bluuebunny/crossref_metadata_2025 huggingface dataset:
Interpupillary distance in a normal black population
Authors: Pivnick EK , Rivas ML , Tolley EA , Smith SD , Presbury GJ
Published: March 2003

This report expands on a study by Pryor [Pryor HB. Objective measurement of interpupillary distance. Pediatrics 1969: 44: 973–977] that related normal values of inner canthal distance (ICD), outer canthal distance (OCD) and interpupillary distance (IPD) for Whites, Asians and Mexican–Americans. To date, no similar values have been reported for Blacks. Utilizing a sample (n=931: 485 males; 446 females) of black people (range, birth–24 years), OCD, ICD, and head circumference (HC) were measured and tabulated. We calculated mean IPD according to Pryor’s formulation and report that the general mean OCD and ICD in our sample differed significantly from, and were consistently higher than, Pryor’s reported measurements for White males and females at each age level (p<0.001). However, ICD in our sample was significantly lower at birth in both sexes, appeared to increase at a more rapid rate relative to Whites during the first 3 months of life, and reached and maintained a higher value beyond the age of 3 months, with most age groups showing a significant difference in mean ICD measurements. At each age level, the mean IPD values in Whites and Blacks were significantly higher (p<0.001). Based upon these findings, we suggest that interpupillary distance of Black children and adults be assessed according to the mean proportions for their race.
Autosomal dominant cataracts and Peters anomaly in a large Australian family
Authors: Withers Stephen J , Gole Glen A , Summers Kim M
Published: March 2003

Peters anomaly is a congenital corneal opacity with underlying defects in the posterior stroma, Descemets membrane and corneal endothelium. It is a disorder resulting from abnormal migration or function of neural crest cells and may include abnormalities of other anterior segment structures, such as the lens and iris. We report a family in which anterior segment abnormalities, including Peters anomaly and cataracts, were inherited in an autosomal dominant fashion. Although the PAX6 gene on chromosome 11 has been shown to be involved in some cases of anterior segment developmental defects, we found no evidence that the condition in this family is linked to the PAX6 gene. Identification of this gene will indicate another gene with major involvement in the development of the anterior segment of the eye.
Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?
Authors: Nebert Daniel W
Published: March 2003

Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of ‘pharmacogenetics’, which is ‘the study of variability in drug response due to heredity’, should help in reducing drug‐caused morbidity and mortality. The recently coined term ‘pharmacogenomics’ usually refers to ‘the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome’. However, the two terms – pharmacogenetics and pharmacogenomics – are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug‐metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single‐nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed ‘functional genomics’. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene–drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as ‘modifier genes’, because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.
Normolipidemia and hypercholesterolemia in persons heterozygous for the same 1592+5G→A splice site mutation in the low‐density lipoprotein receptor gene
Authors: Jensen Hk , Jensen Lg , Holst Hu , Andreasen Ph , Hansen Ps , Larsen Ml , Kølvraa S , Bolund L , Gregersen N , Færgeman O
Published: March 2003

In the present study, we have characterized a unique splice donor G to A substitution in the moderately conserved +5 position in intron 10 of the low‐density lipoprotein (LDL) receptor gene. In two Danish families, carriers of the 1592+5G→A mutation display a clinical phenotype ranging from healthy normocholesterolemic persons to classical heterozygous familial hypercholesterolemia (FH) patients. Reverse transcription‐polymerase chain reaction (RT‐PCR) of RNA from Epstein–Barr virus (EBV)‐transformed lymphoblasts obtained from members of both families demonstrated abnormal splicing generating two aberrant mRNAs due to either alternative splicing and skipping of exon 10 or activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs. These abnormally spliced mRNAs were predicted to encode two abnormal receptor proteins containing an in‐frame deletion of 75 amino acids and an insertion of 22 novel amino acids, respectively. Results obtained by immunofluorescence staining, flow cytometry, and confocal microscopy of transfected Chang and COS‐7 cells expressing normal and mutant LDL receptors were compatible with nearly complete retention of the mutant proteins in the endoplasmic reticulum. Quantitative measurements of LDL receptor mRNAs from EBV‐transformed lymphoblasts, however, did not reveal any significant differences in variant mRNA contents between mutation carriers in the families that could be related to degree of hypercholesterolemia.
A novel mutation (296 del G) of the SOX9 gene in a patient with campomelic syndrome and sex reversal
Authors: Ninomiya S , Yokoyama Y , Teraoka M , Mori R , Inoue C , Yamashita S , Tamai H , Funato M , Seino Y
Published: March 2003

The human SOX9 gene is responsible for the campomelic syndrome (CMPS) and sex reversal. This gene encodes a transcription factor containing a DNA binding domain homologous to the SRY high mobility group (HMG) domain. A novel mutation of SOX9, i.e. a single G deletion in one allele at nt 296 from A of the first ATG in the open reading frame, was identified in a patient with CMPS with sex reversal. The deletion resulted in a frameshift mutation upstream of the HMG box and a stop codon 30 bp downstream of the HMG box. The predicted truncated SOX9 protein contained 108 amino acids instead of the 509 amino acids of the normal SOX9 protein, removing nearly 80% of the SOX9 protein, including the HMG and the C‐terminal transactivation domain. Most patients with CMPS reported previously died within the neonatal period. Our findings that the patient has survived, although has been in daily need of mechanical ventilation support for 5 years and 3 months despite a severely impaired SOX9 protein, do not support a linear relationship between the type of mutation and severity of the clinical outcome.
Ventricular septal defect associated with microdeletions of chromosome 22q11.2
Authors: Yamagishi H , Maeda J , Tokumura M , Yoshiba S , Takahashi E , Fukushima H , Yamagishi C , Matsuo N , Kojima Y
Published: March 2003

Microdeletions of chromosome 22q11.2 (del.22q11) cause DiGeorge syndrome, velo‐cardio‐facial syndrome, and conotruncal anomaly face syndrome, which are commonly associated with conotruncal heart anomalies. Approximately 15% of the patients manifest ventricular septal defect (VSD), and the conal–septal type of VSD has been proposed to be associated with del.22q11, since it is categorized as a conotruncal anomaly. However, the types of VSD associated with del.22q11 remain poorly studied. The purpose of this study is to assess whether conal–septal VSD or other types of VSDs are associated with del.22q11. We analyzed the chromosomes of 22 consecutive patients with conal–septal VSD, prospectively, and evaluated the types of VSD observed in 3 patients with del.22q11, retrospectively. Del.22q11 was not detected in any of the 22 patients with conal–septal VSD. All the VSDs observed in the 3 patients with del.22q11 were a perimembranous type of VSD, which is not a conotruncal anomaly. Our results suggest that perimembranous VSD can be associated with del.22q11, but del.22q11 is not a common cause of conal–septal VSD.
Fetal cells in maternal blood
Authors: Wachtel SS , Shulman Lp , Sammons D
Published: March 2003

Fetal lymphocytes, trophoblasts, and nucleated red blood cells have each been separated from maternal blood by methods such as flow cytometry, magnetic cell sorting, and charge flow separation. The frequency of fetal cells among circulating maternal mononuclear cells remains to be ascertained. Current estimates range from about 10−5 to 10−7, but the numbers may be increased in women carrying aneuploid fetuses. Fetal cells separated from maternal blood have been studied by methods such as polymerase chain reaction and fluorescence in situ hybridization. Among fetal conditions so far identified are sex; human leukocyte antigen and Rh blood types; trisomy 13, 18 and 21; triploidy; and sickle cell anemia and thalassemia. Thus, fetal cell separation might one day be used for screening of the common aneuploidies and, ultimately, for prenatal diagnosis. Individual fetal erythroid precursors have been cultured after separation in some laboratories. Culturing and karyotyping of separated fetal cells might enable diagnosis of a spectrum of chromosomal and genetic disorders. Further development will be required, however, before regular clinical application of these methodologies.
Prevalence of founder BRCA1 and BRCA2 mutations in unselected French Canadian women with breast cancer
Authors: Chappuis PO , Hamel N , Paradis A‐J , Deschênes J , Robidoux A , Potvin C , Cantin J , Tonin P , Ghadirian P , Foulkes WD
Published: March 2003

The frequency of BRCA1 and BRCA2 mutations in women with breast cancer varies according to the age at diagnosis, family history of cancer, and ethnicity/country of origin. We set out to estimate the frequency of seven previously described founder mutations in BRCA1 and BRCA2 in all eligible French Canadian women diagnosed with invasive breast cancer at one Montreal hospital over a 20‐month period. One hundred and ninety‐two patients were eligible and 127 (66.2%) provided blood for genetic testing. We identified 4 women who carried a founder mutation (3.1%, 95% confidence interval 0.9–7.9%) in this population. Interestingly, all the mutations were in BRCA2. The mean age at diagnosis for mutation carriers was 51.2 years (range 49.1–53.5). Two of these 4 cases were lobular invasive carcinomas and 2 were ductal carcinomas, histological grade 1 or 2. Despite a small tumor size (≤20 mm), axillary nodal involvement was present in 3 women. Estrogen receptors were strongly expressed in all cases. Two of the 4 cases reported a strong family history of breast cancer, but a family history of site‐specific breast cancer was a relatively poor indicator of the presence of BRCA2 mutations. The absence of BRCA1 mutations may be a result of chance, but may also reflect different geographical origins of the most common BRCA1 mutations within the French Canadian population.
Identification and characterization of mutations underlying Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA)
Authors: Lee‐Chen GJ , Lin SP , Ko MH , Chuang CK , Chen CP , Lee HH , Cheng SC , Shen CH , Tseng KL , Li CL
Published: March 2003

Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA; MPS IIIA) is caused by a deficiency of the lysosomal enzyme haparan N‐sulphatase (NS). The genomic DNA segments of the NS gene from two Chinese patients with MPS IIIA were amplified by polymerase chain reaction, followed by DNA sequencing to study the molecular lesions. Four mutations (i.e. N42K, D235N, P293S and R377C) and five polymorphisms (i.e. IVS2‐72A → G, IVS2‐26T → C, IVS5+17C → T, IVS5‐37GC → CTGT and R456H) were identified. Transfection of COS‐7 cells with cDNA mutagenized to the corresponding mutations did not yield active enzyme, demonstrating the deleterious nature of the mutations. Western blot analysis revealed a 62‐kDa precursor and 56‐kDa mature forms for cells transfected with wild‐type and polymorphic R456H enzymes. For cells transfected with mutant enzymes, the reduction in precursor and mature forms suggests an increased degradation of the mutant enzymes. The polymorphic DNA haplotype of the NS gene was analysed in 52 unrelated subjects. All five polymorphisms were in Hardy–Weinberg equilibrium. The strong non‐random association among the five polymorphisms suggests little or no recombination in the NS gene.
Non‐syndromic autosomal‐dominant deafness
Authors: Petersen MB
Published: March 2003

Non‐syndromic deafness is a paradigm of genetic heterogeneity. More than 70 loci have been mapped, and 25 of the nuclear genes responsible for non‐syndromic deafness have been identified. Autosomal‐dominant genes are responsible for about 20% of the cases of hereditary non‐syndromic deafness, with 16 different genes identified to date. In the present article we review these 16 genes, their function and their contribution to deafness in different populations. The complexity is underlined by the fact that several of the genes are involved in both dominant and recessive non‐syndromic deafness or in both non‐syndromic and syndromic deafness. Mutations in eight of the genes have so far been detected in only single dominant deafness families, and their contribution to deafness on a population base might therefore be limited, or is currently unknown. Identification of all genes involved in hereditary hearing loss will help in the understanding of the basic mechanisms underlying normal hearing, will facilitate early diagnosis and intervention and might offer opportunities for rational therapy.
A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco
Authors: Belmouden A , Melki R , Hamdani M , Zaghloul K , Amraoui A , Nadifi S , Akhayat O , Garchon H‐J
Published: March 2003

Primary congenital glaucoma (PCG) is a heterogeneous autosomal recessive disorder caused by unknown developmental defect(s) of the anterior chamber of the eye. A member of the cytochrome P450 gene family, CYP1B1, was found to be mutated in PCG patients in different populations, albeit to a variable extent. In this study, CYP1B1 mutations were searched for in 32 unrelated PCG patients from Morocco. Two mutations were detected in 11 (34%) patients. One, 4339delG, is novel and causes a frameshift at residue 179. The other, G61E, was previously found in patients from Turkey and Saudi Arabia. Seven patients were homozygous for 4339delG and two other patients for G61E, whereas the two remaining patients were compound heterozygotes. The close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG. The occurrence of this mutation was tentatively dated at between 900 and 1700 years ago. Typing 4339delG and G61E mutations should help to prevent blindness resulting from a delayed diagnosis of PCG in Morocco.
Role of P‐selectin expression in hepatic ischemia and reperfusion injury
Authors: Singh I , Zibari Gb , Brown Mf , Granger Dn , Eppihimer M , Zizzi H , Cruz L , Meyer K , Gonzales E , McDonald Jc
Published: March 2003

Background. Researchers have shown that reperfusion of ischemic tissues initiates a complex series of reactions that paradoxically injure tissues. Although several mechanisms have been proposed to explain the pathobiology of ischemic/reperfusion (I/R) injury, much attention has focused on adhesion molecules. Our research is intended to show the kinetics of P‐selectin in the liver in response to I/R injury.Methods. Left‐lobar hepatic ischemia was induced for 30 min in 35 C57BL‐6 mice and 20 P‐selectin‐deficient (K‐O) mice. P‐selectin expression was measured in these mice at 20 min, 2, 5, 12 and 24 h reperfusion times, as well as in control and sham animals. The animals were injected with radio‐labeled P‐selectin monoclonal antibody and the organs were harvested for counts/g tissue, expressed as the percentage injected dose. Serum liver enzymes were measured and pathological sections of ischemic and control livers were performed. The unpaired t‐test was used for statistical analysis.Results. P‐selectin expression showed two peaks in this animal model. The first peak was at 20 min and the second peak at 5 h of reperfusion (p<0.001). We documented an 8‐fold increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels 10 h following I/R injury. Pathological specimens showed periportal necrosis consistent with an ischemic event. P‐selectin K‐O mice showed no up‐regulation as a separate control group, and the liver enzymes were significantly lower than the wild‐type mice at 10 h (p<0.001).Conclusion. P‐selectin has a bimodal expression following hepatic I/R injury. The first peak is attributed to the Weibel–Palade bodies and the second to new translational P‐selectin. We noted no difference in the up‐regulation of P‐selectin in the ischemic and non‐ischemic liver lobes in the same animal.
Diabetic retinopathy after combined kidney–pancreas transplantation
Authors: Chow Vincent Cc , Pai Rami P , Chapman Jeremy R , O'connell Philip J , Allen Richard Dm , Mitchell Paul , Nankivell Brian J
Published: March 2003

Diabetic retinopathy (DR) is amenable to good diabetic control; however, only successful pancreas transplantation can achieve sustained normoglycaemia. The aim of this long‐term study was to examine the course of DR in insulin‐dependent diabetic recipients of a simultaneous kidney and pancreas transplant (SPK). Successful SPK recipients (n=46) and failed pancreas transplant with a functioning kidney transplant (n=8) were assessed by baseline and regular post‐transplant ophthalmic examinations (n=432) for up to 10 yr after SPK. At the time of SPK (n=108 eyes), the mean duration of diabetes was 25±7 yr, ten eyes were blind, and 79% of eyes had advanced DR that had panretinal laser (panretinal photocoagulation, PRP). Successful SPK recipients had normal glucose control with a mean HBA1C of 5.2±0.6%. DR remained stable in 75% of both the study and control groups, with no difference between groups. The DR mostly evolved towards inactive proliferative DR. After SPK, 14% of non‐blind eyes showed improvement of DR, 76% remained stable and 10% progressed. Early vitreous haemorrhage occurred in 6.1% of eyes, and was related to established DR. Cataract of all types increased after transplantation (p<0.01), which reduced visual acuity (VA) in affected eyes. The mean overall VA remained unchanged for the study duration. In summary, uremic patients from diabetic nephropathy had a high prevalence of severe proliferative DR and blindness at the time of presentation for SPK. This was subsequently stabilised to inactive proliferative DR by appropriate laser therapy followed by metabolic control achieved by SPK.
Cyclosporine‐induced hemolytic uremic syndrome and hemorrhagic colitis following renal transplantation
Authors: Lapointe Marc , Baillie G Mark , Shanmuga Bhaskar S , Richardson Mary S , Self Sally E , Baliga Prabhakar K , Rajagopalan Pr
Published: March 2003

Nephrotoxicity remains one of the most common side‐effects of cyclosporine in the setting of transplantation. Acute reversible decreases in glomerular filtration rate and chronic irreversible renal damage are the most common manifestations, but hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported. Prognosis of cyclosporine‐associated de novo hemolytic uremic syndrome (CyA‐HUS) is poor, with nearly half of affected patients losing function in the transplanted kidney. Therapeutic options are limited, but good outcomes have been reported by switching patients from cyclosporine to tacrolimus. We report an unusual presentation of CyA‐HUS associated with hemorrhagic colitis following renal transplantation. The patient was successfully managed by switching from cyclosporine to tacrolimus.
Is the presence of surgically treatable coronary artery disease a contraindication to liver transplantation?
Authors: Benedetti Enrico , Massad Malek G , Chami Youssef , Wiley Thelma , Layden Thomas J
Published: March 2003

Advanced coronary artery disease has been traditionally considered an absolute contraindication to orthotopic liver transplantation where chronic liver failure significantly increases the surgical risk for coronary artery bypass grafting. Performing a simultaneous coronary artery bypass grafting and liver transplant is a theoretically attractive strategy in liver transplant candidates with coronary artery disease in need of revascularization. In the present article, we report a successful simultaneous coronary artery bypass grafting and orthotopic liver transplant with 1‐yr post‐operative follow‐up and we discuss the rationale for this approach. In selected cases, the presence of advanced coronary artery disease should not be considered an absolute contraindication to liver transplantation.
Correlates of support for organ donation among three ethnic groups
Authors: McNamara Patrick , Guadagnoli Edward , Evanisko Michael J , Beasley Carol , Santiago‐Delpin Eduardo A , Callender Clive O , Christiansen Elaine
Published: March 2003

Telephone interviews about organ donation were conducted with 4880 white respondents, 634 African–American respondents and 566 Hispanic respondents. Forty‐three percent (42.9%) of whites, 31.2% of Hispanics and 22.6% of African–Americans reported that they were willing to donate their organs after their death (p<0.001). Logistic regression analysis revealed three significant correlates of willingness to donate across all ethnic groups: having had a family discussion about end‐of‐life issues; the belief that a doctor does all he or she can to save a life before pursuing donation; and concerns about surgical ‘disfigurement’ of a relative’s body after donation. Concerns in relation to body disfigurement were more prevalent among African–American and Hispanic respondents (p<0.001) than among white respondents. Public education should: a) stress the need for family communication about end‐of‐life issues including organ donation; b) underline the fact that donation is considered only after all efforts to save the life of the patient are exhausted; and c) reassure minorities that the body of the donor is treated respectfully and not disfigured.
Improved outcomes in cadaveric renal allografts with pulsatile preservation
Authors: Sellers Marty T , Gallichio Michael H , Hudson Sharon L , Young Carlton J , Bynon J Stevenson , Eckhoff Devin E , Deierhoi Mark H , Diethelm Arnold G , Thompson J Anthony
Published: March 2003

Background: Early immunologic and non‐immunologic injury of renal allografts adversely affects long‐term graft survival. Some degree of preservation injury is inevitable in cadaveric renal transplantation, and, with the reduction in early acute rejection, this non‐immunologic injury has assumed a greater relative importance. Optimal graft preservation will maximize the chances of early graft function and long‐term graft survival, but the best method of preservation – pulsatile perfusion (PP) versus cold storage (CS) – is debated.  Methods: Primary cadaveric kidney recipients from January 1990 through December 1995 were evaluated. The effects of implantation warm ischemic time (WIT) (≤20 min, 21–40 min, or >40 min) and total ischemic time (TIT) (< or ≥20 h) on death‐censored graft survival were compared between kidneys preserved by PP versus those preserved by CS. The effect of preservation method on delayed graft function (DGF) was also examined.  Results: There were 568 PP kidneys and 268 CS kidneys. Overall death‐censored graft survival was not significantly different between groups, despite worse donor and recipient characteristics in the PP group. CS kidneys with an implantation WIT >40 min had worse graft survival than those with <40 min (p=0.0004). Survival of PP kidneys and those transplanted into 2 DR‐matched recipients was not affected by longer implantation WIT. Longer TIT did not impact survival. DGF was more likely after CS preservation (20.2% versus 8.8%, p=0.001).  Conclusions: Preservation with PP improves early graft function and lessens the adverse effect of increased warm ischemia in cadaveric renal transplantation. This method is likely associated with less preservation injury and/or increases the threshold for injury from other sources and is superior to CS.
Positive effect on T‐cell regulatory apoptosis by mycophenolate mofetil
Authors: Nakamura M. , Ogawa N. , Shalabi A. , Maley W. R. , Burdick J. F.
Published: March 2003

The regulatory benefit of apoptosis (activation‐induced cell death, AICD) in T cells may be impacted by immunosuppressive agents. We examined this for mycophenolate mofetil (MMF) compared with cyclosporine (CYA). Peripheral blood leukocytes (PBL) were stimulated by either Staph enterotoxin B (SEB) or by anti‐CD3 plus anti‐CD28. Cell division analysis (sequential reduction in carboxyflourescein diacetate succinimidyl ester, CFSE) was used to measure proliferation and determine status of different cell generations. Apoptosis was measured by annexin V staining, and FasL expression by anti‐FasL antibody staining, of activated cells using flow cytometry. CSA and mycophenolic acid (MPA, the active agent of MMF) were added in titration in 3‐day cultures. We found that CSA caused diminution in apoptosis but MPA increased it with SEB stimulation. The CSA effect on apoptosis was present when a more calcineurin‐dependent stimulus, anti‐CD3+anti‐CD28, was used but the MPA effect was less, producing a decrease only in the undivided cells. To look more directly at the differential effect on calcineurin‐dependent AICD gene induction of the two agents, we measured Fas‐L expression with anti‐CD‐3+CD28 stimulation, and confirmed that CYA caused a major decrement in appearance of Fas‐L, whereas MPA caused a converse accumulation of it. This seems to be explained by the block more distal in cell activation, resulting in a build‐up of a precursor in the activation pathways. We conclude that MMF treatment may be rationale as an adjunct to calcineurin inhibitor treatment because of its converse effect on T cell regulatory apoptosis.
Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients
Authors: Kovarik John M , Pescovitz Mark D , Sollinger Hans W , Kaplan Bruce , Legendre Christophe , Salmela Kaija , Book Benita K , Gerbeau Christophe , Girault Daniele , Somberg Kenneth ,   on behalf of the Simulect Phase Iv Study Group
Published: March 2003

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti‐CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post‐transplant from 31 azathioprine‐treated and 66 mycophenolate mofetil‐treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 μg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29±14 mL/h when coadministered with azathioprine and 18±8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37±15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50±20 d; range, 13–84) and mycophenolate mofetil (59±17 d; range, 28–94) compared with dual therapy (36±14 d; range, 12–91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection‐free in each study. A single patient among 57 who were screened developed anti‐idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.
Allogeneic bone marrow transplantation for chronic myeloid leukemia: a retrospective study of busulfan–cytoxan versus total body irradiation–cytoxan as preparative regimen in Koreans
Authors: Kim I , Park S , Kim Bk , Chang Hm , Bang Sm , Byun Jh , Kim Dj , Min Ws , Kim Hj , Kim Cc
Published: March 2003

From January 1990 to December 1997, 53 Korean patients with chronic myeloid leukemia (CML) receiving bone marrow transplantation (BMT) from human leucocyte antigen (HLA)‐identical sibling donors conditioned with either busulfan and cyclophosphamide (BU/CY regimen) or total body irradiation and cyclophosphamide (TBI/CY regimen) were compared retrospectively.   Transplantation‐related mortality was 19% in BU/CY and 12% in TBI/CY, and early death (<100 d) occurred in 3 patients conditioned with BU/CY. Grade II–IV acute graft‐versus‐host disease (GVHD) was 9% of BU/CY and 52% of TBI/CY patients. Overall incidence of chronic GVHD was 50% of BU/CY and 52% of TBI/CY patients. In patients with chronic phase, 5‐yr overall survival was 73% in the BU/CY group compared with 87% in the TBI/CY group (p=NS), and overall disease‐free survival was 75% in the BU/CY group and 59% in the TBI/CY group (p=NS). So far, with a median follow‐up of 45 months, 11 patients have relapsed; three relapses occurred after BU/CY and 8 after TBI/CY. The actuarial 5‐yr relapse rate was 15% after BU/CY, 34% after TBI/CY (p=0.46). For patients transplanted in chronic phase within 1 yr after diagnosis, there was a clear trend for a lower relapse rate in the BU/CY group (5‐yr relapse rate 0%) compared with the TBI/CY group (5‐yr relapse rate 30%).   The BU/CY group had similar BMT‐related toxicity and similar overall survival and showed a clear trend of low relapse compared with the TBI/CY group. Therefore, BU/CY is an acceptable alternative for patients with CML during HLA‐identical sibling allogeneic BMT.
Immunosuppression should be stopped in patients with renal allograft failure
Authors: Smak Gregoor PJH , Zietse R , Van Saase JLCM , Op De Hoek CT , IJzermans JNM , Lavrijssen ATJ , De Jong GMTh , Kramer P , Weimar W
Published: March 2003

Patients returning to haemodialysis or peritoneal dialysis after a failed kidney transplantation sometimes have a renal allograft left in situ for some urine production. Low‐dose immunosuppressive medication is often continued in such patients. To evaluate the morbidity and mortality between patients in time periods with (group A) or without (group B) low‐dose maintenance immunosuppression, the present study was initiated. In a multi‐centre cohort study we analysed data from patient files, which showed failure after at least 3 months graft function between 10 August 1972 and 4 April 1996, including 197 kidney transplantations. A total of 1.7 versus 0.51 infections per patient year was found in groups A and B, respectively (odds ratio [OR]: 3.4, 95% confidence interval [CI]: 2.5–4.5). There was an increased mortality in group A compared to group B (OR 3.4, 95% CI: 1.8–6.3), both from infectious disease (OR 2.8, 95% CI: 1.1–7.0), and cardiovascular disease (OR 4.9, 95% CI: 1.8–13.5). Continuation of immunosuppressive medication did not lead to fewer rejections (defined as a painful, tender graft and/or haematuria and/or low‐grade non‐infectious fever). Transplantectomy‐related morbidity and mortality were acceptable. The increase in morbidity and mortality associated with low‐dose maintenance immunosuppression argues in favour of stopping these medicaments when failed renal allograft patients return to dialysis.
Short‐ and long‐term success of organs transplanted from acute methanol poisoned donors
Authors: López‐Navidad A , Caballero F , González‐Segura C , Cabrer C , Frutos MA
Published: March 2003

Background: The shortage of organs for transplantation has made it necessary to extend the criteria for the selection of donors, among others including those patients who die because of toxic substances such as methanol. Methanol is a toxic which is distributed through all the systems and viscera of the organism and tends to cause a severe metabolic acidosis. It can specifically cause serious or irreversible lesions of the central nervous system (CNS) and retina, and ultimately brain death. We present our experience with 16 organ donors who died as a result of acute methanol intoxication in 10 Spanish hospitals over the last 14 yr. Patients and methods: Between October 1985 and July 1999, 16 organ donors with brain death caused by acute methanol intoxication, 13 females and three males with a mean age of 38.4 ± 7.6 yr (interval: 26–55 yr), allowed 37 elective transplants to be performed: 29 kidneys, four hearts and four livers for 37 recipients, and one urgent liver transplantation to a recipient with fulminant hepatitis.

Results: The immediate postoperative period was favourable for the 38 graft recipients. None of the graft recipients presented gap anion metabolic acidosis in the immediate postoperative period, nor symptomatology or lesions of the CNS characteristic of methanol intoxication. Two patients died during the first month post‐transplantation, a liver recipient and a heart recipient, at 16 and 24 days, respectively, because of acute rejection of the graft. At 1 month after transplantation 35 of the 36 recipients had been discharged from hospital with normal‐functioning grafts. The last of the recipients, a kidney recipient, was discharged at 6 wk with normal‐functioning graft. Actuarial survival of the graft and patient of kidney recipients at 1, 3 and 5 yr was 92.6, 77.8, and 75%, and 100, 88.9 and 83.3%, respectively; with average serum creatinines of 139.9 ± 42.9, 150.4 ± 42.8, and 164.4 ± 82.5 μmol/L, respectively. At 1 yr after transplantation the three heart recipients and two of the three liver recipients had normal‐functioning graft.

Conclusions: Methanol intoxication is not transferred from the donor to the recipient. The survival of the graft and kidney, heart and liver recipients using organs from donors who die because of methanol does not differ in the short‐ and long‐term from the transplants performed with organs from donors who die from other causes.
Mitochondrial dysfunction in bipolar disorder
Authors: Kato Tadafumi , Kato Nobumasa
Published: March 2003

Mitochondrial dysfunction is implicated in bipolar disorder based on the following lines of evidence: 1) Abnormal brain energy metabolism measured by 31 P‐magnetic resonance spectroscopy, that is, decreased intracellular pH, decreased phosphocreatine (PCr), and enhanced response of PCr to photic stimulation. 2) Possible role of maternal inheritance in the transmission of bipolar disorder. 3) Increased levels of the 4977‐bp deletion in mitochondrial DNA (mtDNA) in autopsied brains. 4) Comorbidity of affective disorders in certain types of mitochondrial disorders, such as autosomal inherited chronic progressive external ophthalmoplegia and mitochondrial diabetes mellitus with the 3243 mutation. Based on these findings, we searched for mtDNA mutations/polymorphisms associated with bipolar disorder and found that 5178C and 10398A polymorphisms in mtDNA were risk factors for bipolar disorder. The 5178C genotype was associated with lower brain intracellular pH. mtDNA variations may play a part in the pathophysiology of bipolar disorder through alteration of intracellular calcium signaling systems. The mitochondrial dysfunction hypothesis, which comprehensively accounts for the pathophysiology of bipolar disorder, is proposed.
Molecular linkage studies of bipolar disorders
Authors: Berrettini Wade H
Published: March 2003

Objectives:
To review the reports of linkage findings for bipolar disorder.   Methods: Literature review of published linkage findings in bipolar disorder.   Results: There are several regions of the human genome that have been implicated repeatedly by independent investigators. These include 4p16, 12q24, 18q22, 18p11, 21q21 and 22q11. Two of these regions (18p11 and 22q11) are also implicated in genome scans of schizophrenia, suggesting that these two distinct nosological categories may share some genetic susceptibility. This hypothesis can only be tested when the underlying genes are identified.
Stress and depression: possible links to neuron death in the hippocampus
Authors: Lee Angela L , Ogle William O , Sapolsky Robert M
Published: March 2003

Recent intriguing reports have shown an association between major depression and selective and persistent loss of hippocampal volume, prompting considerable speculation as to its underlying causes. In this paper we focus on the hypothesis that overt hippocampal neuron death could cause this loss and review current knowledge about how hippocampal neurons die during insults. We discuss (a) the trafficking of glutamate and calcium during insults; (b) oxygen radical generation and programmed cell death occurring during insults; (c) neuronal defenses against insults; (d) the role of energy availability in modulating the extent of neuron loss following such insults.

The subtypes of depression associated with hippocampal atrophy typically involve significant hypersecretion of glucocorticoids, the adrenal steroids secreted during stress. These steroids have a variety of adverse affects, direct and indirect, in the hippocampus. Thus glucocorticoids may play a contributing role toward neuron death. We further discuss how glucocorticoids cause or exacerbate cellular changes associated with hippocampal neuron loss in the context of the events listed above.
Are patients with bipolar affective disorder socially disadvantaged? A comparison with a control group
Authors: Abood Zainab , Sharkey Alison , Webb Marcus , Kelly Alan , Gill Michael
Published: March 2003

Background:
 Bipolar affective disorder (BPAD) has considerable implications for personal and social functioning. However a tendency to be over‐represented in high socio‐economic classes has been reported in earlier studies, suggesting that social disadvantage accompanying the illness is not severe. In addition, an association between affective disorders in general and increased residential mobility has been suggested, but it is unclear if such an association exists with BPAD.

Objectives:
 (1) To investigate the suggestion made in previous studies that patients with bipolar disorder are advantaged socially. (2) To test the hypothesis that patients with bipolar disorder show greater residential mobility compared with other patients with psychiatric disorders.

Method:
 Ninety patients with DSM IV diagnosis of bipolar disorder admitted to the acute in‐patient unit of a public‐financed district psychiatric service in Dublin were compared with a control group of 91 randomly selected patients with other psychiatric diagnoses, excluding schizophrenia. Socio‐economic, educational and employment ratings were compared, and also duration of illness, frequency of admission and residential mobility. The data were collected retrospectively from case notes and through semistructured interviews with patients or their relatives. The bipolar group was compared with the control group and to the unipolar depression subgroup.

Results:
 The bipolar and control groups were found to have similar demographic and socio‐economic features, although the bipolar group had more years of education compared with the whole control group but not when compared with the unipolar depression group. The bipolar group showed longer duration of psychiatric disorder, more frequent hospital admissions and more frequent residential moves since the onset of the illness.

Conclusion:
 Bipolar patients requiring in‐patient care in this service experience severe disruption to their lives over prolonged periods.
Antidepressants and neuroplasticity
Authors: D'Sa Carrol , Duman Ronald S
Published: March 2003

Objective:
 We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs.

Methods:
 We review results from various clinical and basic research studies.

Results: 
Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants up‐regulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element‐binding protein (CREB) and the neurotrophin, brain derived‐neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants.

Conclusions:
 These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival.
Pharmacotherapy patterns in the treatment of bipolar disorder
Authors: Russo Patricia , Smith Mark W , Dirani Riad , Namjoshi Madhav , Tohen Mauricio
Published: March 2003

Objectives:  To assess medication use patterns of patients with bipolar disorder, and, through multivariate analysis, to elucidate the role of selected demographic and clinical factors on medication choice and use patterns.

Methods:  Patients were privately insured individuals aged 18–64, continuously enrolled in a health plan for 15 months or longer during the years 1994–1998, and either diagnosed with bipolar disorder or prescribed lithium or valproate at least 90 days after the start of the study period. Medical and pharmacy claims data were used to analyze medication therapy over a 12‐month period.

Results:  First‐generation antipsychotics were used by 16.4% of patients and second‐generation agents by 12.4%. Patients starting on antipsychotics tended to stay with them for 12 months or longer, while patients starting on anticonvulsants or antidepressants were more likely to stop therapy or to switch to another medication class. Patients treated with olanzapine appeared to have more psychiatric comorbidities and more psychiatric hospitalizations than users of first‐generation agents.

Conclusions:  Although mood stabilizers and anticonvulsant agents are widely used to treat bipolar disorder, antipsychotic agents are also present in the treatment regimens of bipolar patients. Demographic and clinical factors were significant predictors of the choice of initial medication therapy and subsequent use patterns. In particular, patient gender and the number of psychiatric and physical comorbidities were significantly related to the course of medication therapy.
Clinical decision‐making using the General Behavior Inventory in juvenile bipolarity
Authors: Findling Robert L , Youngstrom Eric A , Danielson Carla K , DelPorto‐Bedoya Denise , Papish‐David Raïsa , Townsend Lisa , Calabrese Joseph R
Published: March 2003

Objective:
The General Behavior Inventory (GBI) is a questionnaire that has utility in the assessment of mood disorders in adults. The purpose of this study was to examine how the GBI might optimally be used in the assessment of youths.

  Method: Children and adolescents between the ages of 5 and 17 years participated in this study. All youths were evaluated with the Schedule for Affective Disorders and Schizophrenia for School‐Age Children (K‐SADS). Based on the K‐SADS results, subjects were then assigned to one of four groups: a bipolar spectrum group, a depressive disorders group, a disruptive behaviors disorders group, and a no diagnosis group. Guardians completed a version of the GBI modified for parent reporting. Patients 10 years old or greater also completed the GBI as a self‐report measure.

  Results: There were 196 subjects who participated. Both parent report and youth self‐report assigned patients to the appropriate diagnostic group with better than 74% accuracy. Combining information from multiple informants did not significantly improve diagnostic group assignment.

  Conclusions: These data suggest that the GBI may be a useful adjunct in the diagnosis of mood disorders in youths, particularly when diagnostic specificity is more important than sensitivity.
Regulation of ER stress proteins by valproate: therapeutic implications
Authors: Bown Christopher D , Wang Jun‐Feng , Chen Biao , Young L Trevor
Published: March 2003

Objectives:
This paper reviews results of our studies examining the regulation of endoplasmic reticulum (ER) stress proteins by valproate (VPA), and discusses the possible implications in bipolar disorder.

  Methods: Our previous studies in the field are reviewed along with relevant literature.

  Results: Using differential display PCR, we identified GRP78 as a VPA‐regulated gene in rat cerebral cortex. We also showed that other members of the ER stress proteins family, GRP94 and calreticulin, are also upregulated by VPA. Immunohistochemistry identified that ER stress proteins are increased in frontal and parietal cortex, as well as regions of the hippocampus in rat brain following chronic treatment with VPA.

  Conclusions: Regulation of ER stress proteins by VPA may prove to be important to the mechanism of action of the drug. The neuroprotective role of these proteins may also prove to be involved in the pathophysiology of bipolar disorder.