between non‐smoking and smoking mothers increased with maternal age from 182 g (<20 years of age) to 232 g (35+ years of age). There was no significant effect of paternal smoking on birthweight when the mother was a non‐smoker. When the mother was a smoker and the father was a non‐smoker, the birthweight, adjusted for maternal age, was reduced by 153 g (p<0.005). However, when both parents smoked, the birthweight, adjusted for maternal age, was reduced by 201 g (p<0.0005). Even though the prevalence of paternal smoking decreased by 38% during the study period, there was no significant increase in overall mean birthweight.

Implication and relevance of results. The negative effect of maternal smoking on birthweight appears to increase with maternal age. For a non‐smoking pregnant woman to live with a smoking partner has little, if any, effect on birthweight. The negative effect of paternal smoking was only observed when the mother was smoking and might reflect two possible mechanisms: (1) that a smoking mother has a greater cigarette consumption when the partner also smokes, and (2) that a smoking mother is less concerned about passive smoking than a non‐smoking mother.
Three‐dimensional sonographic features of fetal central nervous system anomaly
Authors: HATA TOSHIYUKI , YANAGIHARA TOSHIHIRO , MATSUMOTO MINAKO , HANAOKA UIKO , UETA MARI , TANAKA YASUKO , KANENISHI KENJI , KUNO ATSUSHI , YAMASHIRO CHIZU , OHNISHI YOHICHI , TANAKA HIROKAZU , HAYASHI KEIJI
Published: March 2003

Objective. To visualize an intracranial structure of the fetal central nervous system (CNS) anomaly using transabdominal three‐dimensional (3D) sonography.

Methods. A total of 12 cases with fetal CNS anomalies (one unilateral ventriculomegaly; three hydrocephalus; three anencephaly; three holoprosencephaly; one Dandy‐Walker cyst; and one enlarged cisterna magna) from 17 to 37 weeks of gestation were studied with transabdominal 3D sonography (3.5 MHz).

Results. In unilateral ventriculomegaly, insight view of dilated lateral ventricle, especially dilated atrium was depicted. In hydrocephalus, severely dilated bilateral ventricles and thin brain mantle were very clearly shown. In anencephalus, an absence of the brain and defect of the vault of the skull was clearly noted. In holoprosencephaly, absent interhemispheric fissure, common ventricle, and the extent of thalamic fusion were evident. In Dandy‐Walker cyst, cerebellar hemisphere was clearly depicted due to the agenesis of cerebellar vermis. In enlarged cisterna magna, posterior intracranial view of the fetus showed a large space of cisterna magna. Although the diagnosis of each CNS anomaly was made using conventional two‐dimensional sonography, 3D sonography proved most helpful delineating the exact nature and anatomic level of the anomaly.

Conclusions. These results suggest that 3D sonography provides a novel means of visualizing fetal CNS anomalies in utero. However, it should be noted that our 3D sonography cannot depict intracranial brain structures in normal fetuses or some CNS anomaly such as intracranial tumor.
Birth outcomes in pregnant women treated with low‐molecular‐weight heparin
Authors: SØRENSEN HENRIK TOFT , JOHNSEN SØREN PAASKE , LARSEN HELLE , PEDERSEN LARS , NIELSEN GUNNAR LAUGE , MØLLER MARGRETE
Published: March 2003

Background. Pregnancy and puerperium are associated with an increased risk of venous thromboembolism. Low‐molecular‐weight heparin is the anticoagulant of choice in pregnant women because, unlike warfarin, it does not cross the placenta. However, there are limited data on the risk of adverse birth outcomes following use of low‐molecular‐weight heparin in pregnancy.

Patients and methods. We performed a population‐based cohort study to examine the safety of low‐molecular‐weight heparin use in pregnancy using data from the Pharmacoepidemiological Prescription Database, The Danish Medical Birth Registry and the Regional Hospital Discharge Registry in North Jutland County, Denmark. The birth outcomes in a cohort of 66 pregnant women treated with low‐molecular‐weight heparin between 1991–98 were compared with the birth outcomes of 17,259 pregnant women who did not receive any prescriptive drugs during pregnancy.

Results. No increased risk of malformations, low birth weight or stillbirth was found. However, an increased risk of pre‐term delivery was found (odds ratio: 2.11, 95% confidence interval: 0.96–4.65), which could reflect inherited thrombophilia as an indication of low‐molecular‐weight heparin.

Conclusion. We have provided additional evidence of the safety of low‐molecular‐weight heparin use in pregnancy.