bluuebunny/crossref_metadata_2025 huggingface dataset:
Terminal deletion of the long arm of chromosome 10
Authors: Scigliano S , Grégoire MJ , Schmitt M , Jonveaux PH , LeHeup B
Published: December 2004

The case of two female patients with de novo terminal deletion of the long arm of chromosome 10, one with del(10)(q26.2) and the other with del(10)(q26.3), is reported. Both presented with megabladder associated with urinary tract abnormalities. The case of four similar patients has been previously reported with bladder dilatation secondary to urinary obstruction. These new cases highlight the possible involvement of the bladder and the urethra in the syndrome of chromosome 10q terminal deletion, suggesting a careful renal and urinary tract evaluation in such situations. Moreover, the possibility of monosomy 10qter syndrome should be borne in mind in the case of prenatal diagnosis of apparently isolated bladder obstruction, especially in females.0000
Novel CFTR mutations in black cystic fibrosis patients
Authors: Feuillet‐Fieux MN , Ferrec M , Gigarel N , Thuillier L , Sermet I , Steffann J , Lenoir G , Bonnefont JP
Published: December 2004

Cystic fibrosis (CF) is considered as a rare disease in black Africans. In fact, this disease is likely to be underestimated since clinical features consistent with CF diagnosis are often ascribed to environmental factors such as malnutrition. Very little is known about CFTR mutations in affected patients from Central Africa. We report here four novel mutations, i.e., IVS2 + 28 (intron 2), 459T > A (exon 4), EX17a_EX18del (exons 17–18), and IVS22 + IG > A (intron 22), in such patients. An update of CFTR mutations reported in black patients from various ethnies is included. These data might be helpful for genetic counselling regarding CF in black patients.
Microarray‐based comparative genomic hybridization and its applications in human genetics
Authors: Oostlander AE , Meijer GA , Ylstra B
Published: December 2004

Through the years, several techniques capable of detecting DNA copy number changes have been developed. A number of those, such as karyotyping and fluorescence in situ hybridization (FISH), have proven to be valuable tools in both research and diagnostics. Recently, a new technique, called microarray‐based comparative genomic hybridization (array CGH), has been introduced. Array CGH has proven to be a specific, sensitive, and fast technique, with considerable advantages compared to other methods used for the analysis of DNA copy number changes. Array CGH enables analysis of the whole genome in a single experiment. Until now, its applications have been mainly directed at detecting genomic abnormalities in cancer. However, array CGH is also suitable for the analysis of DNA copy number aberrations that cause human genetic disorders. This review gives an overview of array CGH and its applications in human genetics. Advantages, limitations, and future perspectives of array CGH are discussed.
Research in human genetics: the tension between doing no harm and personal autonomy
Authors: Pelias MK
Published: December 2004

The physician–patient relationship was governed for centuries by the ethical principle of beneficence and the physician's dedication to the principle of doing no harm. This structure shifted, however, to the principle of personal autonomy as medical and surgical knowledge expanded and patients, rather than physicians, became the locus of decision‐making authority. In biomedical research in the United States, however, beneficence of the research professional remained dominant until a spectrum of doubtful research practices was made public in the 1970s and thereafter. Over the past three decades, state and federal governments have instituted regulations that provide increased protections for human research subjects, although research results are rarely shared with subjects because of the provisional nature of unconfirmed laboratory results. Now, however, genetics researchers and others suggest that subjects may well have an interest in present and future results, even though provisional. These issues are presently under discussion and may eventually open new possibilities for sharing research information with subjects who wish to be informed.
Impact of molecular mechanisms, including deletion size, on Prader–Willi syndrome phenotype: study of 75 patients
Authors: Varela MC , Kok F , Setian N , Kim CA , Koiffmann CP
Published: December 2004

Prader–Willi syndrome (PWS) can result from a 15q11–q13 paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. We describe here the phenotypic variability detected in 51 patients with different types of deletions and 24 patients with UPD. Although no statistically significant differences could be demonstrated between the two main types of PWS deletion patients, it was observed that type I (BP1‐BP3) patients acquired speech later than type II (BP2‐BP3) patients. Comparing the clinical pictures of our patients with UPD with those with deletions, we found that UPD children presented with lower birth length and started walking earlier and deletion patients presented with a much higher incidence of seizures than UPD patients. In addition, the mean maternal age in the UPD group was higher than in the deletion group. No statistically significant differences could be demonstrated between the deletion and the UPD group with respect to any of the major features of PWS. In conclusion, our study did not detect significant phenotypic differences among type I and type II PWS deletion patients, but it did demonstrate that seizures were six times more common in patients with a deletion than in those with UPD.
A novel STK11 germline mutation in two siblings with Peutz–Jeghers syndrome complicated by primary gastric cancer
Authors: Shinmura K , Goto M , Tao H , Shimizu S , Otsuki Y , Kobayashi H , Ushida S , Suzuki K , Tsuneyoshi T , Sugimura H
Published: December 2004

Patients with Peutz–Jeghers syndrome (PJS) are known to be at risk of gastric cancer (GC), and the STK11 gene is a susceptibility gene for PJS. However, as no cases of PJS with GC in which a STK11 germline mutation has been identified have ever been reported and other susceptibility genes have also been suggested to be involved in PJS, the relation between STK11 germline mutations and GC in PJS is still unknown. In this study, we used sequencing analysis to investigate the STK11, CDH1, and TP53 loci for a germline mutation in two siblings with PJS with primary GC. A novel type of the STK11 germline mutation, c.890delG, encoding a truncated protein (p.Arg297fsX38) was identified, but no germline mutations of the CDH1 and TP53 genes were detected. No inactivation of the wild‐type allele by somatic mutation or chromosomal deletion or hypermethylation at the 5′‐CpG site of STK11 was detected in the GC. This is the first report of a STK11 germline mutation in a PJS patient with GC and should contribute to establishing correlations between the STK11 germline mutations and GC in PJS patients.
Impact of in vivo complement activation and cryoglobulins on graft outcome of HCV‐infected renal allograft recipients
Authors: Weiner Stefan M , Thiel Jens , Berg Thomas , Weber Sabine , Krumme Bernd , Peter Hans H , Rump Lars C , Grotz Wolfgang H
Published: December 2004

Abstract:  Background:  Chronic hepatitis C virus (HCV) infection is closely associated with mixed cryoglobulinemia. Cryoglobulins can activate complement leading to vascular damage. We examined whether cryoglobulinemia and complement turnover is associated with HCV infection in renal transplant recipients and whether this has an adverse effect on graft outcome.

Methods:  Sera and fresh plasma from 31 HCV‐RNA‐positive patients after renal transplantation (group I) were studied for cryoglobulins, complement hemolytic activity (CH50), and complement split product C3d. In total, 80 HCV‐negative renal transplant recipients (group II) and 72 untreated patients with chronic hepatitis C (group III) without renal transplantation served as controls.

Results:  Cryoglobulins were detected in 45, 28, and 26% of the patients in group I, II, and III, respectively. A high cryocrit (>5%) was present only in patients of group III (p < 0.01%). Mean CH50 values were lower and C3d levels higher in HCV‐positive patients (group I and III) compared with HCV‐negative patients (p < 0.0001). Cryoglobulins were not associated with extrahepatic manifestations or graft dysfunction, except in five patients of group III demonstrating cryoglobulinemic vasculitis. HCV‐positive renal transplant recipients with signs of complement activation showed a significantly greater increase of serum creatinine (0.88 ± 1.14 mg/dL) when compared with baseline than patients without complement activation (0.34 ± 0.37 mg/dL; p = 0.035). There was also a tendency toward a higher extent of proteinuria in patients with complement activation (1.38 ± 2.17 g/d vs. 0.50 ± 0.77 g/d; p = 0.25, NS).

Conclusions:  Cryoglobulins are common in renal allograft recipients, but do not affect graft function. However, complement activation appears to be involved in chronic allograft dysfunction in HCV‐infected recipients.
A new indication for pancreas transplantation: high grade pancreatic dysplasia
Authors: Charpentier Kevin P. , Brentnall Teresa A , Bronner Mary P , Byrd David , Marsh Christopher
Published: December 2004

Abstract:  A 42‐yr‐old male presented with a family history of pancreatic carcinoma inherited an autosomal dominant pattern. The development of endocrine and exocrine pancreatic insufficiency served as early markers for neoplastic transformation. Screening endoscopic ultrasound and ERCP showed abnormalities suggestive of pancreatic dysplasia. Total pancreatectomy was performed and pathology confirmed carcinoma in situ, also known as high‐grade pancreatic ductal dysplasia or Pan IN‐3. The patient's post‐operative course was complicated by life threatening, brittle diabetes. Pancreas transplantation was successfully performed. One year following transplantation, the patient has excellent pancreas graft function. He remains insulin free and has no signs of malignancy. Total pancreatectomy followed by pancreas transplantation is a viable therapeutic option for patients in the dysplastic but still pre‐malignant phase of familial pancreatic adenocarcinoma who develop hypoglycemic unawareness following total pancreatectomy.
Comprehensive examination of gene expression associated with long‐term stable graft acceptance by renal transplant recipients
Authors: Zhang Hui‐qi , Lu Hua , Enosawa Shin , Suzuki Seiichi , Takahara Shiro , Nakajima Toshiharu , Saito Hirohisa , Sakamoto Kaoru
Published: December 2004

Abstract:  Expression levels of mRNA in peripheral blood mononuclear cells from five renal transplant recipients and five non‐transplanted controls were analyzed with GeneChips (GeneChip Instrument system, Affymetrix, Santa Clara, CA, USA). All recipients had retained a well‐functioning kidney graft for more than 15 yr on low‐dose maintenance immunosuppression. Among a total of 12 630 transcripts examined, significant differential expression was observed for 599 genes, whereby 470 genes were up‐regulated and 129 down‐regulated in the transplant recipients compared with controls. Of these, 192 up‐regulated and 46 down‐regulated genes showing a change greater than twofold were divided into eight functional categories as follows (numbers of genes, up/down): immune system (12/14), cell proliferation (17/3), oncology (15/3), transporter/receptor/binding protein (16/5), transcription factors (8/2), enzymes (17/4), expressed sequence tags (91/9), and others (16/6). Predictably, expression of immune‐associated genes was decreased in the recipients. Significant reduction of expression levels of CD3, ICAM‐1, and B7.2, which are critical molecules for interactions between antigen presenting cells and T cells, were observed. In T cell signal transduction, the Ras pathway was likely to be suppressed by activation of hVH‐5. The present data help to elucidate the immunological status in long‐term kidney graft recipients and may provide insights for future regimens to establish donor‐specific hyporesponsiveness.
Synthesis and Characterization of a Homogeneous Chemical Conjugate Between Basic Fibroblast Growth Factor and Saporin
Authors: Buechler Ying Ji , Sosnowski Barbara A. , Victor Kimberly D. , Parandoosh Zahra , Bussell Stuart J. , Shen Chun , Ryder Marie , Houston L. L.
Published: December 2004

Basic fibroblast growth factor (FGF‐2) and saporin were chemically conjugated using the crosslinker, N ‐succinimidyl‐3(2‐pyridyldithio)‐propionate. When purified, the conjugate was found to be heterogeneous as analyzed by SDS/PAGE, size‐exclusion HPLC and reverse‐phase HPLC. Therefore, we sought to synthesize a molecule that would be homogeneous and thus easier to characterize and evaluate its efficacy and toxicity for pharmaceutical drug development. A homogeneous chemical conjugate was successfully synthesized by using a mutant FGF‐2 with Cys96 replaced by Ser ([S96]FGF‐2) and a recombinant saporin mutant containing a single Cys at the –1 position (C‐SAP). The latter was expressed in Escherichia coli and isolated to 99% purity by expanded‐bed adsorption chromatography followed by cation‐exchange chromatography. The cysteine in C‐SAP was activated by Ellman's reagent and then reacted with the only available cysteine (position 78) in [S96]FGF‐2 to produce the homogeneous conjugate, designated as FGF2–C‐SAP. The purified FGF2–C‐SAP was more than 98% pure as judged by HPLC. In vitro biological assays indicated that FGF2–C‐SAP was a potent inhibitor of protein synthesis in a cell‐free system and was cytotoxic to FGF‐receptor‐bearing cells.
Phylogenetic Conservation of 4‐Aminobutyric Acid (GABA) Transporter Isoforms
Authors: Guimbal Cécile , Klostermann Andreas , Kilimann Manfred W.
Published: December 2004

A family of structurally related, Na+/Cl− ‐dependent plasma‐membrane transporters catalyze the uptake of several neurotransmitters, osmolytes and other metabolites into cells. Four different members of this transporter family have been cloned from mammalian sources which all transport 4‐aminobutyric acid (GABA) but differ in their pharmacological profiles and in their tissue distribution. We report on the cloning, sequencing and functional expression of a transporter for GABA and β‐alanine from the electric lobe of Torpedo. According to similarity of amino acid sequence (77% identity), pharmacological properties, and tissue distribution (nervous‐system‐specific), it appears to be the counterpart of the β‐alanine‐sensitive GABA transporter, GAT‐B/GAT‐3/GAT4, previously cloned from rat and mouse. The identification of another GABA transporter isoform from Torpedo (after the recent characterization of a Torpedo GAT‐1 transporter) indicates that GABA‐transporter isoforms are phylogenetically ancient and arose before the divergence of vertebrates. Sequence comparison between isofunctional transporters from evolutionarily distant species aids in the identification of amino acid residues that are critical for functional specificity. The expression of transporters for GABA and β‐alanine raises questions regarding the unidentified physiological role of these amino acids in Torpedo electric lobe.
Protein p53 Modulates Transcription from a Promoter Containing its Binding Site in a Concentration‐Dependent Manner
Authors: Kristjuhan Arnold , Maimets Toivo
Published: December 2004

Tumor suppressor protein p53 hinds to DNA in a sequence‐specific manner and activates transcription from promoters near its binding site. It is also known to repress promoters lacking the p53‐binding site. In this study, we demonstrate that p53 can act as a transcriptional activator or repressor in vivo using the same reporter with the DNA‐binding site CON and these effects depend on the amount of p53 expressed. Both in Saos2 and Cos7 cells, lower concentrations of p53 lead to activation and higher concentrations lead to repression of the model promoter containing the consensus p53‐binding site CON. The N‐terminal part of p53 is necessary for the transcriptional activation. It is not needed, however, for the repression of the same promoter, indicating that different domains of p53 are, involved in activation and repression.
Point mutations in the guanine phosphoribosyltransferase from Giardia lamblia modulate pyrophosphate binding and enzyme catalysis
Authors: Page Jon P. , Munagala Narsimha R. , Wang Ching C.
Published: December 2004

Guanine phosphoribosyltransferase (GPRTase) from Giardia lamblia, an enzyme required for guanine salvage and necessary for the survival of this parasitic protozoan, has been kinetically characterized. Phosphoribosyltransfer proceeds through an ordered sequential mechanism common to many related purine phosphoribosyltransferases (PRTases) with α‐D‐5‐phosphoribosyl‐1‐pyrophosphate (PRPP) binding to the enzyme first and guanosine monophosphate (GMP) dissociating last. The enzyme is a highly unique purine PRTase, recognizing only guanine as its purine substrate (Km = 16.4 µm) but not hypoxanthine (Km > 200 µm) nor xanthine (no reaction). It also catalyzes both the forward (kcat = 76.7 s−1) and reverse (kcat = 5.8·s−1) reactions at significantly higher rates than all the other purine PRTases described to date. However, the relative catalytic efficiencies favor the forward reaction, which can be attributed to an unusually high Km for pyrophosphate (PPi) (323.9 µm) in the reverse reaction, comparable only with the high Km for PPi (165.5 µm) in Tritrichomonasfoetus HGXPRTase‐catalyzed reverse reaction. As the latter case was due to the substitution of threonine for a highly conserved lysine residue in the PPi‐binding loop [Munagala et al. (1998) Biochemistry37, 4045–4051], we identified a corresponding threonine residue in G. lamblia GPRTase at position 70 by sequence alignment, and then generated a T70K mutant of the enzyme. The mutant displays a 6.7‐fold lower Km for PPi with a twofold increase in the Km for PRPP. Further attempts to improve PPi binding led to the construction of a T70K/A72G double mutant, which displays an even lower Km of 7.9 µm for PPi. However, mutations of the nearby Gly71 to Glu, Arg, or Ala completely inactivate the GPRTase, suggesting the requirement of flexibility in the putative PPi‐binding loop for enzyme catalysis, which is apparently maintained by the glycine residue. We have thus tentatively identified the PPi‐binding loop in G. lamblia GPRTase, and attributed the relatively higher catalytic efficiency in the forward reaction to the unusual loop structure for poor PPi binding in the reverse reaction.
Solution structure and stability of the full‐length excisionase from bacteriophage HK022
Authors: Rogov Vladimir V. , Lücke Christian , Muresanu Lucia , Wienk Hans , Kleinhaus Ioana , Werner Karla , Löhr Frank , Pristovšek Primož , Rüterjans Heinz
Published: December 2004

Heteronuclear high‐resolution NMR spectroscopy was employed to determine the solution structure of the excisionase protein (Xis) from the λ‐like bacteriophage HK022 and to study its sequence‐specific DNA interaction. As wild‐type Xis was previously characterized as a generally unstable protein, a biologically active HK022 Xis mutant with a single amino acid substitution Cys28→Ser was used in this work. This substitution has been shown to diminish the irreversibility of Xis denaturation and subsequent degradation, but does not affect the structural or thermodynamic properties of the protein, as evidenced by NMR and differential scanning calorimetry. The solution structure of HK022 Xis forms a compact, highly ordered protein core with two well‐defined α‐helices (residues 5–11 and 18–27) and five β‐strands (residues 2–4, 30–31, 35–36, 41–44 and 48–49). These data correlate well with 1H2O‐2H2O exchange experiments and imply a different organization of the HK022 Xis secondary structure elements in comparison with the previously determined structure of the bacteriophage λ excisionase. Superposition of both Xis structures indicates a better correspondence of the full‐length HK022 Xis to the typical ‘winged‐helix’ DNA‐binding motif, as found, for example, in the DNA‐binding domain of the Mu‐phage repressor. Residues 51–72, which were not resolved in the λ Xis, do not show any regular structure in HK022 Xis and thus appear to be completely disordered in solution. The resonance assignments have shown, however, that an unusual connectivity exists between residues Asn66 and Gly67 owing to asparagine‐isoaspartyl isomerization. Such an isomerization has been previously observed and characterized only in eukaryotic proteins.
Purification and functional characterization of insecticidal sphingomyelinase C produced by Bacillus cereus
Authors: Nishiwaki Hisashi , Ito Katsuhiko , Otsuki Katsuhiko , Yamamoto Hiroyuki , Komai Koichiro , Matsuda Kazuhiko
Published: December 2004

Bacillus cereus isolated from the larvae of Myrmeleon bore was found to secrete proteins that paralyze and kill German cockroaches, Blattela germanica, when injected. One of these active proteins was purified from the culture broth of B. cereus using anion‐exchange and gel‐filtration chromatography. The purified toxin, with a molecular mass of 34 kDa, was identified as sphingomyelinase C (EC 3.1.4.12) on the basis of its N‐terminal and internal amino‐acid sequences. A recombinant sphingomyelinase C expressed in Escherichia coli was as potent as the native protein in killing the cockroaches. Site‐directed mutagenesis (His151Ala) that inactivated the sphingomyelinase activity also abolished the insecticidal activity, suggesting that the rapid insect toxicity of sphingomyelinase C results from its phospholipid‐degrading activity.
Development of recombinant inhibitors specific to human kallikrein 2 using phage‐display selected substrates
Authors: Cloutier Sylvain M. , Kündig Christoph , Felber Loyse M. , Fattah Omar M. , Chagas Jair R. , Gygi Christian M. , Jichlinski Patrice , Leisinger Hans‐Jürg , Deperthes David
Published: December 2004

The reactive site loop of serpins undoubtedly defines in part their ability to inhibit a particular enzyme. Exchanges in the reactive loop of serpins might reassign the targets and modify the serpin–protease interaction kinetics. Based on this concept, we have developed a procedure to change the specificity of known serpins. First, reactive loops are very good substrates for the target enzymes. Therefore, we have used the phage‐display technology to select from a pentapeptide phage library the best substrates for the human prostate kallikrein hK2 [Cloutier, S.M., Chagas, J.R., Mach, J.P., Gygi, C.M., Leisinger, H.J. & Deperthes, D. (2002) Eur. J. Biochem. 269, 2747–2754]. Selected substrates were then transplanted into the reactive site loop of α1‐antichymotrypsin to generate new variants of this serpin, able to inhibit the serine protease. Thus, we have developed some highly specific α1‐antichymotrypsin variants toward human kallikrein 2 which also show high reactivity. These inhibitors might be useful to help elucidate the importance of hK2 in prostate cancer progression.
Photoaffinity labelling of the Human GM2‐activator protein
Authors: Wendeler Michaela , Hoernschemeyer Joerg , Hoffmann Daniel , Kolter Thomas , Schwarzmann Guenter , Sandhoff Konrad
Published: December 2004

The GM2‐activator protein (GM2AP) is an essential cofactor for the degradation of ganglioside GM2 by lysosomal β‐hexosaminidase A. It mediates the interaction between the water‐soluble exohydrolase and its membrane‐bound substrate at the lipid–water interphase. Inherited defects in the gene encoding this glycoprotein result in a fatal neurological storage disorder, the AB variant of GM2‐gangliosidosis. To elucidate the mode of action of this glycoprotein cofactor, we synthesized the two photoaffinity labels [14C]C3‐TPD‐GM2 and [14C]C7‐TPD‐GM2. Incubation of GM2AP with these substrate analogues and subsequent irradiation led to covalent labelling of the protein. After separation of tryptic peptides by reverse‐phase HPLC, the labelled peptide fractions were analysed by MALDI‐TOF and sequenced by ESI‐Q‐TOF mass spectrometry. Both labels were found to be specifically photoincorporated into a part of the surface loop comprising residues V153–L163, a stretch of amino acids that was previously identified as the most flexible region in the crystal structure of the activator. Our results provide strong evidence that this loop constitutes the part of the activator protein that directly interacts with the ganglioside substrate, suggesting that the hydrophobicity and the great structural mobility of this element are crucial for the extraction of the membrane‐embedded glycolipid, its stabilization inside the spacious cavity and its guidance to the enzyme's active site. This study demonstrates that the approach of photoaffinity labelling in conjunction with accurate mass measurements can provide insight into substrate binding interactions that complements structural information.
Hyperparasitic Stagonospora sp. on Botryosphaeria stevensii
Authors: Vajna L.
Published: December 2004

An unknown fungus, Stagonospora sp., has been found on and in stromata of Botryosphaeria stevensii Shoemaker anamorph (Diplodia mutila Fr. & Mont.) and Diatrypella quercina (Persoon) Nitschke. Microscopic investigations indicated that the fungus might be a hyperparasite of some ascomycetous fungi, necrotrophs or weak parasites on sessile oak [Quercus petraea] and turkey oak (Quercus cerris). Dual culture studies carried out with monoconidial isolates of Stagonospora sp. and B. stevensii have demonstrated that Stagonospora sp. is a necrotrophic mycoparasite which might suppress, to some extent, the natural population of B. stevensii. Botryosphaeria stevensii is one of the biotic factors causing oak decline. Morphology of the fungus and symptoms of mycoparasitic interaction are described. Stagonospora sp. found in Hungary is assumed to be identical with hyperparasitic Stagonospora sp. reported from Germany and Austria as parasite of Ascodichaena rugosa and Ascodichaena mexicana in Mexico. This is the first record of hyperparasitic Stagonospora sp. of B. stevensii and D. quercina.
Increases in peritoneal small solute transport in the first month of peritoneal dialysis predict technique survival
Authors: WIGGINS KATHRYN J , BLIZZARD SOPHIE , ARNDT MARY , O'SHEA AMANDA , WATT RHONDA , HAMILTON JAN , COTTINGHAM SHARON , CAMPBELL SCOTT B , ISBEL NICOLE M , JOHNSON DAVID W
Published: December 2004

Background:  Peritoneal transport of small solutes generally increases during the first month of peritoneal dialysis (PD). The aim of this study was to prospectively evaluate the ability of the peritoneal equilibration test (PET), carried out 1 and 4 weeks after the commencement of PD, to predict subsequent technique survival.

Methods:  Fifty consecutive patients commencing PD at the Princess Alexandra Hospital between 1 February 2001 and 31 May 2003 participated in the study. Paired 1 week and 1 month PET data were collated and correlated with subsequent technique survival.

Results:  A significant increase was observed in the dialysate : plasma creatinine ratio at 4 h (D/P Cr) between 1 and 4 weeks after the onset of PD (0.55 ± 0.12 vs 0.66 ± 0.11, P < 0.001). Mean death‐censored technique survival was superior in patients who experienced ≥20% rise in D/P Cr during the first month of PD compared with those who did not (2.3 ± 0.2 vs 1.6 ± 0.2 years, P < 0.05). Using a multivariate Cox proportional hazards model analysis, the significant independent predictors of death‐censored technique survival were an increase in D/P Cr of greater than 20% during the first month (adjusted hazard ratio [HR] 0.20, 95% CI 0.05–0.75), the absence of diabetes mellitus, the absence of ischaemic heart disease, body mass index and baseline peritoneal creatinine clearance.

Conclusions:  A 20% or greater rise in D/P Cr during the first month of commencing PD is independently predictive of PD technique survival. Further investigations of the mechanisms underlying this phenomenon are warranted.
QTc interval and QTc dispersion during haemodiafiltration
Authors: FLOCCARI FULVIO , ALOISI EMANUELE , NOSTRO LORENA , CACCAMO CHIARA , CRISAFULLI ALESSANDRA , BARILLÀ ANTONIO , ALOISI CARMELA , ROMEO ADOLFO , CORICA FRANCESCO , IENTILE RICCARDO , FRISINA NICOLA , BUEMI MICHELE
Published: December 2004

Background and Aim:  Our aim was to evaluate QTc interval and QTc dispersion in 27 end‐stage renal disease (ESRD) patients undergoing Acetate Free Biofiltration (AFB) in order to ascertain any correlations between the electrrocardiographic (ECG) parameters, serum Na+, K+, Ca++, Mg++ and intraerythrocytic Mg++ (Mg++e) concentrations. All measures were made at t0 (session beginning), t1 (first hour), t2 (second hour), t3 (third hour), and t4 (session end).

Results:  Blood pressure, heart rate, bodyweight and total ultrafiltration in the three dialysis sessions were constant. A significant progressive increase occurred in serum Ca++ during the sessions, while there was a significant diminution in serum K+. The pattern for Mg++ concentrations in serum and erythrocytes differed: in serum it decreased, whereas Mg++e increased. At t4, the QTc interval was reduced to a significant extent with respect to the baseline value. QTc dispersion significantly increased at t1 without there being significant variations at other times with respect to t0. At t2, t3 and t4, values promptly returned to baseline levels. QTc had a negative correlation with serum Ca++ levels at t4. In contrast, an inverse correlation was found between QTc dispersion and serum K+ at t1. No other correlations could be found between any other electrolytes, QTc interval or QTc dispersion.

Conclusion:  In conclusion, the decrease observed in the QTc interval at the end of an AFB session was inversely related to serum Ca++ concentrations. Moreover, an increase in QTc dispersion occurred during the first hour of the session, and was negatively correlated with serum K+.
Switchover to generic cyclosporine in stable renal transplant recipients: A single unit experience
Authors: TALAULIKAR GIRISH S , GALLAGHER MARTIN P , CARNEY GAVIN M , JADEER ASAD A , FALK MICHAEL C , HIREMAGALUR BALAJI
Published: December 2004

Background: The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma).

Method: A two‐period, single‐sequence, cross‐over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0–4 h and 0–12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8–1.25.

Results and Conclusion: A total of 38 stable renal transplant patients aged 49.79 ± 11.38 years (mean ± SD), who were 7.84 ± 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 ± 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.
Does asymptomatic hyperuricaemia contribute to the development of renal and cardiovascular disease? An old controversy renewed
Authors: KANELLIS JOHN , FEIG DANIEL I , JOHNSON RICHARD J
Published: December 2004

SUMMARY:  Recent studies in both humans and experimental animals have led to renewed interest in uric acid and its association with hypertension, cardiovascular events and renal disease progression. This has also refuelled a longstanding debate regarding the precise role of this ubiquitous breakdown product of purine metabolism in these disease processes. Various lines of evidence suggest that uric acid may have a direct role in the pathogenesis of hypertension and vascular disease. Regardless of this possibility, it is apparent that serum uric acid levels serve as a powerful ‘biomarker’ or independent predictor of prognosis and outcome in certain renal, cardiovascular and cerebrovascular diseases. Whether these outcomes can be improved by specifically treating asymptomatic hyperuricaemia remains inadequately resolved at this stage. Data from various animal studies suggests that lowering uric acid levels may be of benefit, but the crucial human studies are still lacking. This review will examine some of the recent evidence supporting a causal and contributory role for uric acid in cardiovascular and renal disease. How clarification of the role of uric acid may guide future treatment strategies will also be discussed.
Effectiveness of high trough levels of cyclosporine for 5 months in a case of steroid‐dependent nephrotic syndrome with severe steroid toxicity
Authors: KANO KENICHI , YAMADA YUMI , SHIRAIWA TAEKO , SHIMIZU AKI , NISHIKURA KIYOSHI , ARISAKA OSAMU , TOMITA SHIGEKI , UEDA YOSHIHIKO
Published: December 2004

SUMMARY:  Glucocorticoid treatment for steroid‐dependent nephrotic syndrome (NS) is associated with severe adverse effects, such as bone fractures and epidural lipomatosis. Furthermore, a high trough level of cyclosporine (CsA) over an extended period of time is known to induce CsA nephropathy. We present a girl with steroid‐dependent NS and steroid‐induced vertebral compression fractures and epidural lipomatosis who was treated with a high‐dose of prednisolone after experiencing several relapses. A high CsA trough level (between 147 and 225 ng/mL) over a period of only 5 months was effective in improving the vertebral compression fractures, alleviating the epidural lipomatosis by enabling the discontinuation of prednisolone treatment. Thus, high trough levels of CsA over a short period of time may enable prednisolone to be discontinued in cases of steroid‐dependent NS without causing any clinical, histological, serum and/or urinary CsA‐related adverse effects.
Better medication management for Aboriginal people with mental health disorders: a survey of providers
Authors: Kowanko Inge , Crespigny Charlotte de , Murray Helen , Groenkjaer Mette , Emden Carolyn
Published: December 2004

Objective:  To explore the experiences and training needs of service providers in relation to medication management for Aboriginal people with mental health disorders.

Design:  Survey

Setting:  Aboriginal and mainstream health and human service organisations in metropolitan, rural and remote South Australia.

Subjects:  Aboriginal health workers, nurses, mental health workers, substance misuse workers, managers, liaison officers, social workers, police, pharmacists, general practitioners, community workers, counsellors, paramedics, educators, family support workers and others.

Results:  The major health service issues for Aboriginal people with mental health disorders and their carers are related to access to, and availability and appropriateness of services. Quality use of medications by Aboriginal clients is influenced by drug and alcohol misuse, cost, compliance, feelings about the value of medicines, sharing of medications and unwanted side‐effects. Many workers providing services to Aboriginal people with mental health disorders lack adequate training and/or resources on mental health and safe medication management; yet, are required to provide advice or assistance on these matters.

Conclusions:  The survey provides new, reliable evidence relevant to mental health services and medication management for South Australian Aboriginal people. It highlights the major issues impacting on quality of care and service provision, demonstrates the wide range of health and allied workers providing medication advice and assistance to Aboriginal people, and reveals workforce development needs.

What is already known:   Statistics show the general health status and life expectancy of Australian Aboriginal people are markedly lower than the non‐Aboriginal population. Mental health disorders are pervasive, especially related to alcohol and other drugs. Despite numerous health‐related studies, very little has been documented about medication management for Aboriginal people with mental health disorders.

What this study adds:  Health and social service workers revealed major issues impacting on medication management for Aboriginal people with mental health disorders in urban, rural and remote regions of South Australia. These included racism, problems with alcohol and other drug use, money and transport issues, availability and access to a range of specialist services, and confidentiality and suitability of services. The wide range of backgrounds and occupations of people involved with medicines has been revealed, together with their urgent need for education on cultural safety, mental health, and the safe handling, transport, storage and administration of medicines.
Safety and efficacy of acellular pertussis vaccine in Japan, evaluated by 23 years of its use for routine immunization
Authors: Kuno‐Sakai Harumi , Kimura Mikio
Published: December 2004

Background
: Real evaluation of any vaccine can only be done after the vaccine has been in routine use for a substantially long period of time. In Japan, acellular pertussis vaccine was introduced and totally replaced whole cell pertussis vaccine in 1981. From 1982 to 1988 40.3 million doses of acellular pertussis vaccine were given to 2‐year‐olds and from 1989 to 2001 59.3 million doses of acellular pertussis vaccine were given to 3‐month‐olds. It is now time to evaluate the efficacy and safety of acellular pertussis vaccine by the use of national data officially supplied by the Government.

Methods
: Government national surveillance of pertussis, which began in 1981, was used to analyze epidemiology of pertussis. Official Government reports on acceptance rates of pertussis were analyzed. A peer review has been made on all severe neurological illnesses/death occurring after pertussis immunization which have been applied for through the Vaccine Injury Compensation System, Ministry of Health Labor and Welfare, Japan.

Results
: High acceptance rates of acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) has been maintained and a dramatic decrease in pertussis was noted over the past 23 years. Neurological illnesses temporally associated both with whole cell and with acellular pertussis vaccination has been a rare phenomenon. However, incidences of encephalopathy/encephalitis and status epileptics/frequent convulsions, febrile seizures/provocation of convulsions, and sudden deaths were significantly lower with acellular pertussis vaccination than with whole cell pertussis vaccination.

Conclusion
: With the use of acellular pertussis vaccine which has been accepted by the public, pertussis has been well controlled in Japan.
Tc‐99m‐HMPAO SPECT in the diagnosis of brain death in children
Authors: Okuyaz Çetİn , Gücüyener Kivilcim , Karabacak NeŞe İlgİn , AydIn KürŞad , SerdaroĞlu AyŞe , Cingi Elİf
Published: December 2004

Background
: The diagnosis of brain death is based on both clinical and laboratory findings. However, diagnosis of brain death is still contentious and reliable tests are required. Early recognition and declaration of the diagnosis is the main goal, which is important for discontinuation of life support and organ donation for transplantation. In order to achieve this goal, competent diagnostic procedures should be performed. In this paper the authors review the diagnosis of brain death in eight children from different age groups, with an emphasis on factors concerning the reliability, use and appropriate application time of Tc‐99m‐HMPAO single photon emission computed tomography (SPECT) in early diagnosis in infants and newborns.

Methods
: Eight patients who fulfilled the clinical criteria of brain death underwent Tc‐99m HMPAO SPECT and electroencephalogram (EEG) monitoring.

Results
: All patients had electrocerebral silence on EEG recordings. Six patients showed lack of perfusion in cerebrum in their first SPECT, however, newborns needed a second image for a confirmed diagnosis.

Conclusion
: In infants, SPECT has a high reliability for confirmed diagnosis of brain death; however, in newborns the application time is important for an accurate diagnosis.
Patients with benign rolandic epilepsy have a longer duration of somatosensory evoked high‐frequency oscillations
Authors: Kubota Masaya , Tran Tuan Diep , Hirose Hiroyuki , Kimura Ikumi , Sakakihara Yoichi
Published: December 2004

Background
: High‐frequency oscillations (HFO) ranging between 300–900 Hz have been shown to be superimposed on an early component of somatosensory evoked potentials (SEP) to median nerve stimulation in humans. Although the HFO are speculated to be a localized activity of the GABAergic inhibitory interneurons, the significance in the epileptogenicity remains unclear. The authors of this study analyzed HFO using magnetoencephalography in patients with benign rolandic epilepsy (BRE) to clarify the neurophysio‐logical basis of rolandic discharges (RD).

Methods
: Nine patients with BRE and six patients with other epileptic syndrome (non‐BRE) participated in the study. Somatosensory evoked fields (SEF) including HFO to median nerve stimulation were measured in a magnetically shielded room with a 37‐channel neuromagnetometer.

Results
: Two kinds of HFO, 300Hz‐ and 600Hz‐HFO, were identified and the duration of the HFO in patients with BRE was significantly longer than that in patients with non‐BRE.

Conclusions
: The results suggest that the longer part of HFO (P30m‐related) is closely related to the pathogenesis of RD and that the longer HFO in patients with BRE might be mediated by altered GABAergic inhibition modulated by the cholinergic system.
Dynamic movement of cytochrome c from mitochondria into cytosol and peripheral circulation in massive hepatic cell injury
Authors: Kobayashi Yoshinori , Mori Masaaki , Naruto Takuya , Kobayashi Naoki , Sugai Toshiyuki , Imagawa Tomoyuki , Yokota Shumpei
Published: December 2004

Background
: In the process of apoptosis, it is known that the transition of cytochrome c from mitochondria into the cytosol occurs, and tumor necrosis factor (TNF)‐α is one of the molecules responsible for this event. But in the state of hypercytokine induced by d‐galactosamine (D‐GaIN)/Lipopolysaccharide (LPS), the localization of cytochrome c is little known.

Methods
: Rats were administrated with D‐GaIN(700 mg/kg)/LPS(200 µg/kg). Blood and tissue samples were collected and examined for levels of pro‐inflammatory cytokines, the apoptosis of liver cells, and the localization of cytochrome c.

Result
: Before administration of D‐GaIN/LPS, cytochrome c was definitely localized in the mitochondria. At 2 h after simultaneous administration of D‐GaIN/LPS, cytochrome c had accumulated in the cytosol following abrupt increases of plasma TNF‐α. Massive cell destruction due to apoptosis proved by Terminal deoxynucleo­tidyl transferase‐mediated dUTP nick end labeling staining was observed in liver tissue 4 h later and markedly increased levels of cytochrome c were detected in the plasma 12 h after D‐GaIN/LPS administration.

Conclusion
: Liver injury induced by simultaneous administration of D‐GaIN/LPS was closely associated with the production of TNF‐α, and also with the dynamic movement of cytochrome c from the mitochondria into the cytosol, and then into the systemic circulation. The detection of plasma cytochrome c levels may be a useful clinical tool for the detection of apoptosis in vivo.
Celiac disease with various presentations
Authors: Doganci Tumay , Bozkurt Serap
Published: December 2004

Background: Celiac disease (CD) has a wide clinical spectrum from malabsorption syndrome to extra intestinal presentations. A total of 45 children with CD presented with mainly chronic diarrhea (n:23), anemia (n: 12), and short stature (n: 10) were evaluated in this study. The aim was to find common parameters of CD with various presentations.

Methods: Basic anthropometric, biochemical and hematological parameters in cases with CD with various presentations were compared.

Results: It was found that children with CD presenting with chronic diarrhea were younger. There was no significant difference in hemoglobin levels in children with CD presenting with anemia. Children with CD with short stature had significantly lower serum vitamin B12levels and lower levels of height standard deviation scores, bone age delay, and alkaline phosphatase.

Conclusions: It was concluded that children, especially infants with chronic diarrhea with CD, may not be affected with generalized malabsorption. Anemia and short stature are frequent findings in cases with CD whether they are main presenting symptoms or not. Children with CD presenting with short stature may have lower levels of vitamin B12than other presentations.
Combined androgen blockade in the management of advanced prostate cancer: A sensible or ostensible approach
Authors: ANSARI MOHD S. , GUPTA NARMADA P. , HEMAL ASHOK K. , DOGRA PREM N. , SETH AMLESH
Published: December 2004

Abstract  Background  To compare the efficacy of orchiectomy alone and orchiectomy plus flutamide in treating patients with advanced carcinoma prostate.

Materials and methods  The study was initiated on 1 July 1997 and closed after enrolling 100 patients on 30 June 2000. Patients were prospectively randomized to orchiectomy alone (O) and orchiectomy plus flutamide (OF). A complete response (CR) was defined as the normalization of bone scans and serum prostate‐specific antigen (PSA) levels returning to normal (<4 ng/mL). A partial response (PR) was defined as a 50% reduction in metastasis mass compared to the initial study or a decrease in the PSA level of 50% of the initial value. Progressive disease (PD) was defined as the development of any new hot spot on bone scan or any increase in previously existing PSA level by 25%.

Results  A total of 100 patients were entered in the study. The maximum percentage change in PSA levels in both groups was found in the first 3 months after orchiectomy, that is, 95% and 97% for the O and OF groups, respectively. In more than 80% of the patients this decrease in PSA was maintained for 3 years. The mean percentage change at 3 years in the O and OF groups was 70% and 75% (P = 0.95), respectively, and the overall response rate (CR + PR) was 88.50% and 86.53% in the two groups, respectively (P = 0.85). The follow‐up period ranged between 3 and 5 years (mean, 3.5 years). The mean time to progression was 27 and 29 months in the O and OF groups, respectively. The overall survival rate at 3 and 5 years in two treatment groups was 45.83% and 48.07%, 20.83% and 23.07% in the O and OF groups, respectively (P = 0.75).

Conclusions  Maximum percentage decrease in PSA is seen within the first 3 months of therapy. Orchiectomy alone is as effective as combination therapy in decreasing serum PSA. Overall survival at 3 and 5 years in the orchiectomy only group was as good as that of combination therapy. These data suggest that the routine addition of flutamide to orchiectomy is not advisable.
Spontaneous rupture of varicocele testis associated with advanced pancreatic cancer
Authors: MATSUI YOSHIYUKI , UTSUNOMIYA NORIAKI , ICHIOKA KENTARO , UEDA NORIHUMI , YOSHIMURA KOJI , TERAI AKITO
Published: December 2004

Abstract  We report a rare case of strain‐induced spontaneous rupture of varicocele associated with renal vein involvement by advanced pancreatic cancer. Computed tomography and color Doppler sonography yielded the correct diagnosis and the patient could maintain quality of life without surgery for acute scrotum.