bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverted duplications deletions: underdiagnosed rearrangements??
Authors: Zuffardi O , Bonaglia M , Ciccone R , Giorda R
Published: June 2009

Molecular techniques led to the discovery that several chromosome rearrangements interpreted as terminal duplications were in fact inverted duplications contiguous to terminal deletions. Inv dup del rearrangements originate through a symmetric dicentric chromosome that, after asymmetric breakage, generates an inv dup del and a deleted chromosome. In recurrent inverted duplications the dicentric chromosome is formed at meiosis through non‐allelic homologous recombination. In non‐recurrent inv dup del cases, dicentric intermediates are formed by non‐homologous end joining or intrastrand annealing. Some authors hypothesized that in these cases the dicentric may have been formed directly in the zygote. Healing of the broken dicentric chromosomes can occur not only in a telomerase‐dependent way but also through telomere capture and circularization thus creating translocated or ring inv dup del chromosomes. In all the cases reported up to now, the duplicated region was always longer than the deleted one, but we can safely assume that there is another group of rearrangements where the deleted region is longer than the duplicated portion. In general, in these cases, the cytogeneticist will suspect the presence of a deletion and confirm it by FISH with a subtelomeric probe, but he/she will almost certainly miss the duplication. It is likely that the conventional analysis techniques used until now have led to a substantial underestimate of the frequency of inv dup del rearrangements and that the widespread use of array‐CGH in routine analysis will allow a more realistic estimate. Obviously, the concomitant presence of deletion and duplication has important consequences in genotype/phenotype correlations.
Valuing the benefit of diagnostic testing for genetic causes of idiopathic developmental disability: willingness to pay from families of affected children
Authors: Regier DA , Friedman JM , Makela N , Ryan M , Marra CA
Published: June 2009

Idiopathic developmental disability (DD) has been found to put significant psychological distress on families of children with DD. The cause of the disability, however, is unknown for up to one‐half of the affected children. Chromosomal abnormalities identified by cytogenetic analysis are the most frequently recognized cause of DD, although they account for less than 10% of cases. Array genomic hybridization (AGH) is a new diagnostic tool that provides a much higher detection rate for chromosomal imbalance than conventional cytogenetic analysis. This increase in diagnostic capability comes at greater monetary costs, which provides an impetus for understanding how individuals value genetic testing for DD. This study estimated the willingness to pay (WTP) for diagnostic testing to find a genetic cause of DD from families of children with DD. A discrete choice experiment was used to obtain WTP values. When it was assumed that AGH resulted in twice as many diagnoses and a 1‐week reduction in waiting time compared with conventional cytogenetic analysis, this study found that families were willing to pay up to CDN$1118 (95% confidence interval, $498–1788) for the expected benefit. These results support the conclusion that the introduction of AGH into the Canadian health care system may increase the perceived welfare of society, but future studies should examine the cost‐benefit of AGH vs cytogenetic testing.
VIP gene variants related to idiopathic pulmonary arterial hypertension in Chinese population
Authors: Zhang Y , Zhang J‐Q , Liu Z‐H , Xiong C‐M , Ni X‐H , Hui R‐T , He J‐G , Pu J‐L
Published: June 2009

A variety of studies has linked vasoactive intestinal peptide (VIP) to idiopathic pulmonary arterial hypertension (IPAH). In this study, we investigated the correlation between VIP gene variants and IPAH in Chinese population. A total of 81 consecutive unrelated patients diagnosed as IPAH from 2006 to 2008 and 250 controls were included in the study. VIP gene variants were screened by direct sequencing, and VIP serum level was determined by enzyme‐linked immunosorbent assay. Clinical and hemodynamic data of all patients were also obtained. The variant g.8129T→C in exon 7 was found to be the only variant in the coding region of VIP gene with a significantly higher frequency in patients (40.7%) than in control samples (15.2%). Moreover, there was marked difference in VIP serum level and hemodynamic data between IPAH patients with and without the variant. The variant g.8129T→C in exon 7 of VIP gene was correlated with the clinical phenotype of lower VIP serum level, higher mean pulmonary artery pressure and pulmonary vascular resistance in patients with IPAH comparing to those in patients without this variant. The VIP gene variant g.8129T→C may be one of the risk factors in the pathogenesis of IPAH.
Silencing is Not‐So Golden: A New Model for Inheritance of Lynch Syndrome
Authors: Kobelka CE
Published: June 2009

Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1

Ligtenberg et al. (2009)

Nature Genetics 41: 112–117
‘ERAD'icating Mislocalized Proteins in an Acromesomelic Dwarfism Disorder
Authors: Kang MH
Published: June 2009

Defective cellular trafficking of missense NPR‐B mutants is the major mechanism underlying acromesomelic dysplasia‐type Maroteaux

Hume et al. (2009)

Human Molecular Genetics 18: 267–277
A Controlled SCID: Bringing Reticular Dysgenesis to a Halt
Authors: Kang MH
Published: June 2009

Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2

Pannicke et al. (2009) Nature Genetics 41: 101–105

Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness

Lagresle‐Peyrou et al. (2009)

Nature Genetics 41: 106‐111
Incidence of pancreas graft thrombosis using low‐molecular‐weight heparin
Authors: Schenker Peter , Vonend Oliver , Ertas Neslihan , Wunsch Andreas , Schaeffer Michael , Rump Lars‐Christian , Viebahn Richard
Published: June 2009

Abstract:  Introduction:  Simultaneous pancreas–kidney transplantation is the current treatment of choice for patients with type I diabetes and end stage renal disease. Vascular graft thrombosis (VGT) after pancreas transplantation is the main cause of early graft loss.

Methods:  A total of 188 consecutive pancreas transplantations were performed between January 2000 and December 2006. A retrospective study was carried out in order to compare incidence of VGT and relaparotomy‐for‐bleeding rate of once daily fixed dose low‐molecular‐weight‐heparin (LMWH) to dose‐adjusted intravenous unfractionated heparin (UFH).

Results:  Fifty‐eight patients receiving LMWH and 129 receiving UFH were identified. There were 7% (4/58) VGTs in the LMWH and 17% (22/129) in the UFH group (p = 0.047). The frequency of major bleeding requiring relaparatomy was not significantly different in the groups related to LMWH and UFH, respectively (6.9% vs. 7.8%). One yr patient and pancreas graft survival was 98.9/89.6% in the LMWH and 97.8/74.4% in the UFH group. Donor and recipient characteristics were similar.

Conclusion:  In our experience once daily fixed dose LMWH might not be inferior to dose‐adjusted intravenous heparin in preventing pancreas graft thrombosis.
Microalbuminuria post‐renal transplantation: relation to cardiovascular risk factors and C‐reactive protein
Authors: Ramesh Prasad G.V. , Bandukwala Farah , Huang Michael , Zaltzman Jeffrey S.
Published: June 2009

Abstract:  Microalbuminuria predicts graft loss and all‐cause mortality in renal transplant recipients. In the general population, it clusters with both traditional cardiovascular risk factors and elevated C‐reactive protein (CRP). Our objective was to define the relationship between microalbuminuria and these risk factors in stable renal transplant recipients. We identified 222 stable recipients who were minimum two months post‐transplant and provided three urine albumin‐to‐creatinine ratio (ACR) measurements, excluding those with recent illness and proteinuria. Microalbuminuria was defined as averaged ACR ≥ 2.0 in men and 2.8 mg/mmol in women (Canadian Diabetes Association 2003). Risk factors associated with microalbuminuria were determined by multivariate logistic regression analysis. Averaged ACR correlated to CRP (R = 0.21, p = 0.001). Prevalence of microalbuminuria was 48% (108/222). Patients with microalbuminuria had higher CRP (7.01 ± 8 vs. 3.21 ± 3 mg/L, p < 0.0001) and systolic BP (129 ± 17 vs. 123 ± 12 mmHg, p = 0.004). Microalbuminuria was associated with increasing CRP [odds ratio 1.129 per 1 mg/L (95% CI 1.058–1.204), p = 0.0002], SBP [1.248 per 10 mmHg (1.023–1.522), p = 0.029] and smoking [1.938 (1.023–3.672), p = 0.042]. Post‐transplant microalbuminuria is prevalent and is associated with elevated CRP, elevated BP, and smoking. Its relationship to these factors suggests it may be an indicator of graft and patient health.
Transplantation of a severely lacerated liver – a case report with review of the literature
Authors: Mehrabi Arianeb , Fonouni Hamidreza , Ahmadi Rezvan , Schmied Bruno M. , Müller Sascha A. , Welsch Thilo , Hallscheidt Peter , Zeier Martin , Weitz Jürgen , Schmidt Jan
Published: June 2009

Abstract:  Using lacerated livers for liver transplantation (LTx) can add an option to the extended donor criteria. We present an LTx case using a severely lacerated liver and review of the literature for reported cases. We used a high‐grade lacerated liver from a 19‐yr‐old brain‐dead patient caused by traffic accident. The liver had grade IV and II lacerations in the right and left lobe, respectively. Lacerations were managed by sealants, stitching and perihepatic packing. The liver was transplanted to a 49‐yr‐old man suffering from hepatocellular carcinoma on hepatitis C‐induced liver cirrhosis. The two‐yr follow‐up was uneventful. All published LTx cases using traumatized livers (n = 18) were analyzed. The liver injury ranged from subcapsular hematoma to deep ruptures. Most reported lacerations were in the right lobe, which were managed by digital compression, suturing, electrocautery, and perihepatic packing. The reported complications were primary non‐ (18%), or poor function, liver abscess, bilioma, and subhepatic hematoma each in one case (5.5%). Six‐month graft and patient survival were 71% and 88%, respectively. With meticulous management lacerated livers can be transplanted successfully. Because of complexity of the management, procurement and transplantation should be done by experienced liver surgeons. These organs are marginal grafts and should be offered to selected patients.
From words to action – influence of two organ donation campaigns on knowledge and formal decision making
Authors: Krekula Linda Gyllström , Malenicka Silvia , Linder Margareta , Tibell Annika
Published: June 2009

Abstract: Introduction: In Sweden, two donation campaigns have been carried out; one short term (STC) during October 2001, and one long term (LTC) between the years 2003–2005. The goal was not only to inform the public but also to create a positive attitude, make people talk about donation and formally declare their decision.

Methods: The effects of the two campaigns were evaluated through three opinion polls.

Results: The willingness to donate was widespread (86%) before and after the campaigns. The LTC increased the knowledge of the Donor Card (24–35%, p < 0.001) and the National Donor Registry (19–40%, p < 0.001). The LTC focused on making people register, still though, only a small increase of registrants was found (11–14%, p = 0.043). The proportion expecting the question of organ donation if their relative was to die under circumstances that made organ donation possible increased (73–79%, p = 0.002). No corresponding increase was found regarding the number having informed a relative about their decision (20–23%, ns).

Conclusion: The LTC was successful in increasing the expectation for the donation request. It also improved the knowledge of the Card and the Registry and slightly increased the number having registered. However, neither of the campaigns succeeded in making people inform their relatives.
Impact of induction therapy on bacterial infections and long‐term outcome in adult intestinal and multivisceral transplantation: a comparison of two different induction protocols: daclizumab vs. alemtuzumab
Authors: Kimura Takuya , Lauro Augusto , Cescon Matteo , Zanfi Chiara , Dazzi Alessandro , Ercolani Giorgio , Grazi Gian Luca , Vivarelli Marco , Ravaioli Matteo , Del Gaudio Massimo , Cucchetti Alessandro , Zanello Matteo , LaBarba Giuliano , Pironi Loris , Lazzarotto Tiziana , Pinna Antonio Daniele
Published: June 2009

Abstract:  Introduction:  Induction therapy with daclizumab or alemtuzumab has been recently introduced for intestinal transplantation; however, the impact of such induction therapy on bacterial infections remains to be clarified. The purpose of this study was to evaluate the impact of induction therapy on the incidence of bacterial infections and long‐term patient survival.

Patients and methods:  Over the past seven yr, we performed 39 intestinal (ITx) and multivisceral (MTVx) transplants in 38 adult patients. In the early period, daclizumab was used for induction, and tacrolimus and steroids were administered for maintenance [daclizumab and tacrolimus (DT) group; n = 11]. From 2002, we used alemtuzumab for induction, with low‐dose tacrolimus maintenance [alemtuzumab and tacrolimus (AT) group; n = 23]. The incidence of bacterial infections and patient outcome were compared between the two groups.

Results:  There were no significant differences in recipient and donor demographics, procedure (ITx vs. MTVx), and cold and warm ischemic time between the two groups. Within 30 d after ITx, bacterial infections were observed in seven patients (64%) in the DT and in 14 patients (64%) in the AT group. Between 30 and 180 d after ITx, a total of 17 episodes of bacterial infections were observed in the DT and 26 episodes in the AT group. Three patients in the DT and eight in the AT group died, and all of the deaths were related to infectious complications except one each in DT and AT.

Conclusion:  There was no difference in incidence of bacterial infections and long‐term patient survival between the two groups.
Outcome of hepaticojejunostomy for biliary tract obstruction following liver transplantation
Authors: Langer F.B. , Györi G.P. , Pokorny H. , Burghuber C. , Rasoul‐Rockenschaub S. , Berlakovich G.A. , Mühlbacher F. , Steininger R.
Published: June 2009

Abstract:  Background:  Strictures and concrements are the most common biliary complications following liver transplantation. Endoscopic treatment might not lead to a definitive cure in all patients, especially in strictures involving the biliary bifurcation. The aim of this study was to determine the efficacy and the long‐term outcome of hepaticojejunostomy (HJS) for post‐transplant biliary tract obstruction.

Material and methods:  Thirty‐seven patients were retrospectively studied for resolving of cholestasis and the incidence of recurring biliary obstruction.

Results:  Surgery was performed because of anastomotic strictures in 11, ischemic strictures at the donor common bile duct in seven, strictures involving the bile duct bifurcation in 10, hepatolithiasis without strictures in one and biliary cast formation diagnosed by endoscopic retrograde cholangiography or T‐tube cholangiography in eight patients. Cholestasis instantly improved in 82% of the patients. After a long‐term follow‐up of median 33 months (range 3–149), 28 of the patients (76%) required no further intervention for recurring biliary obstruction following HJS. Anastomotic strictures were observed in six (16%), recurring biliary concrements in two patients (5%).

Conclusion:  HJS did prevent recurrent biliary obstruction in the majority of the patients. We therefore recommend early HJS for complicated post‐transplant biliary tract obstruction not treatable by a limited number of endoscopic interventions.
The impact of meticulous management for hepatic artery thrombosis on long‐term outcome after pediatric living donor liver transplantation*
Authors: Uchida Yoichiro , Sakamoto Seisuke , Egawa Hiroto , Ogawa Kohei , Ogura Yasuhiro , Taira Kaoru , Kasahara Mureo , Uryuhara Kenji , Takada Yasutsugu , Kamiyama Yasuo , Tanaka Koichi , Uemoto Shinji
Published: June 2009

Abstract:  To analyze the risk factors in the development of hepatic artery thrombosis (HAT) and assess the impact of our perioperative management for HAT on the long‐term outcome after pediatric living donor liver transplantation (LDLT), we reviewed 382 patients under 12 yr of age who underwent 403 LDLT from January 1996 to December 2005. One‐ and 10‐yr patient survival rates were 78% and 78% in the patients with HAT (27 patients; 6.7%), and 84% and 76% in the patients without HAT, respectively (p = n.s.). Univariate analysis showed gender (female), body weight (lower), and graft‐to‐recipient weight ratio (higher) were significant risk factors in the patients with HAT (p < 0.05). Patients with Doppler ultrasound signal loss of the hepatic artery (HA) accompanied by an increase of liver enzymes underwent thrombectomy and reanastomosis (S‐group, n = 13), and patients with a weak HA signal underwent anticoagulant therapy (M‐group, n = 13). One patient underwent re‐LDLT. One‐ and five‐yr patient survival rates were 83% and 83% in the S‐group, and 77% and 77% in the M‐group (p = n.s.). The incidence of biliary complications in the S‐group (58%) was significantly higher than that of the M‐group (15%). For a successful long‐term outcome, the early detection of HAT and prompt medical and surgical intervention are crucial to minimize the insult of HAT.
Successful treatment of severe secondary hyperparathyroidsm (Brown tumor) by kidney transplantation and pulses of oral calcitriol
Authors: Spasovski Goce , Masin‐Spasovska Jelka , Gjurchinov Daniel
Published: June 2009

Abstract:  Brown tumor is an extreme form of severe hyperparathyroid bone disease in end‐stage renal disease patients. The evolution of the tumor after renal transplantation and under conservative treatment is still unclear. Herein, we report a 22‐yr‐old girl with parathyroid glandular hyperplasia because of an inadequate compliance and control of the mineral metabolism and subsequently developed Brown tumor of the ribs. A gradual improvement in bone and parathyroid gland status was observed within three yr following successful kidney transplantation and treatment with pulses of oral calcitriol. To the best of our knowledge, this is the first case of such severe secondary hyperparathyroidism with successful conservative treatment in the setting of kidney transplantation with no evidence of vascular calcifications and graft failure.
Tacrolimus in pediatric heart transplantation: ameliorated side effects in the steroid‐free, statin era
Authors: Simmonds Jacob , Dewar Catherine , Dawkins Helen , Burch Michael , Fenton Matthew
Published: June 2009

Abstract: Due to concerns over the side effects of cyclosporine, tacrolimus is widely used in pediatric heart transplantation. However, tacrolimus therapy is also accompanied by potentially serious side effects. This paper examines the side effect profile of tacrolimus in a large group of pediatric heart recipients. Data on renal function, diabetes, hyperlipidemia and hypertension were collected by case‐note review of 100 patients who had received ≥ 12 months treatment with tacrolimus. Forty‐two patients received tacrolimus from the time of transplant (de novo), and 58 were initially treated with cyclosporine (switch). Mean estimated glomerular filtration rate improved in the first six months post transplant in thede novogroup (66.7–84.6 mL/min/1.73 m2, p = 0.002). Conversely, it decreased in those initially treated with cyclosporine (82.1–68.8, p = 0.032), but improved after switch to tacrolimus (77.3–85.6, p = 0.006). Twenty‐one percent exhibited glucose intolerance, and 2% had diabetes. Borderline or elevated fasting cholesterol levels were present in 4.4%. Hypertension was seen in 67% at the point of switch from cyclosporine, which fell to 36% at latest follow‐up (p = 0.001). These results present an encouraging outlook for this cohort of patients. The relatively low levels of complications shown may be due to early weaning of steroids, and concomitant statin therapy.
Reactivation of hepatitis B two years after rituximab therapy in a renal transplant patient with recurrent focal segmental glomerulosclerosis: a note of caution
Authors: Gossmann Jan , Scheuermann Ernst‐Heinrich , Kachel Heinz‐Georg , Geiger Helmut , Hauser Ingeborg A.
Published: June 2009

Abstract:  We report on the reactivation of hepatitis B in a renal transplant patient who had been treated with rituximab for recurrent focal segmental glomerulosclerosis two and a half yr previously. He lost his anti‐hepatitis B surface antigens and anti‐hepatitis B core antigen antibodies and developed hepatitis B virus (HBV)‐DNA positive hepatitis. Hepatitis C, which had been successfully treated by alpha interferon 10 yr before, remained quiescent. We suggest regular controls of HBV‐DNA, anti‐HBV antibodies and transaminases for prolonged periods in patients with status post‐hepatitis B treated with rituximab. Prophylactic therapy with lamivudine and/or hepatitis B hyperimmune globulin may be considered in patients with a decrease in anti‐HBV antibodies.
Hematologic complications of anti‐CMV therapy in solid organ transplant recipients
Authors: Danziger‐Isakov Lara , Mark Baillie G.
Published: June 2009

Abstract: Cytomegalovirus (CMV) infection complicates the post‐operative course of patients receiving solid organ transplants. While ganciclovir has significantly reduced the direct effects of CMV infection, some patients cannot tolerate the optimal therapeutic exposure required for CMV prevention and treatment. Few reports directly address the incidence, consequences, and risk factors for hematologic toxicities related to ganciclovir therapy. Nevertheless, leukopenia, thrombocytopenia, and anemia occur in 5–50% of patients. Current strategies, focused on ganciclovir dose reduction, may increase the risk of CMV reactivation and drug‐resistant disease. The current article reviews the incidence, risk factors, and consequences of ganciclovir‐associated hematologic adverse events in transplant recipients. Management strategies, including ganciclovir dose reduction, and the addition of CMV hyperimmune globulin are discussed. Exposing this relatively frequently occurring, but uncommonly discussed, toxicity should lead to better avoidance and treatment strategies, without placing patients at increased risk of CMV disease.
Living donor liver transplantation and its effect on the donor–recipient relationship – a qualitative interview study with donors
Authors: Papachristou C. , Walter M. , Schmid G. , Frommer J. , Klapp B.F.
Published: June 2009

Abstract:  An important aspect in the preoperative evaluation and a legal precondition for an living donor liver transplantation (LDLT) is a family or emotionally close relationship between donor and recipient. We investigated the development of the donor–recipient relationship after LDLT. We conducted semi‐structured clinical interviews with 18 donors as part of a regular postoperative follow‐up and analyzed them using the method of Grounded Theory. The donation does not lead to any major changes in the donor‐recipient relationship, probably due to careful pre‐selection. It does however enhance the existing positive or conflicting character of the relationship. Donors sometimes downplay negative aspects in the relationship and emphasize the improvement as a way of dealing with a major life event. A donation cannot fulfill expectations linked to it and it is unfavorable to be used to improve the relationship. Potential misuse or instrumentalization of the donation by the donor are possible. Postoperative feelings of gratitude are an issue after surgery. A good relationship enhances a better management of the postoperative course. The preoperative donor–recipient relationship should be as free of conflict as possible. A thorough preoperative evaluation of the donor–recipient relationship is particularly important to assess the donors’ suitability and clarify conflicts and unrealistic expectations.
Clinical experience with histidine‐tryptophan‐ketoglutarate solution in abdominal organ preservation: a review of recent literature
Authors: Fridell Jonathan A. , Mangus Richard S. , Tector A. J.
Published: June 2009

Abstract:  Histidine‐tryptophan‐ketoglutarate (HTK) solution was introduced by Bretschneider as a cardioplegia solution in the early 1980s and has subsequently been applied to organ preservation for transplantation in Europe during the 1980s and in North America during the last six yr. With the increasing use of HTK for primary preservation, it is important that the transplant community be aware of the properties of this solution and the advantages and disadvantages of its use. Even if a center uses an alternative preservation solution, it is likely that import offers will be made for allografts that have been preserved in HTK. In this review article, recent literature describing the clinical use of HTK in abdominal transplantation will be summarized with references to earlier reports when indicated.
Conversion to sirolimus with calcineurin inhibitor elimination vs. dose minimization and renal outcome in heart and lung transplant recipients
Authors: Demirjian S. , Stephany B. , Abu Romeh I.S. , Boumitri M. , Yamani M.H. , Poggio E.D.
Published: June 2009

Abstract:  Sirolimus (SRL) has been used as an alternative immunosuppressant strategy to allow either dose minimization or complete withdrawal of calcineurin inhibitors (CNI) therapy to improve renal outcome. One hundred thirty‐one heart and 55 lung transplant patients were converted from a CNI to SRL based immunosuppression, with CNI elimination in 25 patients, and dose reduction in 161 patients. Fifty‐six (28%) patients died and 65 (33%) patients had a 25% or more decline in estimated glomerular filtration rate (eGFR) during a median follow‐up of 18 months. The three groups (SRL only group n = 25; SRL + tacrolimus n = 94; SRL + cyclosporine n = 67) had an initial improvement in estimated glomerular filtration rate (p = 0.05), with subsequent similar slow decline in mean eGFR (repeated measures ANOVA, p = 0.96). After controlling for important potential confounding variables, the three groups had similar renal outcome (p = 0.40) and overall survival (p = 0.45). In conclusion, the benefits of CNI withdrawal vs. minimization as part of SRL‐based regimens are similar with regard to renal outcomes and patient survival.
1,25‐dihydroxyvitamin D synthesis after renal transplantation: the role of fibroblast growth factor 23 and cyclosporine
Authors: Sato Tetsuhiko , Fukagawa Masafumi , Uchida Kazuharu , Katayama Akio , Nagasaka Takaharu , Matsuoka Susumu , Goto Norihiko , Tominaga Yoshihiro , Kobayashi Takaaki , Nakao Akimasa
Published: June 2009

Abstract:  1,25‐dihydroxyvitamin D3 (1,25D) is tightly regulated by circulating factors, containing fibroblast growth factor 23 (FGF23). However, this control is disturbed in chronic kidney disease. Renal transplantation (RTX) alters 1,25D homeostasis. To examine the clinical relevance of 1,25D in RTX, we drew blood samples from 27 renal transplant recipients (20 cyclosporine‐based, seven non‐cyclosporine‐based) and examined serum concentrations of 25‐hydroxyvitamin D3 (25D), 1,25D, and FGF23. Our protocol for cyclosporine was as follows, an initial dose of 8 mg/kg two d before RTX, and subsequently adjusted on the basis of the pharmacokinetic profile. No baseline differences were observed between cyclosporine‐based and non‐cyclosporine‐based regimens before RTX. All variables except 1,25D levels changed similarly between the two groups. In the cyclosporine‐based regimen, 1,25D levels increased steeply on day 2 and re‐increased from days 7 to 21. Post‐transplant FGF23 levels sharply decreased until day 14. Interestingly, the cyclosporine‐treated group revealed an unexpected tendency between circulating 1,25D and FGF23 on day 21. Multiple regression analyses indicated the cyclosporine pharmacokinetic profile as a significant predictor for 1,25D levels. Post‐transplant 1,25D production is induced by a steep fall in serum FGF23 and prompt graft function on day 2; 1,25D levels thereafter may be stimulated by circulating abundant cyclosporine.
Acclimation to future atmospheric CO2 levels increases photochemical efficiency and mitigates photochemistry inhibition by warm temperatures in wheat under field chambers
Authors: Gutiérrez Diego , Gutiérrez Elena , Pérez Pilar , Morcuende Rosa , Verdejo Angel L. , Martinez‐Carrasco Rafael
Published: June 2009

A study was conducted over 2 years to determine whether growth under elevated CO2 (700 μmol mol−1) and temperature (ambient + 4 °C) conditions modifies photochemical efficiency or only the use of electron transport products in spring wheat grown in field chambers. Elevated atmospheric CO2 concentrations increased crop dry matter at maturity by 12–17%, while above‐ambient temperatures did not significantly affect dry matter yield. In measurements with ambient CO2 at ear emergence and after anthesis, growth at elevated CO2 concentrations decreased flag leaf light‐saturated carbon assimilation. The quantum yield of electron transport (ΦPSII) measured at ambient CO2 and higher irradiances increased at ear emergence and decreased after anthesis in plants grown at elevated CO2. At higher light intensities, but not in low light, photochemical quenching (qP) decreased after growth in elevated CO2 conditions. Growth under CO2 enrichment increased dark‐ (Fv:Fm) and light‐adapted (Fv′:Fm′) photochemical efficiencies, and decreased the chlorophyll a:b ratio, suggesting an increase in light‐harvesting complexes relative to PSII reaction centres. A relatively higher decrease in carbon assimilation than the decrease in ΦPSII pointed to a sink other than CO2 assimilation for electron transport products at defined growth stages. With higher light intensities, warmer temperatures increased ΦPSII and Fv′:Fm′ at ear emergence and decreased ΦPSII after anthesis; in ambient—but not elevated—CO2, warmer temperatures also decreased qP after anthesis. CO2 fixation increased or did not change with temperature, depending on the growth stage and year. We conclude that elevated CO2 decreases the carbon assimilation capacity, but increases photochemistry and resource allocation to light harvesting, and that elevated levels of CO2 can mitigate photochemistry inhibition as a result of warm temperatures.
Methyl jasmonate dramatically enhances the accumulation of phenolic acids in Salvia miltiorrhiza hairy root cultures
Authors: Xiao Ying , Gao Shouhong , Di Peng , Chen Junfeng , Chen Wansheng , Zhang Lei
Published: June 2009

The aim of this work was to examine rosmarinic acid and its derivative lithospermic acid B accumulation, as well as related gene transcript and metabolite profiling in Salvia miltiorrhiza Bunge (Lamiacae) hairy root cultures, in response to methyl jasmonate (0.1 mM). Results showed methyl jasmonate dramatically enhanced both rosmarinic acid and lithospermic acid B accumulation, from approximately 3.25 to 6.02%, and 2.94 to 19.3% of dry weight, respectively. Meantime, several rosmarinic acid biosynthetic gene transcripts were coordinately induced, with phenylalanine ammonia‐lyase, cinnamic acid 4‐hydroxylase, tyrosine aminotransferase, 4‐hydroxyphenylpyruvate reductase and 4‐hydroxyphenylpyruvate dioxygenase transcripts displaying the most rapid and substantial increases. Liquid chromatographic–tandem mass spectrometry was used to characterize the profile of metabolites involved in rosmarinic acid biosynthesis pathway, in both control and elicited‐treated hairy root cultures. Further canonical correlation analysis constructed a gene‐to‐metabolite network, locating possible gene candidates which would directly link to phenolic acids (rosmarinic acid and lithospermic acid B) production, and thereby, would help to prompt the possibility of a key gene‐based metabolic engineering for the synthesis of active pharmaceutical compounds in S. miltiorrhiza.
Antisense suppression of type 1 diacylglycerol acyltransferase adversely affects plant development in Brassica napus
Authors: Lock Yee‐Ying , Snyder Crystal L. , Zhu Weiming , Siloto Rodrigo M. P. , Weselake Randall J. , Shah Saleh
Published: June 2009

Diacylglycerol acyltransferase (DGAT) catalyzes the acyl‐coenzyme A (CoA) dependent acylation of sn‐1,2‐diacylglycerol to form triacylglycerol in the terminal step of seed oil formation. Previous work has suggested that the level of DGAT activity may have a substantial effect on the flow of carbon into triacylglycerol, implying that the enzyme may represent a promising target for seed oil modification through biotechnological approaches. In the current study, Brassica napus DH12075 was transformed with an antisense type 1 DGAT construct, resulting in a reduction in DGAT1 gene expression, total DGAT activity and seed oil content. In addition, reduced seed yield and germination rates were observed along with severe developmental abnormalities. These data suggest that in addition to its critical role in seed oil formation, DGAT1 enzyme may also be important for normal seed development in B. napus, although the underlying mechanism(s) remain to be determined.
The history of lithium therapy
Authors: Shorter Edward
Published: June 2009

The use of lithium in psychiatry goes back to the mid‐19th century. Early work, however, was soon forgotten, and John Cade is credited with reintroducing lithium to psychiatry for mania in 1949. Mogens Schou undertook a randomly controlled trial for mania in 1954, and in the course of that study became curious about lithium as a prophylactic for depressive illness. In 1970, the United States became the 50th country to admit lithium to the marketplace. Meanwhile, interest in lithium for the prophylaxis of depression was growing apace and today the agent is widely prescribed for that indication, even though it has not been accepted by the Food and Drug Administration. Lithium was almost derailed by a small group of opponents from the Maudsley Hospital and its status today is threatened by the “mood stabilizers.”
A critical appraisal of lithium’s efficacy and effectiveness: the last 60 years
Authors: Grof Paul , Müller‐Oerlinghausen Bruno
Published: June 2009

The history that depicts the evaluation of lithium’s efficacy presents an interesting contrast: on the one hand, conviction that, of all psychotropic drugs, lithium has the best demonstrated efficacy; on the other hand, repeated attempts to question it. Those contesting lithium’s stabilizing abilities have argued from several angles, for example that the proof was methodologically incorrect or insufficient, that the number of responders is small, or that the response is poor in practice and does not last. But there is a good explanation for this paradox. While the early challenges to lithium’s value in recurrent mood disorders reflected mainly that psychiatry had not yet developed a methodology suitable for testing long‐term efficacy, more recent questioning has resulted mostly from retesting its efficacy and effectiveness in a substantially broadened bipolar spectrum, outside the classical diagnosis. Lithium, however, continues to stabilize very well the patients suffering from typical bipolar disorder—the condition for which its efficacy was originally demonstrated. More recently, lithium has also proven to dramatically reduce suicidal behavior and mortality and to augment markedly the efficacy of antidepressants in unresponsive patients.
Anticonvulsants in bipolar disorders: current research and practice and future directions
Authors: Bowden Charles L
Published: June 2009

Objectives:  To determine the clinical effectiveness of drugs with anticonvulsant properties for interventions in persons with bipolar disorder and to place these findings in the context of clinicians’ practices and their implications for future research to more effectively manage bipolar disorders.

Methods:  Major electronic databases were searched up to February 2009 for clinical trial data, both original studies and reviews, on drugs with anticonvulsant properties studied for bipolar disorders.

Results:  Valproate, principally as divalproex, has strong evidence for effectiveness in mania, moderately strong evidence for benefits in prophylaxis of recovered states, and recent proof‐of‐concept evidence for benefits in bipolar depression. Lamotrigine has strong evidence for evidence for effectiveness in maintenance treatment of bipolar disorder, principally for benefits in depressive states. Lamotrigine has been established as ineffective in mania and has lacked efficacy in acute bipolar depression in most randomized trials. Carbamazepine has strong evidence for effectiveness in mania, but lacks adequate studies in other aspects of bipolar disorder treatment. Its adverse effect profile and pharmacokinetic interference with a wide range of drugs, including many employed in bipolar disorder, warrants limitation of use to patients who have responded inadequately to other regimens.

Conclusions:  Three drugs, valproate, lamotrigine, and carbamazepine, have strong evidence‐based support for use in clinical states of bipolar disorder. Other anticonvulsant drugs investigated in bipolar disorder either have evidence of lack of benefits in bipolar disorder or have been inadequately studied to determine possible effectiveness.
Lithium specificity in bipolar illness: a classic agent for the classic disorder
Authors: Gershon Samuel , Chengappa KN Roy , Malhi Gin S
Published: June 2009

For over half a century, lithium has been the gold standard amongst the pharmacological armamentarium used to treat bipolar disorder. Its ascendancy in this regard has been attributed partly to its primacy of discovery and clinical implementation; however, it is important to consider how it has achieved success and retained its prominence and whether this is because of its unique profile and specificity of actions. In this paper, we briefly discuss the clinical evidence in support of lithium specificity and argue for its continuing use in those patients most likely to benefit, namely, patients with ‘classic’ bipolar disorder. Further, we suggest that accurate characterization of ‘lithium responders’ through focused research is likely to yield novel treatments and assist in better understanding of the pathophysiology of the illness. In addition, the unique antisuicidal actions of lithium warrant further examination, as do its impressive properties as a prophylactic agent. This is particularly so given the high morbidity associated with bipolar disorder and its potential for suicide. Hence, in this paper, after describing the changing diagnostic backdrop against which much of the research to date has been conducted, we discuss the clinical therapeutic profile of lithium in both the acute and long‐term management of bipolar disorder and its phenotypic specificity of action. We demonstrate that lithium possesses significant clinical and therapeutic efficacy that is very individual and thus remains the treatment of choice for bipolar disorder when used specifically in select patients.
Antipsychotic agents in the treatment of bipolar mania
Authors: Tohen Mauricio , Vieta Eduard
Published: June 2009

Objectives:  Antipsychotics have been widely used in the treatment of bipolar mania. The purpose of this manuscript was to briefly review the evidence of typical and atypical antipsychotics for the treatment of bipolar mania.

Methods:  A detailed literature review was conducted on the use of typical and atypical antipsychotics in the treatment of bipolar mania using standard search engines. A summary of the published literature on each agent is described followed by a discussion on the overall comparison of the different agents.

Results:  For typical antipsychotics, up until recently, there was a paucity of published evidence on their strengths and limitations in the treatment of bipolar mania. Recent studies have demonstrated clear evidence on the efficacy of haloperidol on the treatment of acute mania. The literature suggests a faster onset of action of haloperidol as compared to either lithium or atypical antipsychotics. A limitation of typical antipsychotics however, is the risk of tardive dyskinesia, extrapyramidal side effects and a possible increased risk of non‐adherence. Evidence on the efficacy for atypical antipsychotics has been demonstrated for aripiprazole, clozapine, olanzapine, quetiapine, risperidone and ziprasidone. Limitations as regards the use of atypical antipsychotics include the risk of weight gain and dyslipidemia. Comparison among different atypical antipsychotics agents are difficult to determine as there are no conclusive head to head studies. There is also a paucity of studies comparing atypical antipsychotics with lithium.

Conclusions:  Evidence exists on the efficacy of both typical and atypical antipsychotics on the treatment of acute mania such that they are now clearly first‐line along with lithium. An important limitation of the published literature is that most of the studies were designed to obtain regulatory approval for the different agents therefore the generalizability of the findings to clinical practice remains unclear.
Medicating mood with maintenance in mind: bipolar depression pharmacotherapy
Authors: Malhi Gin S , Adams Danielle , Berk Michael
Published: June 2009

Objectives:  Bipolar depression is a core feature of bipolar disorder, a phase in which many patients spend the majority of time and one that confers a significant degree of burden and risk. The purpose of this paper is to briefly review the evidence base for the pharmacotherapy of bipolar depression and to discuss the recommendations for its optimal management.

Methods:  A detailed literature review was undertaken with a particular emphasis on pharmacological treatment strategies for bipolar depression across the acute and maintenance phases of the illness. Electronic library and Web‐based searches were performed using recognised tools (MEDLINE, PubMED, EMBASE and PsychINFO) to identify the pertinent literature. A summary of the evidence base is outlined and then distilled into broad clinical recommendations to guide the pharmacological management of bipolar depression.

Results:  Partitioning treatment into acute and maintenance therapy is difficult based on the paucity of current evidence. The evidence from treatment trials favours the use of lithium and lamotrigine as first‐line treatment in preference to valproate, and indicates that, for acute episodes, quetiapine and olanzapine have perhaps achieved equivalence at least in terms of efficacy. However, the effectiveness of the atypical antipsychotics in maintenance therapy is constrained by the potential for significant side effects of individual agents and the lack of both long‐term research data and clinical experience in treating bipolar disorder as compared to other agents. Conversely, lithium and the anticonvulsants are generally slower to effect symptomatic change, and this limits their usefulness.

Conclusions:  There has been a tendency for research trials of bipolar depression to differentiate the illness cross‐sectionally into the acute and maintenance phases of bipolar depression; however, in clinical terms, bipolar depression invariably follows a longitudinal course in which the phases of illness are inextricably linked, and useful acute treatments are typically continued in maintenance. Therefore, when medicating mood in acute bipolar depression it is imperative to keep maintenance in mind as it is this aspect of treatment that determines long‐term success.
Maintenance treatment in bipolar disorder: a reassessment of lithium as the first choice
Authors: Coryell William
Published: June 2009

Objective:  In consideration of the declining use of lithium over the past several decades, this review focuses on three topics to argue for lithium’s status as first choice as the maintenance treatment of bipolar disorder.

Methods:  This review (i) describes success rates for patients assigned to lithium and those assigned to placebo in early (1973–1976) and recent (2000–2003) trials, as well as those assigned to alternative mood stabilizers versus placebo; (ii) summarizes the results of studies that compared lithium to alternative mood stabilizers by the degree of weight gain during maintenance therapy; and (iii) reviews evidence that lithium exhibits unique antisuicidal properties.

Results:  Differing success rates in early and more recent maintenance trials strongly suggest a cohort effect in which the lithium responders are relatively unavailable for recent maintenance trials. Moreover, among mood stabilizers studied in randomized trials, lithium appears least likely to cause substantial weight gain, and a considerable literature has developed to suggest that lithium has antisuicidal effects that extend beyond its benefits in relapse prevention.

Conclusion:  The evidence reviewed here strongly supports the consideration of lithium when prophylactic treatment is first begun for a bipolar patient.
Pharmacologic treatment of rapid cycling and mixed states in bipolar disorder: an argument for the use of lithium
Authors: Muzina David J
Published: June 2009

Lithium has long been considered as less than ideal in the management of rapid cycling and mixed states in bipolar disorder. However, these forms of bipolarity represent a generally more difficult phase of the illness to treat with any medication. Increasing knowledge about lithium’s other beneficial effects, including protection against suicide and neuromodulatory effects which may protect the brain, make it a first‐line treatment for any form of bipolar disorder. As newer therapies become available or receive further exploration, we should look to the past and re‐embrace lithium as a core therapeutic modality for bipolarity as we move forward in the field, particularly for forms of the disorder such as rapid cycling and mixed states, historically thought to be more treatment resistant.
The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis
Authors: Machado‐Vieira Rodrigo , Manji Husseini K , Zarate Jr Carlos A
Published: June 2009

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof‐of‐concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long‐term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium’s neurotrophic effects since Cade’s original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK‐3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium’s neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium’s neurotrophic effects in BD are an example of an old molecule acting as a new proof‐of‐concept agent. Continued work to decipher lithium’s molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.