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Biomedical subjects

Robert Schneider

Publications and source records attributed to Robert Schneider.

At least 19 recordsLinked to original sources

Tumor-induced osteomalacia.

Tumor-induced osteomalacia, also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome in which vitamin D resistant osteomalacia occurs due to the presence of a tumor. The following case report describes a young woman who seeks a second opinion from a rheumatologist and is found to have oncogenic osteomalacia. Not often discussed in the rheumatology literature, oncogenic osteomalacia is a rare and interesting disease entity in which diagnosis is often more challenging than treatment.

Adult↗

14-3-3sigma is a p37 AUF1-binding protein that facilitates AUF1 transport and AU-rich mRNA decay.

Short-lived cytokine mRNAs contain an AU-rich destabilizing element (ARE). AUF1 proteins bind the ARE, undergo shuttling, and promote cytoplasmic ARE-mRNA decay through a poorly understood mechanism. We therefore identified AUF1-interacting proteins that may play a role in ARE-mRNA decay. We used mass-spectrometry to identify 14-3-3sigma protein as an AUF1-interacting protein. 14-3-3sigma binds selectively and strongly to p37 AUF1 and to a lesser extent to the p40 isoform, the two isoforms most strongly associated with ARE-mRNA decay, but not to the two larger isoforms, p42 and p45. The 14-3-3sigma interaction site on p37 was mapped to a region found only in the two smaller AUF1 isoforms and which overlaps a putative nuclear localization signal (NLS). Stable overexpression of 14-3-3sigma significantly increased cytoplasmic accumulation of p37 AUF1 and reduced the steady-state level and half-life of a reporter ARE-mRNA. siRNA silencing of AUF1 eliminated the effect of 14-3-3sigma overexpression. 14-3-3sigma therefore binds to p37 AUF1, retains it in the cytoplasm probably by masking its NLS, and enhances rapid turnover of ARE-mRNAs.

14-3-3 Proteins↗

Discordantly high spinal bone mineral density values in patients with adult lumbar scoliosis.

STUDY DESIGN: Retrospective study. OBJECTIVE: The purposes of this study were: 1) to investigate the validity of bone mineral density measurements with DEXA in patients with adult lumbar scoliosis and 2) to investigate the association between osteoporosis and adult lumbar scoliosis. SUMMARY OF BACKGROUND DATA: Osteoporosis and lumbar degenerative scoliosis are phenomena encountered with increased frequency in aging, often concurrently. It has been suggested that scoliosis predisposes to osteoporosis, but degenerative scoliosis could falsely elevate spinal bone mineral density measurements. METHODS: The feasibility of measuring Cobb's angle in DEXA scans was established in 48 surgical candidates with standing anteroposterior lumbar radiographs and supine DEXA scans. Charts and radiographs of 454 consecutive adult patients evaluated at an osteoporosis center were reviewed thereafter. The association between age, lumbar curve, and various bone density measurements was investigated. Bone density measurements between nonscoliotic and scoliotic patients with and without a history of adolescent scoliosis were compared. RESULTS: Cobb's angle on DEXA scan was measured with an error of 4 degrees and correlated highly with the plain lumbar radiographs. The prevalence of scoliosis was 9.47% in this cohort of patients. Advancing age was associated with an increase in osteoporosis in both scoliotic and nonscoliotic patients. Scoliotic patients demonstrated increased spinal bone mineral density (BMD) measurements compared with nonscoliotic patients, resulting in discrepancies between hip and spine BMD values. This discrepancy correlated with aging and curve magnitude (up to 30% for curves of 43 degrees ). Scoliotic patients demonstrated significantly lower hip BMD values than nonscoliotic. Curve magnitude did not correlate with severity of osteoporosis. CONCLUSIONS: Cobb's angle measurements on DEXA scans are reliable and comparable to conventional radiographs. Spinal BMD values are less valuable for monitoring osteoporosis than hip values in scoliotic patients; an increasing discrepancy with age was noted. Scoliotic patients exhibited discordantly high spinal BMD values, despite significant hip osteoporosis. The discrepancy correlated with aging and curve magnitude. Scoliosis was common among the osteoporotic population (9.47%). Lumbar scoliosis is a useful clinical marker for osteoporosis, irrespective of scoliosis history and magnitude. Viable alternatives for osteoporosis evaluation of adult patients with lumbar scoliosis are hip DEXA values, in conjunction with other BMD measurements.

Absorptiometry, Photon↗

Effects of a randomized controlled trial of transcendental meditation on components of the metabolic syndrome in subjects with coronary heart disease.

BACKGROUND: The metabolic syndrome is thought to be a contributor to coronary heart disease (CHD), and components of the syndrome have been identified as possible therapeutic targets. Previous data implicate neurohumoral activation related to psychosocial stress as a contributor to the metabolic syndrome. The aim of this study was to evaluate the efficacy of transcendental meditation (TM) on components of the metabolic syndrome and CHD. METHODS: We conducted a randomized, placebo-controlled clinical trial of 16 weeks of TM or active control treatment (health education), matched for frequency and time, at an academic medical center in a total of 103 subjects with stable CHD. Main outcome measures included blood pressure, lipoprotein profile, and insulin resistance determined by homeostasis model assessment (calculated as follows: [(fasting plasma glucose level [in milligrams per deciliter] x fasting plasma insulin level [in microunits per milliliter]) x 0.0552]/22.5); endothelial function measured by brachial artery reactivity testing; and cardiac autonomic system activity measured by heart rate variability. RESULTS: The TM group had beneficial changes (measured as mean +/- SD) in adjusted systolic blood pressure (-3.4 +/- 2.0 vs 2.8 +/- 2.1 mm Hg; P = .04), insulin resistance (-0.75 +/- 2.04 vs 0.52 +/- 2.84; P = .01), and heart rate variability (0.10 +/- 0.17 vs -0.50 +/- 0.17 high-frequency power; P = .07) compared with the health education group, respectively. There was no effect of brachial artery reactivity testing. CONCLUSIONS: Use of TM for 16 weeks in CHD patients improved blood pressure and insulin resistance components of the metabolic syndrome as well as cardiac autonomic nervous system tone compared with a control group receiving health education. These results suggest that TM may modulate the physiological response to stress and improve CHD risk factors, which may be a novel therapeutic target for the treatment of CHD.

Aged↗

Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells.

Blimp1, a transcriptional repressor, has a crucial role in the specification of primordial germ cells (PGCs) in mice at embryonic day 7.5 (E7.5). This SET-PR domain protein can form complexes with various chromatin modifiers in a context-dependent manner. Here, we show that Blimp1 has a novel interaction with Prmt5, an arginine-specific histone methyltransferase, which mediates symmetrical dimethylation of arginine 3 on histone H2A and/or H4 tails (H2A/H4R3me2s). Prmt5 has been shown to associate with Tudor, a component of germ plasm in Drosophila melanogaster. Blimp1-Prmt5 colocalization results in high levels of H2A/H4 R3 methylation in PGCs at E8.5. However, at E11.5, Blimp1-Prmt5 translocates from the nucleus to the cytoplasm, resulting in the loss of H2A/H4 R3 methylation at the time of extensive epigenetic reprogramming of germ cells. Subsequently, Dhx38, a putative target of the Blimp1-Prmt5 complex, is upregulated. Interestingly, expression of Dhx38 is also seen in pluripotent embryonic germ cells that are derived from PGCs when Blimp1 expression is lost. Our study demonstrates that Blimp1 is involved in a novel transcriptional regulatory complex in the mouse germ-cell lineage.

Active Transport, Cell Nucleus↗

Use of an absorbable membrane to position biologically inductive materials in the periprosthetic space of cemented joints.

A device is presented that positions ultrahigh molecular weight polyethylene (UHMWPE) debris against periprosthetic bone surfaces. This can facilitate the study of aseptic loosening associated with cemented joint prostheses by speeding the appearance of this debris within the periprosthetic space. The device, composed of a 100 microm thick bioabsorbable membrane impregnated with 1.4 x 10(9) sub-micron particles of UHMWPE debris, is positioned on the endosteum of the bone prior to the insertion of the cemented orthopedic implant. An in vitro pullout study and an in vivo canine pilot study were performed to investigate its potential to accelerate "time to aseptic loosening" of cemented prosthetic joints. Pullout studies characterized the influence of the membrane on initial implant fixation. The tensile stresses (mean+/-std.dev.) required to withdraw a prosthesis cemented into canine femurs with and without the membrane were 1.15+/-0.3 and 1.54+/-0.01 MPa, respectively; these findings were not significantly different (p > 0.4). The in vivo pilot study, involving five dogs, was performed to evaluate the efficacy of the debris to accelerate loosening in a canine cemented hip arthroplasty. Aseptic loosening and lameness occurred within 12 months, quicker than the 30 months reported in a retrospective clinical review of canine hip arthroplasty.

Absorbable Implants↗

A 3-year study of addiction mutual-help group participation following intensive outpatient treatment.

BACKGROUND: Addiction-focused mutual-help group participation is associated with better substance use disorder (SUD) treatment outcomes. However, little has been documented regarding which types of mutual-help organizations patients attend, what levels of participation may be beneficial, and which patients, in particular, are more or less likely to participate. Furthermore, much of the evidence supporting the use of these organizations comes from studies examining participation and outcomes concurrently, raising doubts about cause-effect connections, and little is known about influences that may moderate the degree of any general benefit. METHOD: Alcohol-dependent outpatients (N=227; 27% female; M age=42) enrolled in a randomized-controlled telephone case monitoring trial were assessed at treatment intake and at 1, 2, and 3 years postdischarge. Lagged-panel, hierarchical linear models tested whether mutual-help group participation in the first and second year following treatment predicted subsequent outcomes and whether these effects were moderated by gender, concurrent axis I diagnosis, religious preference, and prior mutual-help experience. Robust regression curve analysis was used to examine dose-response relationships between mutual-help and outcomes. RESULTS: Mutual-help participation was associated with both greater abstinence and fewer drinks per drinking day and this relationship was not found to be influenced by gender, Axis I diagnosis, religious preference, or prior mutual-help participation. Mutual-help participants attended predominantly Alcoholics Anonymous and tended to be Caucasian, be more educated, have prior mutual-help experience, and have more severe alcohol involvement. Dose-response curve analyses suggested that even small amounts of participation may be helpful in increasing abstinence, whereas higher doses may be needed to reduce relapse intensity. CONCLUSIONS: Use of mutual-help groups following intensive outpatient SUD treatment appears to be beneficial for many different types of patients and even modest levels of participation may be helpful. Future emphasis should be placed on ways to engage individuals with these cost-effective resources over time and to gather and disseminate evidence regarding additional mutual-help organizations.

Adult↗

Occlusion.

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Dental Occlusion↗

HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding.

Histone lysine methylation can have positive or negative effects on transcription, depending on the precise methylation site. According to the "histone code" hypothesis these methylation marks can be read by proteins that bind them specifically and then regulate downstream events. Hetero-chromatin protein 1 (HP1), an essential component of heterochromatin, binds specifically to methylated Lys(9) of histone H3 (K9/H3). The linker histone H1.4 is methylated on Lys(26) (K26/H1.4), but the role of this methylation in downstream events remains unknown. Here we identify HP1 as a protein specifically recognizing and binding to methylated K26/H1.4. We demonstrate that the Chromo domain of HP1 is mediating this binding and that phosphorylation of Ser(27) on H1.4 (S27/H1.4) prevents HP1 from binding. We suggest that methylation of K26/H1.4 could have a role in tethering HP1 to chromatin and that this could also explain how HP1 is targeted to those regions of chromatin where it does not colocalize with methylated K9/H3. Our results provide the first experimental evidence for a "phospho switch" model in which neighboring phosphorylation reverts the effect of histone lysine methylation.

Animals↗

LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

Androgens↗

Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons.

BACKGROUND: Over 85% of pediatric orbital rhabdomyosarcoma (RMS) are cured with combined chemotherapy and radiation. However, the late effects of photon radiation compromise function and cosmetic outcome. Proton radiation can provide excellent tumor dose distributions while sparing normal tissues better than photon irradiation. METHODS AND MATERIALS: Conformal 3D photon and proton radiotherapy plans were generated for children treated with proton irradiation for orbital RMS at Massachusetts General Hospital. Dose-volume histograms (90%, 50%, 10%) were generated and compared for important orbital and central nervous system structures. Average percentages of total dose prescribed were calculated based on the 3 dose-volume histogram levels for normal orbital structures for both the proton and photon plans. The percent of normal tissue spared by using protons was calculated. RESULTS: Seven children were treated for orbital rhabdomyosarcoma with proton irradiation and standard chemotherapy. The median follow-up is 6.3 years (range, 3.5-9.7 years). Local and distant controls compare favorably to those in other published accounts. There was an advantage in limiting the dose to the brain, pituitary, hypothalamus, temporal lobes, and ipsilateral and contralateral orbital structures. Tumor size and location affect the degree of sparing of normal structures. CONCLUSIONS: Fractionated proton radiotherapy is superior to 3D conformal photon radiation in the treatment of orbital RMS. Proton therapy maintains excellent tumor coverage while reducing the radiation dose to adjacent normal structures. Proton radiation therapy minimizes long-term side effects.

Brain↗

Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes.

Methylation of lysine 4 of histone H3 (K4/H3) is linked to transcriptional activity, whereas methylation of K9/H3 is tightly associated with gene inactivity. These are well characterized sites of methylation within histones, but there are numerous other, less characterized, sites of modification. In Saccharomyces cerevisiae, methylation of K36/H3 has been linked to active genes, but little is known about this methylation in higher eukaryotes. Here we analyzed for the first time the levels and spatial distribution of di- and tri-methyl (di- and tri-Me) K36/H3 in metazoan genes. We analyzed chicken genes that are developmentally regulated, constitutively active, or inactive. We found that active genes contain high levels of these modifications compared with inactive genes. Furthermore, in actively transcribed regions the levels of di- and tri-Me K36/H3 peak toward the 3' end of the gene. This is in striking contrast to the distributions of di- and tri-Me K4/H3, which peak early in actively transcribed regions. Thus, di/tri-Me K4/H3 and di/tri-Me K36/H3 are both useful markers of active genes, but their genic distribution indicates differing roles. Our data suggest that the unique spatial distribution of di- and tri-Me K36/H3 plays a role in transcriptional termination and/or early RNA processing.

Animals↗

Low bone mineral density in adolescents with beta-thalassemia.

The pervasiveness of low bone mass (LBM) in beta-thalassemia (Thal) patients (pts) is escalating as the average life expectancy of these pts increases. Adolescence is a period of substantial bone accrual, which is crucial for future bone strength. Studies of LBM are prevalent among adults with Thal. However, limited information exists about bone accrual and LBM in adolescents with the disease. Thirty-one pts with beta-Thal (26 Thal major [TM], 5 Thal intermedia [TI]), aged 9-20 years (mean: 15.3 years), 14 males and 17 females, underwent measurement of spinal bone mineral density (BMD) by DEXA (Lunar, Prodigy). Height, weight, body mass index, and Tanner stage were assessed at the time of the BMD measurement. A total of 16.1% of the patients had normal bone mass (Z > or = -1), 22.6% had reduced bone mass (Z = -1 to -2), and 61.3% had low bone mass (Z < or = -2). BMD Z correlated with height and weight Z scores. Some 53.9% of subjects had normal gonadal function and 46.1% had induced puberty with gonadal steroids. BMD Z significantly worsened with age (P < .0001). However, there was no difference in the LBM prevalence between subjects with normal versus those with induced puberty: BMD Z was -2 or less in 71.4% of subjects with normal puberty versus 66.7% in those with induced puberty. Our results indicate a high prevalence of LBM among adolescents with Thal regardless of adequate transfusion and chelation regimens. Bone accrual was found to be suboptimal in adolescents with normal or induced puberty. Thus, calcium and vitamin D supplementation with antiresorptive therapies should be evaluated in the adolescent Thal pt with close monitoring of growth and sexual development.

Adolescent↗

Histone deimination antagonizes arginine methylation.

Methylation of arginine residues within histone H3 has been linked to active transcription. This modification appears on the estrogen-regulated pS2 promoter when the CARM1 methyltransferase is recruited during transcriptional activation. Here we describe a process, deimination, that converts histone arginine to citrulline and antagonizes arginine methylation. We show that peptidyl arginine deiminase 4 (PADI4) specifically deiminates, arginine residues R2, R8, R17, and R26 in the H3 tail. Deimination by PADI4 prevents arginine methylation by CARM1. Dimethylation of arginines prevents deimination by PADI4 although monomethylation still allows deimination to take place. In vivo targeting experiments on an endogenous promoter demonstrate that PADI4 can repress hormone receptor-mediated gene induction. Consistent with a repressive role for PADI4, this enzyme is recruited to the pS2 promoter following hormone induction when the gene is transcriptionally downregulated. The recruitment of PADI4 coincides with deimination of the histone H3 N-terminal tail. These results define deimination as a novel mechanism for antagonizing the transcriptional induction mediated by arginine methylation.

Arginine↗

Direct binding of INHAT to H3 tails disrupted by modifications.

The N-terminal tails of histones are central to the regulation of chromatin structure. They form a binding platform for multiple protein complexes, which in turn regulate DNA processes such as transcription. Using peptide mass fingerprinting we identified INHAT (inhibitor of acetyltransferases) as a specific histone H3 N-terminal tail-binding complex. INHAT comprises two essential subunits, SET and pp32. We demonstrate that both SET and pp32 bind directly to the N terminus of H3. The binding is differentially affected by various modifications within the H3 N terminus. In particular, single phosphorylations within the H3 tail abrogates binding of INHAT, as does the simultaneous acetylation of multiple lysine residues. The histone modifications that affect INHAT binding are therefore compatible with its known role in transcriptional repression. We suggest that the charge of the histone tail is a major determinant in allowing INHAT to bind chromatin and coordinate the activity of multiple histone acetyltransferases.

Acetyltransferases↗

Comparison of the dimensional accuracy of injection-molded denture base materials to that of conventional pressure-pack acrylic resin.

PURPOSE: This study compared the linear dimensional changes of 3 injection-molded denture base materials to that of conventionally processed polymethylmethacrylate (PMMA) resin. MATERIALS AND METHODS: An impression of an aluminum maxillary edentulous arch was made with a condensation silicone impression material (Denture Elasticon) to fabricate a gypsum master cast that was replicated as a silicone mold. A maxillary complete denture with acrylic teeth was waxed to full contour on the master cast and replicated to make 40 wax dentures. ERA attachments cast in metal (Rexillium) with indices milled into the centers were waxed into 3 positions in each denture for recording dimensional measurements of the wax denture. Ten dentures were allocated to each of 4 groups; Group 1 was processed using conventionally processed PMMA (Microlon), Group 2 used injection-molded PMMA (SR-lvocap), Group 3 employed injection-molded nylon (Valplast), and Group 4 used injection-molded styrene (Northern). All processed specimens were stored at room temperature (25 degrees C, ambient humidity) for 1 week (while still on the master cast) before anteroposterior and cross-arch measurements were made using the ERA reference points with a digital caliper. After separation from the master cast and following water storage at 37 degrees C for 7 days additional measurements were made. RESULTS: An analysis of the results showed that the effect of processing was not the same for the 3 dimensions studied, regardless of which dimension was considered (p < 0.0001). The pattern of dimensional changes associated with the material type was not the same between the wax and processing stages as it was for the change between the processing and decasting stages (p < 0.0001). CONCLUSIONS: Processing the denture base materials produced unequal deformation in different dimensions (anterior-posterior and cross-arch). Each material tested also responded differently to the processing stages.

Acrylic Resins↗

Low bone mass in prepubertal children with thalassemia major: insights into the pathogenesis of low bone mass in thalassemia.

OBJECTIVE: Low bone mass occurs frequently in the aging thalassemic population. However, limited information exists on bone mass in children with thalassemia major (TM) during their first decade of life. STUDY DESIGN: Spinal bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) in 18 children (age 5.8 +/- 1.5 yr; M:F 8:10) with TM on hypertransfusion and iron chelation therapy. Serial BMD measurements were available for 11 of the 18 children. RESULTS: Weight and height z scores were 0.81 +/- 4.2 and -0.47 +/- 1.7 respectively. At the first BMD, four (22.2%) patients presented with BMD z scores less than -2.5, seven (38.8%) had BMD z scores between -1 and -2.5, while the remaining seven (38.8%) had normal BMDs (z score above -1). The mean decline of BMD z score was -0.38/year (p = ns). BMD z scores correlated with height z scores (p = 0.039), but not with liver enzymes, serum ferritin levels, or thalassemia genotypes. CONCLUSIONS: Low bone mass is present in most children with TM despite hypertransfusion and optimal chelation, adequate growth and lack of endocrine complications.

Blood Transfusion↗