bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic determinants of type 2 diabetes mellitus
Authors: Busch CP , Hegele RA
Published: March 2003

Type 2 diabetes refers to a group of disparate metabolic diseases, which are typically characterized by insulin resistance in peripheral tissues, together with impaired insulin secretion from pancreatic β‐cells. The complexity of type 2 diabetes is related to factors such as genetic heterogeneity, interactions between genes, and the modulating role played by the environment. Recent progress has included defining the molecular basis of monogenic forms of type 2 diabetes, such as familial partial lipodystrophy and the subtypes of maturity‐onset diabetes of the young (MODY), and also the identification of chromosomal regions that may harbor type 2 diabetes susceptibility genes. Many common variants in functional and positional candidate genes, including ADRB3, PPARG, ENPP1, and CAPN10, have also been studied for their possible role as determinants of type 2 diabetes, with varying levels of agreement between studies. The availability of a relatively complete sequence of the human genome will increase the amount of genetic information that can be used to evaluate hypotheses for the genetic basis of type 2 diabetes. To make sense of human type 2 diabetes in the post‐genomic era, it is essential to have well‐defined phenotypes in addition to sufficient numbers of individuals with the appropriate pedigree structure from families and/or communities.
Familial case of Potocki–Shaffer syndrome associated with microdeletion of EXT2 and ALX4
Authors: Hall CR , Wu Y , Shaffer LG , Hecht JT
Published: March 2003

Multiple exostosis, biparietal foramina, minor craniofacial abnormalities, and mental retardation are characteristic of the syndrome associated with a proximal deletion of 11p (MIM # 601224), which has been shown to be a true contiguous gene deletion syndrome. The presence of multiple exostosis is associated with deletion of the EXT2 gene. Similarly, the presence of biparietal foramina has been shown to be associated with the deletion of ALX4 located proximally to EXT2. Specific genes related to mental retardation and craniofacial abnormalities, however, have yet to be identified. We report on a family with a microdeletion of 11(p11.2p11.2) with multiple exostosis and biparietal foramina without mental retardation or craniofacial abnormalities. Our results suggest that genes related to mental retardation and craniofacial development must be located outside of the D11S1785–D11S1385 region.
The effect of six polymorphisms in the Apolipoprotein B gene on parameters of lipid metabolism in a Danish population
Authors: Bentzen J , Jørgensen T , Fenger M
Published: March 2003

Lipoproteins are vehicles for the distribution of plasma lipids and polymorphisms in the genes for apolipoproteins could influence the amount of lipid in plasma. We examined the effect of six single nucleotide polymorphisms in codons 71, 591, 2488, 2712, 3611, and 4154 of the apolipoprotein B gene on fasting levels of triglyceride, VLDL‐, LDL‐, HDL‐ and total cholesterol and on body mass index (BMI) in a cohort of 2656 Danes aged 40–70 years using a linear model correcting for the effects of gender, age, BMI, smoking, alcohol consumption and physical activity. The codon 2488 polymorphism was the most influential of the tested polymorphisms, significantly influencing triglyceride (P = 0.002), LDL‐cholesterol (P ≤ 0.0004), VLDL‐cholesterol (P = 0.006) and total cholesterol (P = 0.0001). The codon 2712 polymorphism had an impact on triglyceride (P = 0.007) and VLDL‐cholesterol (P = 0.001), while the codon 71 polymorphism influenced LDL‐ and total cholesterol (P = 0.04 andP = 0.02, respectively). An interaction between smoking and codon 591 (P = 0.03) and smoking and codon 3611 (P = 0.02) on BMI was observed, as well as modest interactions between codon 3611 and codons 2488 and 2712 on lipid parameters. All polymorphisms were in close linkage disequilibrium. The population was not in Hardy–Weinberg equilibrium in four of the six polymorphisms but the lack of equilibrium was restricted mainly to the 60‐year olds.
An exonic mutation of the GH‐1 gene causing familial isolated growth hormone deficiency type II
Authors: Takahashi I , Takahashi T , Komatsu M , Sato T , Takada G
Published: March 2003

A heterozygous base change was identified in exon 3 of the growth hormone (GH)‐1 gene in a Japanese family with autosomal dominant GH deficiency. All of the patients from this family had a heterozygous G to T transversion at the first 5′‐site nucleotide of exon 3. Analysis of the GH‐1 cDNA, synthesized from lymphoblasts of the patients, revealed an abnormal shorter transcript as well as a normal‐sized transcript. Direct sequencing of this abnormal transcript showed that the transcript completely lacked exon 3. In familial isolated GH deficiency (IGHD) type II, several heterozygous mutations have been reported at the donor splice site in intron 3 of the GH‐1 gene or inside intron 3, which causes aberrant GH messenger RNA splicing, resulting in the deletion of exon 3. This deletion causes a lack of amino acid residues 32–71 in the mature GH protein. This mutant GH is well‐known to exert a dominant negative effect on the secretion of mature normal GH protein. Thus, in the subject family, a heterozygous G‐to‐T transversion at the first nucleotide of the exon 3 deletes exon 3 in mature GH mRNA and causes GH deficiency. The present authors suggest that the first nucleotide of exon 3 is critical for the splicing of GH‐1 mRNA.
DGAT1 promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women
Authors: Ludwig EH , Mahley RW , Palaoglu E , Özbayrakçı S , Balestra ME , Borecki IB , Innerarity TL , Farese RV
Published: March 2003

Triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferases (DGAT), microsomal enzymes that use diacylglycerol and fatty acyl CoAs as substrates. Because DGAT1 expression is up‐regulated during adipocyte differentiation and DGAT1 deficiency is associated with leanness in mice, we hypothesized that alterations in DGAT1 expression may affect human body weight. We identified five polymorphisms in the human DGAT1 promoter and 5′ non‐coding sequence in a random Turkish population. Functional analysis of one common variant, C79T, revealed reduced promoter activity for the 79T allele in cultured cell lines. In 476 Turkish women, the 79T allele was associated with lower body mass index (BMI) (p = 0.004), conferring an odds ratio of 2.0 (95% CI = 1.30–3.07, p = 0.0001) for BMI ≤ 20. Interestingly, after controlling for the influence of BMI, the 79T allele was also associated with higher plasma HDL cholesterol levels (p = 0.0006) and lower diastolic blood pressure (p = 0.019) in these women. No association was found in Turkish men (n = 846). Our findings suggest that genetic variation at the DGAT1 locus may influence BMI and other metabolic parameters associated with cardiovascular risk in selected human populations.
Mutation analysis of the STK11/LKB1 gene and clinical characteristics of an Australian series of Peutz–Jeghers syndrome patients
Authors: Scott RJ , Crooks R , Meldrum CJ , Thomas L , Smith CJA , Mowat D , McPhillips M , Spigelman AD
Published: March 2003

Peutz–Jeghers syndrome (PJS) is a rare cancer predisposition, which is characterized by the presence of hamartomatous polyposis and mucocutaneous pigmentation. A significant proportion of both familial and sporadic forms of this disorder are associated with mutations in the STK11 (serine/threonine kinase 11)/LKB1 gene. In this report we present a series of Australian PJS cases, which suggest that mutations in the STK11 gene do not account for many families or patients without a family history. The most likely explanation is either the presence of another susceptibility gene or genetic mosaicism in the non‐familial patients.
Bronchoalveolar lavage in lung transplantation
Authors: Tiroke AH , Bewig B , Haverich A
Published: March 2003

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) has become a crucial tool in the management of lung transplant recipients. Detection of pulmonary infectious pathogens by culture, cytology, and histology of BAL, protected brush specimens, and transbronchial biopsies (TBB) is highly effective. Morphologic and phenotypological analyses of BAL cells may be suggestive for certain complications after lung transplantation. For interpretation of BAL findings, the natural course of BAL cell morphology and phenotypology after lung transplantation must be considered. During the first 3 months after pulmonary transplantation, elevated total cell count in BAL and neutrophilic alveolitis are common, representing the cellular response to graft injury and interaction of immunocompetent cells of donor and recipient origin. With increasing time after transplantation the CD4/CD8 ratio decreases due to lowered percentages of CD4 cells in BAL. During bacterial pneumonias, the cellular profile of BAL is characterized by a marked granulocytic alveolitis. Lymphocytic alveolitis with a decreased CD4/CD8 ratio is suggestive of acute rejection, but is also found in viral pneumonias and obliterative bronchiolitis. In the case of a combined lymphocytosis and neutrophilia without any evidence of infection, obliterative bronchiolitis should be considered.Functional analyses of BAL cells can give additional information about the immunologic status of the graft, even before histologic changes become evident but have not been established in routine transplant monitoring. However, functional studies suggest an important role of activated, alloreactive and donor‐specific T lymphocytes in the pathogenesis of acute and chronic lung rejection. Investigations of soluble components in BAL have given further insight into the immunologic processes after lung transplantation. In this overview, the characteristics of BAL after lung transplantation will be summarized, and its relevance for the detection of pulmonary complications will be discussed.
Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation
Authors: Martín‐Sanz P , Boscá L , Olmedilla L , Perez‐Peña J , Garutti I , Sanz J , Calleja J , Avellanal M , Ortega A , Aleixandre A , Barrigón S
Published: March 2003

Involvement of the nitric oxide (NO) system in complications following human orthotopic liver transplants (OLT) has been reported, but the contribution of the graft to the modulation of the NO system during reperfusion in normal OLT has not been characterized. We have studied the contribution of the graft efflux to the modulation of the NO system in 20 consecutive OLT. We evaluated its effects on isolated vascular reactivity of the rabbit and on rat cultured macrophages stimulated with lipopolysaccharide (LPS).In none of the donor liver biopsies was expression of inducible NO synthase (iNOS) activity by Northern or Western blot analysis found. Graft efflux after the onset of liver reperfusion, but not pre‐transplant patient plasma, reversibly inhibited the acetylcholine‐induced relaxation of norepinephrine‐contracted rabbit aortic rings. Moreover, graft efflux reversibly inhibited NO production in rat macrophages treated with LPS, as evidenced by both a decrease in nitrite plus nitrate formation and a decrease in the production of [ C]citrulline from [ C]arginine. Addition of a 10% dilution of graft efflux to cultured rat macrophages incubated with LPS increased iNOS mRNA levels, suggesting direct inhibition of the enzyme but not of its expression. These results cannot be ascribed to the depletion of arginine – the iNOS substrate – since they can be reproduced even in the presence of an excess (10 mM) of exogenously added arginine. No correlation was found between the iNOS inhibitory activity in each sample and the corresponding clinical parameters related to either the graft function after the OLT or the existence of post‐reperfusion syndrome.Our results indicate the existence of a soluble factor in the graft efflux from human OLT that reversibly and unspecifically inhibits NOS activity. Its involvement in the physiology and/or pathology of human liver diseases deserves further study.
An alternate mechanism of glucocorticoid anti‐proliferative effect: promotion of a Th2 cytokine‐secreting profile
Authors: Almawi Wy , Melemedjian Ok , Rieder Mj
Published: March 2003

Glucocorticoids (GCs) are used as immunosuppressive and anti‐inflammatory agents in organ transplantation and in treating autoimmune diseases and inflammatory disorders and they exert their effects by several mechanisms, the most significant of which is inhibition of cytokine production and action. Recent reports suggested that GCs inhibit cytokine expression indirectly through promotion of a T helper cell type 2 (Th2) cytokine‐secreting profile, thereby resulting in preferential blockade of pro‐inflammatory monokine and T helper cell type 1 (Th1) cytokine expression. The target of GCs appeared to be monocytes–macrophages, whereby altered regulation of interleukin (IL)‐1/IL‐1 receptor antagonist (IL‐1ra), coupled with profound blockade of IL‐12 synthesis and inhibition of interferon (IFN)‐Γ‐induced major histocompatibility complex (MHC) class II expression, lead to a preferential cognate stimulation of Th2 cells at the expense of Th1 cells. It is possible that this may have involved the expansion of a Th2‐cell pool or, in addition, frank stimulation of uncommitted naive CD4+ T cells toward the Th2 lineage. In addition, GCs may have blocked Th1 cytokine expression, thereby inhibiting ongoing Th1 cytokine secretion, and consequently provided for the unimpeded production of Th2 cytokines. Collectively, this indicates that, in exerting their anti‐proliferative effects, GCs act indirectly by altering Th1/Th2 cytokine balance, blocking the (pro‐inflammatory) Th1 program and favoring the (anti‐inflammatory) Th2 program.
Comparison of rejection rate and functional outcome of small bowel transplantation alone or in conjunction with the ileocecal valve versus combined small and large bowel transplantation
Authors: Raofi Vandad , Holman Dawn M , Dunn Ty B , Fontaine Magali J , Mihalov Michael M , Vitello Joseph M , Asolati Massimo , Benedetti Enrico
Published: March 2003

Preservation of the ileocecal valve improves absorptive function and decreases the amount of small bowel needed for survival in patients with short gut syndrome. We compared the results of small and large bowel transplant (SLBTx), small bowel transplant only (SBTx), and SBTx with the ileocecal valve (ICVTx) in a porcine model. Total enterectomy was performed on 18 Yorkshire‐Landrace pigs followed by orthotopic SBLTx (n=6), SBTx (n=6), and ICVTx (n=6). A jejunostomy and an ileostomy were constructed for biopsies. Overall mean survival was 17 d with no statistically significant difference between groups. Rejection was seen in 6/6 SLBTx, 4/6 SBTx, and 4/6 ICVTx recipients. Acute rejection was seen in 84.3% of SLBTx, 52.3% of SBTx, and 42.5% of the ICVTx mucosal biopsy samples. Two cases of intra‐abdominal infection were in the ICVTx group only. Weight loss was 147 g/d in the SLBTx group, 643 g/d in the SBTx group, and 393 g/d in the ICVTx group. While the functional outcome after SLBTx and ICVTx was noticeably better than the SBTx group, the increased rejection and intra‐abdominal infection rates make transplanting the large bowel or the ileocecal valve a less attractive clinical option.
Carvedilol improves functional class in patients with severe left ventricular dysfunction referred for heart transplantation
Authors: Pamboukian Salpy V , Aminbakhsh Amin , Thompson Christopher R , Amin Haitham , Mortimer Susan , D'Yachkova Yulia , Ignaszewski Andrew P
Published: March 2003

Purpose. Limited options are available to improve the functional class of patients awaiting cardiac transplantation. We assessed the effect of carvedilol on New York Heart Association (NYHA) class, heart rate (HR), blood pressure (BP), jugular venous pressure (JVP), electrolytes and renal function in patients with markedly decreased left ventricular (LV) function referred for cardiac transplantation assessment.

Methods. Sixty‐one patients (age=52±12 yr, EF=23±7%, VO2 max=16±5 mL/kg/min) referred to the cardiac transplant clinic were reviewed before and after the addition of carvedilol (starting dose 3.125 mg twice daily to target dose of 25 mg twice daily) to usual heart‐failure therapy. Over a 1‐yr period, at each visit prior to initiation, at baseline initiation visit and at each follow‐up visit, NYHA class, BP, HR, JVP, electrolytes, and renal function were obtained. Statistical analysis was performed using random effects regression approach. A multiple logistic regression analysis was performed on 52/61 patients to determine possible associations between NYHA improvement and the following patient characteristics: sex, etiology of cardiomyopathy, initial NYHA class, and dose of carvedilol.

Results. Three patients died (2 after stopping carvedilol) and 3 were transplanted. Median follow‐up was 100 d. Sixteen patients reached the target dose after a mean of 137 d (2.75 visits). Estimated time‐to‐target dose is 8 months (5.6 visits). BP tended to increase (p=0.07 for change in trend) with no change in JVP, electrolytes or renal function. HR decreased 6±3 b.p.m. (p=0.03). Of 14 patients NYHA class I/II at baseline, none were class III/IV at last follow‐up visit. Of 47 patients NYHA class III/IV at baseline, 25 were class I/II, and 22 were class III/IV at last follow‐up (p<0.001). Multiple logistic regression analysis did not demonstrate any factor predictive of subsequent NYHA class improvement.

Conclusions. Despite less than target doses in most patients, a favorable effect of carvedilol on functional class in patients with severe congestive heart failure (CHF) referred for transplant was observed. Those with good functional status remained stable and those with poor functional status improved or remained stable. No baseline patient characteristic predicted improvement. The shortage of donor organ requires optimal use of medical regimens which may improve functional class while awaiting transplantation and which may delay the necessity for heart transplantation. Therefore, addition of carvedilol to usual medical therapy may be beneficial even in patients with severe LV dysfunction and poor NYHA classification.
Tacrolimus‐induced hemolytic uremic syndrome and end‐stage renal failure after liver transplantation
Authors: Rerolle Jean‐Philippe , Akposso Kodzo , Lerolle Nicolas , Mougenot Béatrice , Ponnelle Tibor , Rondeau Eric , Sraer Jean‐Daniel
Published: March 2003

Background. Hemolytic uremic syndrome (HUS) is a rare complication in solid organ transplantation. It can be associated with severe hypertension. Several risk factors have been identified including immunosuppressive drugs such as cyclosporin A and, more recently, tacrolimus.  Methods. Here we report a case of tacrolimus‐induced HUS in a 61‐yr‐old woman after liver transplantation. Hypertension, microangiopathic anemia and end‐stage renal failure occurred 2 yr after liver transplantation.  Results. At admission, she had malignant hypertension with a severe hypertensive retinopathy, renal failure (creatininemia: 800 μmol/L) and microangiopathic anemia (Hb: 7.3 g/dL, a low platelet count and elevated lactate dehydrogenase). At renal biopsy, histologic findings were ischemic and sclerotic glomeruli with hyaline thrombi, severe mesangiolysis and interstitial fibrosis.  Conclusion. Despite steroid treatment, antihypertensive agents and fresh frozen plasma therapy, end‐stage renal failure was observed and chronic hemodialysis treatment was required.
The use of contaminated donor organs in transplantation
Authors: Zibari Gb , Lipka J , Zizzi H , Abreo Kd , Jacobbi L , McDonald Jc
Published: March 2003

Introduction. Organ transplantation has become an accepted means of treating end‐stage organ disease in recent years with acceptable patient and graft survival. Transplant recipients have an increased risk of infectious complications due to multiple factors including decreased host resistance from chronic end‐stage organ failure as well as from the immunosuppression required to prevent graft rejection.  Hypothesis. Therefore, the use of contaminated allografts could result in life‐threatening infections in organ recipients.  Method. In this study, transplant patients receiving organs from donors with positive blood or urine cultures, from 1993 to 1997, were retrospectively reviewed.  Results. There was a total of 599 organ donors in our state. Forty‐six (7.5%) had positive blood cultures and 25 (4.5%) had positive urine cultures. A total of 179 patients received organs from these contaminated donors, 36 of which were transplanted at our center. In this group, there were 16 kidney, 9 liver, and 11 heart transplants. Both donors and recipients received prophylactic broad‐spectrum antibiotics, which were adjusted based on culture and sensitivity results. The most common organisms isolated from the blood were staphylococci followed by streptococci and Gram‐negative organisms. Three of the 9 liver transplant patients in the series died with a mortality of 33%. Two of the 3 patients who died had sepsis but the responsible organisms were different from those recovered from the donor. The rest (66%) did well and have acceptable liver function. None of the 16 renal transplant recipients developed an infection and all survived. One patient developed acute irreversible rejection requiring transplant nephrectomy. There was one death in the heart transplant group resulting in a mortality of 9%. This death was not attributed to infectious processes. Three of 11 heart transplant patients grew organisms in the post‐operative period that were similar to those found in the corresponding donors. However, no patient suffered significant morbidity or mortality from these infections and all recovered. The recipients of contaminated organs had levels of organ function similar to those of randomly chosen recipients of non‐contaminated organs, and both groups had similar lengths of hospital stay.  Conclusion. Only 3 of 36 organ recipients had infections caused by organisms found in the contaminated donor organs for a rate of 8%. Contaminated donor organs seem to fare as well as non‐contaminated donor organs and there was no increase in morbidity or mortality. Contamination of organs should not be an absolute contraindication to the use of these organs in transplantation.
Intratubular calcification in a post‐renal transplanted patient with secondary hyperparathyroidism
Authors: Iguchi Seitaro , Nishi Shinnichi , Shinbo Junnichi , Iino Noriaki , Kazama J Junichiro , Shimada Hisaki , Ueno Mitsuhiro , Saitou Kazuhide , Tanigawa Toshiki , Takahashi Kouta , Gejyo Fumitake
Published: March 2003

Iguchi S, Nishi S, Shinbo J, Iino N, Kazama JJ, Shimada H, Ueno M, Saitou K, Tanigawa T, Takahashi K, Gejyo F. Intra‐tubular calcification in a post‐renal transplanted patient with secondary hyperparathyroidism. Clin Transplantation 2001: 15 (Supplement 5): 51–54. ©Munksgaard, 2001

In this article, we present a case in which marked intratubular calcification occurred in the transplanted kidney. The patient received living renal transplantation without control of severe secondary hyperparathyroidism, and the tacrolimus hydrate was used as an immunosuppressive agent, the adverse effects of which can induce intratubular calcification. Biopsy of the renal allograft revealed many intratubular calcifications in the cortex region of the specimen, although the histological grade was borderline for the Banff classification. The pathogenic causes of intratubular calcification were difficult to distinguish from the adverse effects of tacrolimus and the uncontrolled hyperparathyroidism.
Telepathology for the biopsy specimens from human allografted kidney: effectiveness and pitfalls
Authors: Ito Hisao , Shomori Kohei , Adachi Hironobu , Taniyama Kiyomi
Published: March 2003

Ito H, Shomori K, Adachi H, Taniyama K. Telepathology for the biopsy specimens from human allografted kidney: effectiveness and pitfalls. Clin Transplantation 2001: 15 (Supplement 5): 55–58. ©Munksgaard, 2001

This study was conducted to examine the validity and accuracy of telepathology for biopsy specimens from allografted kidney. The still video images of paraffin sections were transmitted via a two‐way telephone by use of a digitized telephone network, ISDN. The quality of the transmitted images was sufficient for the diagnosis, especially at higher magnification. A total of 37 needle biopsy specimens from the 31 allografted kidneys were presented for consultation and diagnosed by an expert pathologist at Tottori University, until July 2000. The average number of transmitted images was 7.1 (range 3–12). Of the 37 specimens, diagnoses by telepathology agreed well with those made through direct microscopy in the 30 specimens. Insufficient or improper diagnosis was made in four specimens, in which proper and pathognomonic still images were not transmitted. Three cases were not diagnosed by telepathology because of the difficulty in making differential diagnosis. From these results, we concluded that telepathology is usuful for transplantation pathology, in spite of limitations in some cases.
Effect of macrovescicular steatosis and other donor and recipient characteristics on the outcome of liver transplantation
Authors: Zamboni Fausto , Franchello Alessandro , David Ezio , Rocca Giuseppe , Ricchiuti Alessandro , Lavezzo Bruna , Rizzetto Mario , Salizzoni Mauro
Published: March 2003

The influence of steatosis and of other donor and recipient characteristics in affecting liver performance post‐orthotopic liver transplantation (OLT) was evaluated in 311 consecutive liver transplantations made in 278 patients. Donor variables considered were age, sex, blood group, cause of death, intensive care unit (ICU) days, need for vasopressors, hepatic enzymes and bilirubin, total and warm ischemia time, and macro‐ and microvescicular steatosis. Recipient variables considered were age, sex, blood group, biliary output, and post‐OLT peak levels of hepatic enzymes. Patient and graft survival were the main outcome indicators.  In the multivariate analysis, macrovescicular steatosis involving 25% or more of the hepatocytes was the only variable independently associated with shorter patient survival (p<0.05). Five (62.5%) of the eight livers with macrovescicular steatosis involving 25% or more of the hepatocytes incurred in a delayed non‐function (DNF) and one (12.5%) in a primary non‐function (PRNF). The incidence of DNF and PRNF in the group with macrovescicular steatosis involving less than 25% of the liver cells was 1.6% (p<0.001) and 2.3%, respectively. Microvescicular steatosis of any degree was not associated with a worse prognosis.  Macrovescicular steatosis involving 25% or more of the hepatocytes identifies marginal livers, the use of which significantly increases the risk of graft non‐function post‐OLT.
Cytological monitoring of peripheral blood, bronchoalveolar lavage fluid, and transbronchial biopsy specimens during acute rejection and cytomegalovirus infection in lung and heart–lung allograft recipients
Authors: Tikkanen Jussi , Lemström Karl , Halme Maija , Pakkala Seppo , Taskinen Eero , Koskinen Petri
Published: March 2003

Study objectives: Acute rejection and cytomegalovirus (CMV) infection are important complications after lung and heart–lung transplantation. We sought to investigate whether acute rejection and CMV infection demonstrated as CMV antigenemia had an effect on the cell profiles of peripheral blood (PB), bronchoalveolar lavage fluid (BAL‐F), or TBB histology.  Patients and design: In this prospective study, composition of cells in PB, BAL‐F, and TBB samples from 20 lung or heart–lung transplantation patients were analyzed during episodes of acute rejection or CMV antigenemia. Rejection was graded according to the International Society for Heart and Lung Transplantation criteria. As controls, samples with no evidence of rejection or infection were used. To evaluate the effect of time on cellular findings, samples were divided into three groups according to time after transplantation: 1–30, 31–180, and more than 180 d after transplantation.  Results: Acute rejection was associated with mild blood basophilia (p<0.05; specificity 94%, sensitivity 42%). In BAL‐F during rejection, the number of basophils (p<0.05), eosinophils (p<0.05), and lymphocytes (p<0.05; specificity 77%, sensitivity 64%) was increased compared to controls during the post‐operative month 1. Later‐occurring rejections were associated with increased amounts of neutrophils in BAL‐F (p<0.05; specificity 82%, sensitivity 74%). In TBB histology, acute rejections were associated with perivascular and/or peribronchial infiltration of lymphocytes (p<0.001) and plasma cells (p<0.05) compared to controls. In our patients receiving gancyclovir prophylaxis, CMV antigenemia did not significantly alter the cell profiles in PB and BAL‐F nor the inflammatory cell picture in TBB histology.  Conclusion: TBB histology remains the ‘gold standard’ for diagnosing rejection in lung and heart–lung transplantation patients, as the inflammatory cell findings in TBB specimens are highly specific for rejection. The cellular changes associated with rejection, mild PB basophilia and increased proportions of lymphocytes in early‐ and neutrophils in later‐occurring rejection, observed in BAL‐F cannot be considered specific for rejection, but may warrant clinical suspicion of rejection.
Rapid kidney allograft failure in patients with polyoma virus nephritis with prior treatment with antilymphocyte agents
Authors: Hussain Syed , Bresnahan Barbara A , Cohen Eric P , Hariharan Sundaram
Published: March 2003

Interstitial nephritis owing to polyoma virus infection (PVi) mimics acute allograft rejection. The risk factors for graft failure associated with PVi are unknown. This prompted us to analyse the relationship between the use of antilymphocyte agents (ALA) and graft dysfunction in renal transplant recipients with PVi.

Renal transplant recipients who were diagnosed to have PVi nephritis at the Medical College of Wisconsin were included in this study. PVi nephritis was confirmed by urine cytology and characteristic renal histological findings in a total of 14 cases. Other viruses were excluded by immunohistochemistry studies. Patients were divided into two groups: Group A (n=7) received ALA (OKT3/ATGAM) as treatment for presumptive acute rejection and Group B (n=7) did not receive ALA therapy. The progression of renal function (GFR) was estimated by a 100/plasma creatinine and an actuarial kidney survival was estimated by the Kaplan–Meier method.

The demographics (age, gender, race, retransplant and kidney versus. kidney/pancreas), prior treatment with steroids for presumptive acute rejection, and renal function at the time of PVi diagnosis were similar between groups. The fall in GFR/month was 6 mL/min/month with prior ALA therapy compared with 1 mL/min/month in those who did not receive ALA, p=0.002. All seven grafts were lost in the ALA group compared with only two of seven grafts in the other group, p=0.005.

The use of ALA was associated with a rapid fall in GFR and graft failure in patients with PVi nephritis. Careful diagnosis of PVi is warranted in renal allograft recipients prior to initiating ALA therapy.
Effects of total body irradiation on the vascular endothelium
Authors: Takatsuka Hiroyuki , Wakae Takeshi , Mori Ako , Okada Masaya , Okamoto Takahiro , Kakishita Eizo
Published: March 2003

Takatsuka H, Wakae T, Mori A, Okada M, Okamoto T, Kakishita E. Effects of total body irradiation on the vascular endothelium. Clin Transplant 2002: 16: . © Blackwell Munksgaard, 2002

Total body irradiation (TBI) is used as conditioning for stem cell transplantation. We studied its effects on the vascular endothelium in 55 consecutive patients undergoing stem cell transplantation with TBI (TBI group n=35) or without TBI (non‐TBI group: n=20). Fifty patients underwent bone marrow transplantation and five underwent peripheral blood stem cell transplantation. The levels of thrombomodulin, plasminogen activator inhibitor‐1, and cyclic GMP were measured before and after TBI. At both times, the thrombomodulin and plasminogen activator inhibitor‐1 levels were within the normal range in all patients from the two groups, without any significant differences between the groups. The cyclic GMP level was increased after TBI in six of 35 patients. Five of these six patients died as a result of complications of transplantation, while one patient survived in whom the cyclic GMP level rapidly returned to normal. In contrast, the cyclic GMP level remained normal in all patients not receiving TBI. These results suggest that conditioning with TBI stimulates vascular endothelial cells, even if it does not cause immediate direct injury. Such stimulation may be related to vascular endothelial dysfunction, the development of which may be mediated by nitric oxide.
Correlation between optimal tacrolimus doses and the graft weight in living donor liver transplantation
Authors: Sugawara Y , Makuuchi M , Kaneko J , Ohkubo T , Imamura H , Kawarasaki H
Published: March 2003

The optimal doses of tacrolimus (FK) needed to reach and maintain a target blood level vary among cases of living donor liver transplantation (LDLT). One hundred and twenty four LDLTs in 122 patients were included in this study. Tacrolimus was administered by continuous intravenous infusion at a rate of 2.5 μg/kg/h just after the operation. The time needed to reach the target blood level and the dose needed to maintain this level for 1 week (17–18 ng/mL) were defined as the initial duration (ID) and secondary dose (SD), respectively. In the first 100 LDLTs, the correlations between ID or SD and some clinical factors were examined and equations for predicting ID or SD were derived. In the latest 24 LDLTs, FK was administered using these equations and the actual and calculated ID and SD values were compared. A multiple regression analysis revealed that only the graft weight/recipient standard liver volume (GW/SLV) ratio (%) correlated with ID or SD. Stepwise regression analysis led to the equations ID (h)=0.4 × GW/SLV ratio + 0.2; SD (μg/kg/h)=0.02 × GW/SLV ratio – 0.4. Simple regression analysis revealed a significant correlation between the actual and calculated ID and SD values (p < 0.0001). Initial duration and SD can be estimated from equations using the GW/SLV ratio.
Five‐year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil
Authors: Offermann Gerd
Published: March 2003

Abstract: Mycophenolate mofetil (MMF) combined with cyclosporine and prednisolone significantly lowers acute rejection frequency in the early post‐renal transplantation phase. To date only registry data with very high transplant numbers have shown that MMF significantly influences long‐term outcome. A comparative retrospective analysis of the 5‐yr results with MMF in a single transplant center was thus undertaken vs. other standard immunosuppressive regimens. The results of 1579 renal transplantations were grouped by treatment modality, subjected to Kaplan–Meier analysis, and compared using the log rank test. Both the total population and subgroups showed a non‐significant trend towards better graft survival with MMF, evident at 2 yr and persisting for 5 yr. Extrapolation indicates that on combination therapy with MMF vs. azathioprine, approximately 10% more patients will be alive at 10 yr with a functional graft.
Comorbidity of obsessive‐compulsive disorder in recovered inpatients with bipolar disorder
Authors: Krüger Stephanie , Bräunig Peter , Cooke Robert G
Published: March 2003

Objective:

To determine the frequency of obsessive‐compulsive disorder (OCD) in inpatient subjects with bipolar disorder (BD) and to examine the clinical characteristics of BD subjects with OCD.  Method: The sample consisted of 143 inpatient subjects with DSM‐III‐R BD‐I and BD‐NOS (BD‐II), recovered from a current episode of either depression or mania. Demographic and clinical variables were obtained on the day of admission. Current comorbid conditions including OCD were determined by the Structured Clinical Interview for DSM‐III‐R following recovery from the acute affective episode.  Results: The frequency of current OCD was 7% (N=10). All BD subjects with OCD were BD‐II, were male, and had a diagnosis of current dysthymia. They had fewer episodes and a higher incidence of prior suicide attempts than bipolar subjects without OCD. None of the bipolar subjects with OCD fulfilled criteria for cyclothymia.  Conclusions: Our findings suggest that BD‐II, OCD, dysthymia, and suicidality cluster together in some subjects with BD. We discuss the clinical implications of our findings.
Can the expression of histocompatibility antigen be changed by lithium?
Authors: Kang Byung‐Jo , Park Sang‐Wun , Chung Tai‐Ho
Published: March 2003

Objectives

: This study attempted to determine whether human leukocyte antigen (HLA) type changes would be caused by lithium.   Methods: A total of 15 patients were chosen as subjects (4 males, 11 females) and completed tests in class I. Eight of the 15 patients completed tests in class II. Their mean age was 27±7 years. For an average of 51±17 days, lithium, 600–1200 mg/day (mean daily dose: 920±211 mg) was administered for the HLA testing and then compared with the HLA type prior to the time the drug was administered. Class I type test was performed according to the Terasaki microcytotoxicity method and class II type by the Erlich polymerase chain reaction method.   Results: Of the 15 subjects, 11 had changes in HLA‐A, B, C types and two of the eight subjects had changes in HLA DR type.   Conclusion: Lithium, in the therapeutic dose, is considered to bring about changes in HLA expressions in as short a time period as 2 months.
Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review
Authors: Post Robert M , Frye Mark A , Denicoff Kirk D , Leverich Gabriele S , Dunn Robert T , Osuch Elizabeth A , Speer Andrew M , Obrocea Gabriela , Jajodia Kamal
Published: March 2003

Recent evidence suggests that lithium therapy (even as supplemented by antidepressants and neuroleptics) is inadequate for the majority of patients with bipolar illness, and particularly those with rapid cycling. Valproate and carbamazepine have emerged as adjuncts and alternatives, but they, too, often require additional approaches with lithium, thyroid hormones, and other putative mood stabilizers, including nimodipine (and related dihydropyridine calcium channel blockers), lamotrigine, gabapentin, topiramate, and the atypical neuroleptics. Evaluating how these agents and the unimodal antidepressants are optimally applied and sequenced in the treatment of bipolar illness with its multiple subtypes, patterns and comorbidities will require much future investigation and the development of new methodological clinical trial approaches.
Lithium regulates PKC‐mediated intracellular cross‐talk and gene expression in the CNS in vivo
Authors: Chen Guang , Masana Monica I , Manji Husseini K
Published: March 2003

It has become increasingly appreciated that the long‐term treatment of complex neuropsychiatric disorders like bipolar disorder (BD) involves the strategic regulation of signaling pathways and gene expression in critical neuronal circuits. Accumulating evidence from our laboratories and others has identified the family of protein kinase C (PKC) isozymes as a shared target in the brain for the long‐term action of both lithium and valproate (VPA) in the treatment of BD. In rats chronically treated with lithium at therapeutic levels, there is a reduction in the levels of frontal cortical and hippocampal membrane‐associated PKC α and PKC ɛ. Using in vivo microdialysis, we have investigated the effects of chronic lithium on the intracellular cross‐talk between PKC and the cyclic AMP (cAMP) generating system in vivo. We have found that activation of PKC produces an increase in dialysate cAMP levels in both prefrontal cortex and hippocampus, effects which are attenuated by chronic lithium administration. Lithium also regulates the activity of another major signaling pathway – the c‐Jun N‐terminal kinase pathway – in a PKC‐dependent manner. Both Li and VPA, at therapeutically relevant concentrations, increase the DNA binding of activator protein 1 (AP‐1) family of transcription factors in cultured cells in vitro, and in rat brain ex vivo. Furthermore, both agents increase the expression of an AP‐1 driven reporter gene, as well as the expression of several endogenous genes known to be regulated by AP‐1. Together, these results suggest that the PKC signaling pathway and PKC‐mediated gene expression may be important mediators of lithium's long‐term therapeutic effects in a disorder as complex as BD.
Persistent attentional dysfunction in remitted bipolar disorder
Authors: Wilder‐Willis Kelly E , Sax Kenji W , Rosenberg H Lee , Fleck David E , Shear Paula K , Strakowski Stephen M
Published: March 2003

Objectives:
Although previous research has shown that attentional dysfunction is common during acute mood episodes in individuals with bipolar disorder (BPD), few studies have examined whether attentional deficits are evident during periods of symptom stability. The goal of this study was to determine whether clinically stable individuals with BPD would have attentional disturbances relative to healthy subjects.   Methods: Fourteen patients with BPD and 12 healthy comparison subjects participated in the study, and were administered the Degraded Stimulus Continuous Performance Test (DSCPT), Digit Span Distractibility Test (DSDT) and Grooved Pegboard Test (GPT). Psychiatric symptoms were assessed with the Young Mania Rating Scale and the Scale for the Assessment of Positive Symptoms. Medication side effects were measured with the Simpson Rating Scale.   Results: The patient group responded significantly more slowly than the control group on the DSCPT (z=−2.52, p=0.01) and the GPT (z=−3.37, p=0.001). There was a trend towards the BPD patients demonstrating impaired perceptual sensitivity on the DSCPT (z=1.68, p=0.09). The two groups did not differ on the DSDT (z=−1.06, p=0.3). Poor performance on the GPT and DSCPT target reaction time were not associated with symptom ratings or medications.   Conclusion: The findings suggest that impairments in fine motor skills and reaction time may be present in clinically stable patients with BPD, even after accounting for psychiatric symptoms and medication effects. Performance decrements on attentional tasks may be in part reflective of motor impairments in patients with BPD.
The prophylactic effect of long‐term lithium administration in bipolar patients entering treatment in the 1970s and 1980s
Authors: Rybakowski Janusz K , Chlopocka‐Wozniak Maria , Suwalska Aleksandra
Published: March 2003

Objectives:
The aim of the study was to assess the prophylactic effect of long‐term lithium administration in patients with bipolar mood disorders entering treatment in the 1970s and 1980s at the outpatient clinic of the Department of Psychiatry, University of Medical Sciences, Poznan, Poland.   Methods: The clinical characteristics of two groups of patients before and during lithium therapy were compared, namely, the 60 bipolar patients who entered lithium prophylaxis in the 1970s and 49 patients who entered in the 1980s. Both groups received the drug over a 10‐year period.   Results: The patients who entered lithium in the 1970s had fewer previous episodes of depression and more of mania than the patients who entered the therapy in the 1980s, although the total number of affective episodes was similar in both groups. The overall prophylactic efficacy of lithium over a 10‐year period of administration was similar in both groups, except for a trend towards a greater number of depressive episodes in the first year of lithium prophylaxis in the 1980s group. The excellent lithium responders constituted 35% of the 1970s patients and 27% of those in the 1980s group. The 1970s patients were maintained on a higher level of serum lithium compared to the patients in the 1980s group and had more lithium‐induced side effects.   Conclusions: A decrease in lithium prophylactic efficacy in consecutive decades was not observed. Small differences between the bipolar patients entering lithium therapy in the 2 decades were observed in terms of the previous history of illness and during the course of lithium administration.
31P‐MRS study of acetyl‐L‐carnitine treatment in geriatric depression: preliminary results
Authors: Pettegrew Jay W , Levine Joseph , Gershon Samuel , Stanley Jeffrey A , Servan‐Schreiber David , Panchalingam Kanagasabai , McClure Richard J
Published: March 2003

Objective:  
This 12‐week study of two elderly, depressed subjects investigated the effect of acetyl‐L‐carnitine (ALCAR) treatment on the Hamilton Depression Rating Scale (HDRS) and on measures of high‐energy phosphate and membrane phospholipid metabolism.

Methods:  
Two mildly depressed (HDRS 15–20), non‐demented male subjects 70 and 80 years old were compared with six non‐demented controls (all males, mean age of 73.6 ± 3.6 years). High‐energy and membrane phospholipid metabolites were measured by phosphorus magnetic resonance spectroscopic imaging (31P MRSI) analysis. HDRS and 31P MRSI measurements were taken at entry, 6 and 12 weeks for the depressed subjects.

Results:  

31P MRSI analysis revealed elevated levels of phosphomonesters [PME(s – τc)] in the prefrontal region of these mildly depressed subjects, which decreased with ALCAR treatment and showed a trend for correlation of the PME(s – τc) levels with HDRS. ALCAR treatment also resulted in increasing levels of the prefrontal phosphocreatine (PCr), which correlated with HDRS.

Conclusions:  
In the prefrontal region, the mildly depressed subjects compared with controls had elevated PME(s – τc) levels which normalized after 12 weeks of ALCAR and increased PCr levels after ALCAR treatment. These preliminary findings suggest further studies are warranted.
A clinical monitoring form for mood disorders
Authors: Sachs Gary S , Guille Constance , McMurrich Stephanie L
Published: March 2003

Objective:  The Clinical Monitoring Form (CMF) for mood disorders was developed as a time efficient record keeping tool for routine clinical use. This report presents preliminary data evaluating the correlation between the CMF's dimensional subscales for depression and mood elevation and formal mood rating scales across a wide spectrum of mood states.

Methods:  To harvest data for 500 follow‐up visits required collection of data from consecutive records accumulated during the conduct of seven double blind clinical trials involving a total of 58 participants. These trials utilized the CMF as a source document in conjunction with formal study outcome scales, e.g. Hamilton Rating Scale for Depression (HRSD), the Montgomery‐Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS) and the Mania Rating Scale (MRS) from the Schedule of Affective Disorders‐Current (SUM‐C). Correlation coefficients were calculated to examine the relationship between the formal rating scales, Clinical Global Impression and the depression (SUM‐D) and mood elevation (SUM‐ME) subscales of the CMF.

Results:  Robust correlations were observed between SUM‐D and the formal depression scales, HRSD and MADRS, r=0.79, r=0.88, respectively. Similar robust correlations were also found between the SUM‐ME and the formal mood elevation scales, YMRS and the MRS, r=0.84, r=0.86, respectively.

Conclusion:  The CMF appears to offer a reasonable alternative to the formal rating scales typically used in research studies.