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PubMed1998

Two types of pattern modification detected on the follow-up of benign melanocytic skin lesions by digitized epiluminescence microscopy.

Digital epiluminescence microscopy (DELM) is currently being developed for the diagnosis of pigmented skin lesions (PSL) and the early diagnosis of malignant melanoma. So far there are only few studies documenting if modifications in PSL may be detected by DELM over time. Our purpose was to determine if DELM is an adequate tool for the follow-up of PSL and if any detectable modifications occur within PSL over time. We followed 150 PSL over 2 years in 67 patients using a DELM system. At the end of the follow-up period, the retrieved DELM images were analysed by two observers and evaluated for the presence and type of modifications. Modifications were observed in 69% of the PSL. These modifications were of two types. Type 1 corresponded to an increase in the pigment content of the lesion without modification of either its size or architecture, and was probably related to sun-related seasonal variation. Type 2 included an increase in the size and various variations in the architecture, corresponding to a progression of the lesion. Correlation of the type of modification with the type of PSL, as defined by its epiluminescence microscopy (ELM) patterns, indicated that type 2 modifications were associated with lesions initially showing ELM signs of 'dysplasia', whereas lesions showing only type 1 modifications did not show such patterns. We have documented the feasibility of following up PSL with DELM. The pattern of modification of a PSL over time could be correlated with its nature.

Adolescent↗
PubMed1992

Physiology of "atypical" atrioventricular junctional reentrant tachycardia occurring following radiofrequency catheter modification of the atrioventricular node.

The physiology of atypical atrioventricular junctional reentrant tachycardia (AVJRT) occurring following catheter modification of the AV node is poorly defined. Six patients undergoing radiofrequency current catheter modification of the AV node had inducible atypical AVJRT before or after AV nodal modification. Typical AVJRT was differentiated from atypical AVJRT by a ventriculoatrial (VA) time < 60 msec in the His-bundle electrogram recording. Five of six patients had typical AVJRT and two had atypical AVJRT prior to AV nodal modification. Following anterior approach AV nodal modification, previously undetected atypical AVJRT was induced in four patients. Earliest retrograde atrial activation in the posterior septum was documented in all patients with atypical AVJRT prior to modification and in three of four patients with atypical AVJRT following modification. The AH intervals during tachycardia were 320 +/- 52 msec in typical AVJRT, 88 +/- 33 msec in the premodification atypical AVJRTs, and 172 +/- 12 msec in the postmodification atypical AVJRTs (P = 0.0001). The AH/HA ratios were 4.1 +/- 0.9 in typical AVJRT, 0.5 +/- 0.2 in the premodification atypical AVJRTs, and 0.9 +/- 0.2 in the postmodification atypical AVJRTs (P = 0.0001). Two patients with postmodification atypical AVJRT underwent further posterior approach AV node modification that resulted in VA block. One patient with postmodification atypical AVJRT had further anterior approach AV nodal modification that resulted in heart block. The retrograde limb of the atypical AVJRT seen following anterior approach AV nodal modification is a posterior, slow pathway.

Atrioventricular Node↗
PubMed1999

SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation.

PML is a nuclear phosphoprotein that was first identified as part of a translocated chromosomal fusion product associated with acute promyelocytic leukaemia (APL). PML localises to distinct nuclear multi-protein complexes termed ND10, Kr bodies, PML nuclear bodies and PML oncogenic domains (PODs), which are disrupted in APL and are the targets for immediate early viral proteins, although little is known about their function. In a yeast two-hybrid screen, we first identified a ubiquitin-like protein named PIC1 (now known as SUMO-1), which interacts and co-localises with PML in vivo. More recent studies have now shown that SUMO-1 covalently modifies a number of target proteins including PML, RanGAP1 and IkappaBalpha and is proposed to play a role in either targeting modified proteins and/or inhibiting their degradation. The precise molecular role for the SUMO-1 modification of PML is unclear, and the specific lysine residues within PML that are targeted for modification and the PML sub-domains necessary for mediating the modification in vivo are unknown. Here we show that SUMO-1 covalently modifies PML both in vivo and in vitro and that the modification is mediated either directly or indirectly by the interaction of UBC9 with PML through the RING finger domain. Using site-specific mutagenesis, we have identified the primary PML-SUMO-1 modification site as being part of the nuclear localisation signal (Lys487 or Lys490). However SUMO-1 modification is not essential for PML nuclear localisation as only nuclear PML is modified. The sequence of the modification site fits into a consensus sequence for SUMO-1 modification and we have identified several other nuclear proteins which could also be targets for SUMO-1. We show that SUMO-1 modification appears to be dependant on the correct subcellular compartmentalisation of target proteins. We also find that the APL-associated fusion protein PML-RARA is efficiently modified in vitro, resulting in a specific and SUMO-1-dependent degradation of PML-RARA. Our results provide significant insights into the role of SUMO-1 modification of PML in both normal cells and the APL disease state.

Consensus Sequence↗
PubMed2024

TGIRT-seq to profile tRNA-derived RNAs and associated RNA modifications.

RNA modifications are key regulators for RNA processes. tRNA-derived RNAs are small RNAs with size between 15 and 50 bases long that are processed from mature or precursor tRNAs. Despite their more recent discovery, tRNA-derived RNAs have been found to play regulatory roles in many cellular processes including gene silencing, protein synthesis, stress response, and transgenerational inheritance. Furthermore, tRNA-derived RNAs are highly abundant in bodily fluids, posing as potential biomarkers. A unique feature of tRNA-derived RNAs is that they are rich in RNA modifications. Many of the RNA modifications on tRNA-derived RNAs disrupt Watson-Crick base pairing and will thus stall reverse transcriptase, such as N1-methyladenosine (m1A), N1-methylguanosine (m1G) and N2, N2-dimethylguanosine (m22G). These RNA modifications add another layer of regulation onto tRNA-derived RNAs' functions and are of interests for future research. However, these RNA modifications could also lead to lower detection of modification-containing RNAs in genome-wide small RNA sequencing analysis due to reverse transcriptase stall. To circumvent this bias, TGIRT (Thermostable Group II Intron Reverse Transcriptase) has been used to readthrough RNA modifications inserting mismatches. These mismatch signatures can then be used to precisely map the modification sites at base resolution. Here we describe the step-by-step experimental protocol to start with purified RNAs from cells or tissues and use TGIRT to make small RNA sequencing library for Illumina sequencing to profile the abundance of tRNA-derived RNAs and the associated RNA modifications.

RNA, Transfer↗
PubMed1982

Adaptation in bacterial chemotaxis: CheB-dependent modification permits additional methylations of sensory transducer proteins.

Sensory transduction in E. coli consists of two phases, excitation and adaptation, both of which involve the methyl-accepting chemotaxis proteins (MCPs). These molecules relay transmembrane signals and are reversibly methylated during adaptation of E. coli to environmental stimuli. Each MCP contains multiple sites of methylation, and we identified six of these sites in MCPI. Recently, a second covalent modification of MCPs has been identified, which is not methylation. This modification, designated CheB-dependent modification, is stimulated by repellents and causes a net increase in the negative charge of MCPI and MCPII by one or two charges. We demonstrate that one CheB modification occurs on the methyl-accepting methionine-and lysine-containing tryptic peptide in MCPI and MCPII, and the second CheB modification is on an arginine-containing tryptic peptide. The CheB modification allows three additional methyl groups to be incorporated into the methyl-accepting methionine-lysine peptide, while not actually creating all of these methylation sites. The two CheB modifications occur sequentially. A possible mechanism by which CheB modification permits additional methylations and the role of CheB modification in bacterial chemotaxis are discussed.

Bacterial Proteins↗
PubMed1994

Atypical forms of supraventricular tachycardia due to atrioventricular node reentry in children after radiofrequency modification of slow pathway conduction.

OBJECTIVES: This study was performed to investigate the prevalence, mechanisms and clinical significance of supraventricular tachycardias inducible in children or adolescents after radiofrequency modification of slow pathway conduction for the treatment of atrioventricular (AV) node reentrant tachycardia. BACKGROUND: Limited data have been reported with regard to the physiology of AV node reentrant tachycardia in young patients. Radiofrequency catheter ablation allows evaluation of the effects of selective modification of the different pathways involved in AV node reentrant tachycardia. METHODS: Selective modification of slow pathway conduction was performed in 18 young patients (12.9 +/- 3.4 years old) with typical (anterograde slow-retrograde fast) AV node reentrant tachycardia. Radiofrequency energy was applied across the posteromedial or midseptal tricuspid annulus, guided by slow pathway potentials and anatomic position. Programmed stimulation was performed after modification of slow pathway conduction defined as noninducibility of typical AV node reentrant tachycardia. RESULTS: Modification of slow pathway conduction was achieved in each patient, with a median of four applications of radiofrequency energy. However, atypical forms of supraventricular tachycardia were inducible in 9 of 18 young patients after slow pathway modification: AV node reentrant tachycardia with 2 to 1 AV block (seven patients); anterograde fast-retrograde slow AV node reentrant tachycardia (five patients); and sustained accelerated junctional tachycardia (two patients). In comparison, atypical forms of tachycardia were inducible in only 2 of 59 adult patients with AV node reentrant tachycardia undergoing slow pathway modification in the same laboratory (p = 0.01). Additional applications of radiofrequency energy to the posteromedial tricuspid annulus rendered AV node reentrant tachycardia with 2 to 1 block and the fast-slow form of AV node reentrant tachycardia noninducible. Junctional tachycardia terminated spontaneously in both patients. During 9.8 +/- 3 months of follow-up, slow-fast AV node reentrant tachycardia has recurred in one patient, whereas fast-slow AV node reentrant tachycardia has occurred in two patients, both with inducible fast-slow tachycardia after the initial modification of slow pathway conduction. CONCLUSIONS: Initial applications of radiofrequency energy may selectively modify the anterograde conduction of slow pathway fibers in young patients with AV node reentrant tachycardia. This may result in AV node reentrant tachycardia with 2 to 1 AV block or a reversal of the reentrant circuit (fast-slow tachycardia). Induction of these tachyarrhythmias indicates that further applications of radiofrequency energy are required for the successful modification of slow pathway conduction in young patients. The increased prevalence of inducible atypical arrhythmias among young patients suggests differences in the anatomic or electrophysiologic substrate of AV node reentrant tachycardia that may evolve as a function of age.

Adolescent↗
PubMed2006

The scope of duty hour-associated residency structure modifications.

OBJECTIVE: The purpose of this study was to characterize the duty hours-associated modifications made to the educational and patient care structure of obstetrics and gynecology residency programs, and the relationship of these modifications to residency program setting and size. STUDY DESIGN: A survey of accredited obstetrics and gynecology residency programs in the United States (excluding New York State) was performed between June 21st and July 16th, 2004. Program representatives were queried on the difficulty encountered in complying with each of the 6 components of the ACGME common duty hour requirements and the prevalence of residency modifications affecting the educational and patient care structure. RESULTS: Fifty-eight percent (123/211) of the study population completed the questionnaire. Ensuring a minimum 10-hour rest period between shifts was rated the most difficult requirement. Ninety-eight percent of respondents reported various types of modifications to program structure, including modification of on-call structure (94%), redistribution of responsibilities among resident levels (85%), modification of resident participation in patient care processes (80%), and modification of resident assignments to clinical services (75%). A minimum of 38% of programs reported reductions in resident participation in patient care, regardless of clinical service type or care setting. The prevalence of hiring attending physicians was significantly higher among non-university-based programs (18%), compared to university-based programs (3%, P = .007). CONCLUSION: Duty hour-related changes have resulted in near universal program modifications. One third of programs have made modifications that have resulted in a decrease in the available clinical experiences for residents.

Humans↗
PubMed2004

The influence of lifestyle modification on carotid artery intima-media thickness in a suburban Japanese population.

To evaluate the influence of lifestyle modification with and without lipid-lowering drug therapy on the carotid arterial wall, we did a 2 year prospective ultrasound study of carotid intima-media thickness (IMT) in 1390 male and female residents of a suburban Japanese town. According to total cholesterol (TC) level at baseline, subjects were classified into a lifestyle modification alone group (TC >/= 220 mg/dl, n = 437), a lifestyle modification with lipid-lowering drug group (TC >/= 220 mg/dl, n = 159), and a control group (TC < 220 mg/dl, n = 794). After 2 years of follow-up, both sexes of both treatment groups showed significant reductions of TC, low-density lipoprotein cholesterol (LDL-C), and IMT, although TC continued over 220 mg/dl in some subjects in the lifestyle modification group. The reduction of TC and LDL-C was significantly higher in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Although the IMT reduction was not statistically different between the treatment groups of either sex, the reduction of IMT was greater in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Our results indicate that comprehensive lifestyle modification can reduce carotid IMT in the general population, with or without the use of lipid-lowering drugs and that cholesterol reduction is of benefit even when TC level remain above the recommended level.

Adult↗
PubMed2006

Multiple neutral loss monitoring (MNM): a multiplexed method for post-translational modification screening.

Post-translational modifications of proteins are involved in determining the activity of proteins and are essential for proper protein function. Current mass spectrometric strategies require one to specify a particular type of modification, in some cases also a particular charge state of a protein or peptide that is to be studied before the actual analysis. Due to these requirements, most of the modifications on proteins are not considered in such an experiment and, thus, a series of similar analyses need to be performed to ensure a more extensive characterization. A novel scan strategy has been developed, multiple neutral loss monitoring (MNM), allowing for the comprehensive screening of post-translational modifications (PTM) on proteins that fragment as neutral losses in a mass spectrometer. MNM method parameters were determined by performing product ion scans on a number of modified peptides over a range of collision energies, providing neutral loss energy profiles and optimal collision energies (OCE) for each modification, supplying valuable information pertaining to the fragmentation of these modifications and the necessary parameters that would be required to obtain the best analysis. As the optimal collision energy was highly dependent on the type of modification and the charge state of the peptide, the MNM scan was operated with a collision energy gradient. Autocorrelation analyses identified the type of modification, and convolution mapping analyses identified the associated peptide. The MNM scan with the new collision energy parameters was successfully applied to a mixture of four modified peptides in a BSA digest. The implementation of this technique will allow for comprehensive screening of all modifications that fragment as neutral losses.

Algorithms↗
PubMed2006

Curcumin/turmeric solubilized in sodium hydroxide inhibits HNE protein modification--an in vitro study.

Free radical mediated lipid peroxidation has been implicated in multiple diseases. A major oxidation by-product of this deleterious process is 4-hydroxy-2-nonenal (HNE). HNE is cytotoxic, mutagenic and genotoxic and is involved in disease pathogenesis. Curcumin, a non-steroidal anti-inflammatory agent (occurring as the yellow pigment found in the rhizomes of the perennial herb Curcuma longa known as turmeric), has emerged as the newest "nutraceutical" agent that has been shown to be efficacious against colon cancer and other disorders, including correcting cystic fibrosis defects. Since curcumin has been reported to have anti-oxidant properties we hypothesized that it will inhibit HNE-modification of a protein substrate. Using an ELISA that employed HNE-modification of solid phase antigen following immobilization, we found that the curcumin solubilized in dilute alkali (5mM sodium hydroxide, pH 11) inhibited HNE-protein modification by 65%. Turmeric also inhibited HNE-protein modification similarly (65%) but at a much lower alkali level (130muM sodium hydroxide, pH 7.6). Alkali by itself (5mM sodium hydroxide, pH 11) was found to enhance HNE modification by as much as 267%. Curcumin/turmeric has to inhibit this alkali enhanced HNE-modification prior to inhibiting the normal HNE protein modification induced by HNE. Thus, inhibition of HNE-modification could be a mechanism by which curcumin exerts its antioxidant effects. The pH at which the inhibition of HNE modification of substrate was observed was close to the physiological pH, making this formulation of curcumin potentially useful practically.

Aldehydes↗
PubMed1996

Stabilization of barstar by chemical modification of the buried cysteines.

The internal packing of residues in the small monomeric protein barstar was severely perturbed by chemical modification of the two buried cysteine residues with the thiol reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) after prior unfolding of the protein using guanidine hydrochloride (GdnHCl). The modification produces mixed disulfides between 5-thio(2-nitrobenzoic acid) and the two Cys residues. To understand the effects of the modification of the individual cysteine residues, Cys40 and Cys82, the modification was also carried out on the two single Cys --> Ala mutant forms of barstar, C40A and C82A, whose structures, activities, and stabilities were first shown to be similar to those of wt barstar. Equilibrium GdnHCl-induced denaturation studies on wt barstar show that the modification causes the midpoint of the denaturation curve to increase by 0.6 M and the stability to increase by 1.3 kcal mol-1. Both C40A and C82A also denature at higher concentrations of GdnHCl after modification. Modification of Cys40 has approximately the same stabilizing contribution as does modification of Cys82. The structures of the modified and unmodified proteins have been compared using circular dichroism (CD) spectroscopy, UV difference absorption spectroscopy, and fluorescence spectroscopy. It is shown that the 5-thio(2-nitrobenzoic acid) groups introduced by reaction with DTNB are buried in hydrophobic environments in the modified C40A and C82A mutant proteins, as well as in modified wt barstar. The far-UV CD spectra of the modified and unmodified proteins are similar, but the mean residue ellipticity at 220 nm of wt barstar is reduced by 30% upon modification. Such a decrease is not seen for either C40A or C82A. The barnase-inhibiting activities of the three modified proteins are shown to be similar to those of the corresponding unmodified proteins. Thus, the severe perturbations of the internal packing, which result in a significant increase in stability, do not appear to affect the overall fold of barstar.

Bacterial Proteins↗
PubMedDate not supplied

P-Mod: an algorithm and software to map modifications to peptide sequences using tandem MS data.

The discovery of unanticipated protein modifications is one of the most challenging problems in proteomics. Whereas widely used algorithms such as Sequest and Mascot enable mapping of modifications when the mass and amino acid specificity are known, unexpected modifications cannot be identified with these tools. We have developed an algorithm and software called P-Mod, which enables discovery and sequence mapping of modifications to target proteins known to be represented in the analysis or identified by Sequest. P-Mod matches MS/MS spectra to peptide sequences in a search list. For spectra of modified peptides, P-Mod calculates mass differences between search peptide sequences and MS/MS precursors and localizes the mass shift to a sequence position in the peptide. Because modifications are detected as mass shifts, P-Mod does not require the user to guess at masses or sequence locations of modifications. P-Mod uses extreme value statistics to assign p value estimates to sequence-to-spectrum matches. The reported p values are scaled to account for the number of comparisons, so that error rates do not increase with the expanded search lists that result from incorporating potential peptide modifications. Combination of P-Mod searches from multiple LC-MS/MS analyses and multiple samples revealed previously unreported BSA modifications, including a novel decarboxymethylation or D-->G substitution at position 579 of the protein. P-Mod can serve a unique role in the identification of protein modifications both from exogenous and endogenous sources and may be useful for identifying modified protein forms as biomarkers for toxicity and disease processes.

Algorithms↗
PubMed1992

Cellular oxidative modification of low density lipoprotein does not require lipoxygenases.

The oxidative modification of low density lipoprotein (LDL) may play an important role in the pathogenesis of atherosclerosis. LDL can be oxidatively modified in vitro by endothelial cells, mouse peritoneal macrophages, or copper ions. Studies using lipoxygenase inhibitors have suggested that lipoxygenase(s) is required for the cellular modification of LDL [Rankin, S. M., Parthasarathy, S. & Steinberg, D. (1991) J. Lipid Res. 32, 449-456]. We have reexamined the effect of lipoxygenase inhibitors on cellular modification and found that (i) inhibitors specific for 5-lipoxygenase do not block LDL modification; (ii) inhibitors that block lipoxygenase by donating one electron to the enzyme (reductive inactivation) prevent LDL modification by cells and also modification mediated by copper ions, implying that they act as general antioxidants; (iii) the lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid blocks 15-lipoxygenase activity in intact macrophages at concentrations 100 times less than those required to block LDL modification by macrophages; and (iv) 5,8,11,14-eicosatetraynoic acid is cytotoxic at concentrations about twice those required to prevent modification. Furthermore, macrophages and the RECB4 line of endothelial cells modify LDL with similar efficiencies despite dramatic differences in 15-lipoxygenase activity. Thus we conclude that neither 5-lipoxygenase nor 15-lipoxygenase is required for modification of LDL by cultured cells.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2005

The use and impact of assistive devices and other environmental modifications on everyday activities and care in young children with cerebral palsy.

PURPOSE: The study describes use of assistive devices and other environmental modifications, and their impact on everyday activities and care in young children with cerebral palsy (CP). METHOD: Ninety-five children (55 boys, 40 girls; mean age 58 months, SD 18 months) and their parents were studied using a cross-sectional design. The Pediatric Evaluation of Disability Inventory (PEDI) was applied to assess daily activities using the three measurement scales: functional skills, caregiver assistance, and modifications of the environment. Use of modifications was described related to the five severity levels of the Gross Motor Function Classifications System (GMFCS). Impact was rated on the Caregiver Assistance scale of the PEDI and on a five-point Likert scale. RESULTS: Out of the 1075 provided environmental modifications, 980 were in regular use to support mobility, self-care and social function among 84 children. The number increased with GMFCS levels; children at levels IV and V used 80% of the modifications, with large variations between the children at same level. Adaptations of housing and transportation facilitated effective use of assistive devices. Half of the parents rated the modifications to have moderate to very large effect on the child's mobility, 25% on self-care skills, and 20% on social function. Furthermore, 65% reported that the modifications lightened the caregiving for mobility, 75% for self-care and 25% for social function. Functional independence and care demands often benefited from different types of modifications. CONCLUSION: The variations in use and benefits of environmental modifications indicate need of comprehensive assistive technology assessments, including child factors, family factors, technology factors and service system factors.

Activities of Daily Living↗
PubMed2006

A one-carbon modification of protein lysine associated with elevated oxidative stress in human substantia nigra.

We describe for the first time a naturally occurring lysine modification that is converted to methyllysine by reduction with sodium borohydride. This modification is approximately 1.7 times as abundant in soluble proteins from human substantia nigra pars compacta as in proteins from other brain regions, possibly as a result of elevated oxidative stress in the nigra. Proteins from cultured PC12 cells exposed to oxidative stress conditions also contain elevated levels of this lysine modification. The abundance of the naturally occurring modification is roughly 0.08 nmoles/mg protein in either unstressed brain or PC12 cells. Modification levels remain stable in isolated proteins incubated for 2 h at 37 degrees C in pH 7 buffer. We propose that the endogenous modification is the lysine Schiff base, epsilon-N-methylenelysine, and that lysine modifications may result from a reaction with formaldehyde in vivo. Rat brain contains approximately 60 nmoles/g wet weight of formaldehyde, which probably includes both free and reversibly bound forms. Adding approximately 35 microm HCHO to PC12 cell growth medium introduces methylenelysine modifications in cell proteins and impairs cell viability. The existence of this post-translational modification suggests new mechanisms of oxidative stress that may contribute to tissue degeneration, including loss of nigral dopamine neurons during normal aging and in Parkinson's disease.

Aged↗
PubMed2005

Posttranslational protein modification in Archaea.

One of the first hurdles to be negotiated in the postgenomic era involves the description of the entire protein content of the cell, the proteome. Such efforts are presently complicated by the various posttranslational modifications that proteins can experience, including glycosylation, lipid attachment, phosphorylation, methylation, disulfide bond formation, and proteolytic cleavage. Whereas these and other posttranslational protein modifications have been well characterized in Eucarya and Bacteria, posttranslational modification in Archaea has received far less attention. Although archaeal proteins can undergo posttranslational modifications reminiscent of what their eucaryal and bacterial counterparts experience, examination of archaeal posttranslational modification often reveals aspects not previously observed in the other two domains of life. In some cases, posttranslational modification allows a protein to survive the extreme conditions often encountered by Archaea. The various posttranslational modifications experienced by archaeal proteins, the molecular steps leading to these modifications, and the role played by posttranslational modification in Archaea form the focus of this review.

Archaea↗
PubMed2006

Transjugular intrahepatic portosystemic stent shunt (TIPSS) modification in the management of post-TIPSS refractory hepatic encephalopathy.

BACKGROUND: Post-transjugular intrahepatic portosystemic stent shunt (TIPSS) hepatic encephalopathy (HE) can occur in up to one third of patients. In 5%, this can be refractory to optimal medical treatment and may require shunt modification. The efficacy of shunt modification has been poorly studied. AIMS: To evaluate the efficacy of and natural history following TIPSS modification for treatment of refractory HE. METHODS: From a dedicated database, we selected and further studied patients who had TIPSS modification for refractory HE. RESULTS: Over a 14 year period, of 733 TIPSS insertions, 211(29%) patients developed HE post-TIPSS. In 38 patients, shunt modification (reduction (n = 9) and occlusion (n = 29)) was performed for refractory HE. Indications for TIPSS were: variceal bleeding (n = 32), refractory ascites (n = 5), and other (n = 1). Child's grades A, B, and C were noted in 11%, 47%, and 42% of cases, respectively. HE improved in 58% of patients and remained unchanged or worsened in 42%, with similar results for occlusions and reductions. Following shunt modification, variceal bleeding recurred in three patients and ascites in three. Twenty five patients have died (liver related in 15) at a median duration of 10.2 months. Three patients died due to procedure related complications following shunt occlusions (mesenteric infarction (n = 2) and septicaemia (n = 1)). Median survival of patients whose HE did not improve following shunt modification was 79 days compared with 278 days in patients whose did (p<0.05). No variables independently predicted response to shunt modification. CONCLUSIONS: TIPSS modification is a useful option for patients with refractory HE following TIPSS insertion. Due to the significant risk of iatrogenic complications with shunt occlusions, shunt reduction is a safer and preferred option.

Adult↗
PubMed2004

Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins.

BACKGROUND: In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome). In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B) genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function. RESULTS: We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns. CONCLUSIONS: These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.

Cells, Cultured↗