NCCN melanoma practice guidelines. National Comprehensive Cancer Network.
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Humans↗
Biomedical subjects
S Miller
Publications and source records attributed to S Miller.
Bowling related injuries of the hand and upper extremity; a review.
Bowling is one of the oldest and most popular indoor sports. The earliest evidence of bowling dates back to ancient Egypt. Archaeologists discovered equipment for a game resembling bowling. Modern forms of bowling appeared in England as early as the 1100s. Bowling can cause a variety of hand and upper extremity injuries either due to acute or reparative forces. Greater number of such injuries is being encountered as the popularity of the game has increased. The goal of this article is to present an overview of bowling related injuries, their mechanisms along with preventive and treatment measures.
Arm Injuries↗
Spontaneous regression of a herniated disk. A case report with a four year follow-up.
A 32-year-old male was seen with a "large" lumbar disk herniation on a magnetic resonance image. His pain was described as mild and he was treated nonoperatively. Four years later the disk showed almost complete spontaneous regression. No other reports of a longer follow-up MR image interval have been reported in the literature.
Adult↗
Interstrain variation in the deoxynucleotide composition of Cryptococcus neoformans: nucleotide composition of Cryptococcus neoformans.
The deoxynucleotide (dNMP) composition of ten strains of C. neoformans was analysed by 32P-labelling and two-dimensional thin-layer chromatography. This technique is very sensitive for detecting rare deoxynucleotide adducts and analogues (minor bases) in DNA. The results indicate considerable variation among strains in DNA nucleotide composition.
Autoradiography↗
[Surgical therapy of locally confined prostate carcinoma].
Since prostate specific antigen (PSA) has been established as marker for screening, a dramatic increase of prostatic cancer incidence has been observed over the past years. A further consequence of PSA-measurements lies in the observation that nowadays the majority of newly diagnosed prostatic carcinoma is in a clinically localized stage and therefore amendable to radical prostatectomy in a curative intervention. An important task yet to be solved is to find parameters able to estimate the malignant potential of the tumor preoperatively. Long-term results of radical prostatectomy are explained and the possibilities for reduction of intra- and perioperative complications are discussed.
Biomarkers, Tumor↗
Mutations in the glutathione-gated KefC K+ efflux system of Escherichia coli that cause constitutive activation.
The kefC gene of Escherichia coli encodes a potassium efflux system that is gated by glutathione (GSH) and by GSH adducts. Independently isolated kefC mutations that result in spontaneous activation of the efflux system have been analyzed. Three mutations affect residues located adjacent to the conserved Rossman fold in the carboxyl-terminal domain. Two mutations lie in a sequence predicted to form a cytoplasmically located loop in the membrane domain of KefC. All of the mutants retain normal regulation by the YabF protein and by GSH adducts. A mutation in the Rossman fold, R416S, alters the normal regulation of KefC by GSH. In contrast to the wild-type protein, which is inactive in the presence of GSH, the R416S mutant is only active in the presence of GSH or its analogue, ophthalmic acid. Other mutations in this region or elsewhere in the protein have their spontaneous activity augmented by depletion of the GSH pool. These data identify a specific role for the carboxyl-terminal domain of KefC in regulating KefC activity and are discussed in the light of recent data that suggest that GSH adducts can bind within a Rossman fold.
Bacterial Proteins↗
Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease.
Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes. Its catalytic centers, however, are encoded exclusively by two mitochondrial genes, CO1 and CO2 (encoding CO subunits I and II, respectively). We searched these genes, as well as other mitochondrial genes, for mutations that might alter CO activity and cosegregate with AD. In the present study, specific missense mutations in the mitochondrial CO1 and CO2 genes but not the CO3 gene were found to segregate at a higher frequency with AD compared with other neurodegenerative or metabolic diseases. These mutations appear together in the same mitochondrial DNA molecule and define a unique mutant mitochondrial genome. Asymptomatic offspring of AD mothers had higher levels of these mutations than offspring of AD fathers, suggesting that these mutations can be maternally inherited. Cell lines expressing these mutant mitochondrial DNA molecules exhibited a specific decrease in CO activity and increased production of reactive oxygen species. We suggest that specific point mutations in the CO1 and CO2 genes cause the CO defect in AD. A CO defect may represent a primary etiologic event, directly participating in a cascade of events that results in AD.
Aged↗
Phage P22 tailspike protein: crystal structure of the head-binding domain at 2.3 A, fully refined structure of the endorhamnosidase at 1.56 A resolution, and the molecular basis of O-antigen recognition and cleavage.
The tailspike protein of Salmonella phage P22 is a viral adhesion protein with both receptor binding and destroying activities. It recognises the O-antigenic repeating units of cell surface lipopolysaccharide of serogroup A, B and D1 as receptor, but also inactivates its receptor by endoglycosidase (endorhamnosidase) activity. In the final step of bacteriophage P22 assembly six homotrimeric tailspike molecules are non-covalently attached to the DNA injection apparatus, mediated by their N-terminal, head-binding domains. We report the crystal structure of the head-binding domain of P22 tailspike protein at 2.3 A resolution, solved with a recombinant telluromethionine derivative and non-crystallographic symmetry averaging. The trimeric dome-like structure is formed by two perpendicular beta-sheets of five and three strands, respectively in each subunit and caps a three-helix bundle observed in the structure of the C-terminal receptor binding and cleaving fragment, reported here after full refinement at 1.56 A resolution. In the central part of the receptor binding fragment, three parallel beta-helices of 13 complete turns are associated side-by-side, while the three polypeptide strands merge into a single domain towards their C termini, with close interdigitation at the junction to the beta-helix part. Complex structures with receptor fragments from S. typhimurium, S. enteritidis and S. typhi253Ty determined at 1.8 A resolution are described in detail. Insertions into the beta-helix form the O-antigen binding groove, which also harbours the active site residues Asp392, Asp395 and Glu359. In the intact structure of the tailspike protein, head-binding and receptor-binding parts are probably linked by a flexible hinge whose function may be either to deal with shearing forces on the exposed, 150 A long tailspikes or to allow them to bend during the infection process.
Amino Acid Sequence↗
Equatorial X-ray Emissions: Implications for Jupiter's High Exospheric Temperatures
Observations with the High Resolution Imager on the Rontgensatellit reveal x-ray emissions from Jupiter's equatorial latitudes. The observed emissions probably result from the precipitation of energetic (>300 kiloelectron volts per atomic mass unit) sulfur and oxygen ions out of Jupiter's inner radiation belt. Model calculations of the energy deposition by such heavy ion precipitation and of the resulting atmospheric heating rates indicate that this energy source can contribute to the high exospheric temperatures(>800 kelvin at 0.01 microbar) measured by the Galileo probe's Atmospheric Structure Instrument. Low-latitude energetic particle precipitation must therefore be considered, in addition to other proposed mechanisms such as gravity waves and soft electron precipitation, as an important source of heat for Jupiter's thermosphere.
Journal Article↗
A DNA polymerase alpha accessory protein exhibits structural and functional similarities to SV40 large tumor antigen.
Untransformed cells have been proposed to require a protein homologous to SV40 large tumor antigen (TAg) which functions as a component of the replicase complex during the initiation of DNA synthesis. By definition, this should be a phosphoprotein which interacts with the retinoblastoma protein (pRb) in G0 or early G1, and is capable of binding to and potentiating the activity of DNA polymerase alpha (pol alpha). This protein should also be an ATP-dependent helicase which interacts with the single-stranded DNA (ssDNA) binding protein, RP-A. Because of these requirements, a TAg homologous protein could be expected to contain epitopes with amino acid sequences similar to those of TAg at critical functional sites, such as ATP, pRb and pol alpha binding sites. TAg and a putative cellular homolog of TAg, DNA pol alpha accessory protein (alpha AP), were compared for pRb and pol alpha interaction, and for immunological identity. The analyses utilized immunoaffinity-purified TAg and pRb from a baculovirus expression system, and DNA pol alpha/primase and alpha AP chromatographically isolated from a mouse lymphocytic leukemia cell line. Monoclonal antibodies specific for the pol alpha or pRb binding sites on TAg interacted with alpha AP strongly enough to be employed for immunoaffinity purification of alpha AP. Anti-pRb and anti-TAg reciprocally coimmunoprecipitated pRb bound to TAg and pRb bound to alpha AP. The functional consequences of pol alpha interaction with TAg or alpha AP in the presence or absence of pRb was determined using pol alpha nucleotide incorporation assays. alpha AP exhibited the capacity to stimulate pol alpha activity, a capacity which was diminished in the presence of pRb. Lastly, TAg and alpha AP independently co-purified with pol alpha through a multi-step chromatographic protocol. These data indicate that a pol alpha accessory protein, alpha AP, exhibits functional and immunological similarities to SV40 TAg, suggest that alpha AP is involved in regulation of the initiation of DNA synthesis, and support the proposal that alpha AP may be a normal cell protein homologous to SV40 large T antigen.
Animals↗
Semen quality and fertility of men employed in a South African lead acid battery plant.
Previous studies of the associations of measures of occupational lead exposure with measures of semen quality and infertility among male workers have produced conflicting results. The current study was undertaken to examine these associations among a population of workers with a broad range of measures of current and historical lead exposure. Ninety-seven lead-exposed workers from a South African lead acid battery facility provided semen samples that were analyzed for sperm density, sperm count, sperm motility, sperm morphology, and presence of antisperm antibodies. Questionnaire data were collected for reported histories of sub- or infertility. Current blood leads ranged from 28 to 93 micrograms/dl. Semen lead ranged from 1 to 87 micrograms/dl. Reasonably consistent and significant associations were found between an increased percentage of sperm with abnormal morphology and higher measures of current blood lead, cumulative blood lead, and duration of exposure. An increased percent of immotile sperm was associated only with zinc protoporphyrin (ZPP) among the lead exposure measures. There were no associations of sperm density or sperm count with any of the lead exposure measures. A weak association of increased percent of sperm with antisperm antibodies with increased semen lead was present. There were no consistent associations of measures of lead exposure with measures of fertility or procreativity. This study, while supporting the association of lead exposure with increased risk of abnormal sperm morphology seen in some previous studies, does not lend support to previously reported associations of sperm density or count or infertility with measures of lead exposure. However, the relatively high range of current blood leads, high prevalence of abnormalities in semen quality, and the lack of a control population, suggest that these negative findings should be interpreted with caution.
Cross-Sectional Studies↗
A highly polymorphic microsatellite marker in the human MHC class III region, close to the BAT2 gene.
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Chromosome Mapping↗
Heparan sulfate potentiates the autocrine action of basic fibroblast growth factor in astrocytes: an in vivo and in vitro study.
Increasing evidence indicates that heparan sulfate proteoglycans have a critical role in the regulation of the activity of basic fibroblast growth factor by interacting with it or its receptor. In this study we examined the possibility that heparan sulfate can modulate the basic fibroblast growth factor system at a more fundamental level than activity regulation, by influencing the synthesis of basic fibroblast growth factor and its receptor messenger RNAs. Previous studies in vitro indicate that basic fibroblast growth factor promotes proliferation and differentiation of astrocytes. Accordingly, we examined the possibility that the action of heparan sulfate on the basic fibroblast growth factor system could have a critical role in the modulation of reactivity and/or proliferation of astrocytes in vitro and in vivo. We report that basic fibroblast growth factor applied to pure astrocyte cultures or rat neocortex promoted an increase in the messenger RNA for basic fibroblast growth factor itself and for its receptor. Furthermore, basic fibroblast growth factor applied directly into the brain elicited an increase in messenger RNA for the astrocytic marker glial fibrillary acidic protein. All of these actions, both in vitro and in vivo, were highly potentiated when heparan sulfate was applied in combination with basic fibroblast growth factor. These results suggest that basic fibroblast growth factor regulates astrocytic proliferation or reactivity via an autocrine cascade that involves induction of its own receptor and that this action is modulated by heparan sulfate.
Animals↗
Adverse effects of low dose amiodarone: a meta-analysis.
OBJECTIVES: We sought to assess the odds of experiencing adverse effects with low dose amiodarone therapy compared with placebo. BACKGROUND: An estimate of the likelihood of experiencing amiodarone-related adverse effects with exposure to low daily doses of the drug is lacking in the published reports, and little information is available on adverse effect event rates in control groups not receiving the drug. METHODS: Data from four published trials involving 1,465 patients were included in a meta-analysis design. The criteria for inclusion were 1) double-blind, placebo-controlled design; 2) absence of a crossover design between patient groups; 3) mean follow-up of at least 12 months; 4) maintenance amiodarone dose < or = 400 mg/day; and 5) presence of an explicit description of adverse effects. Data were pooled after testing for homogeneity of treatment effects across trials, and summary odds ratios were calculated by the Peto-modified Mantel-Haenszel method for each adverse effect. RESULTS: The mean amiodarone dose per day ranged from 152 to 330 mg; 738 patients were randomized to receive amiodarone and 727 placebo. Exposure to amiodarone in this dose range, for a minimal duration of 12 months, resulted in odds similar to those of placebo for hepatic and gastrointestinal adverse effects, but in significantly higher odds than those of placebo (p < 0.05) for experiencing thyroid (odds ratio [OR] 4.2, 95% confidence interval [CI] 2.0 to 8.7), neurologic (OR 2.0, 95% CI 1.1 to 3.7), skin (OR 2.5, 95% CI 1.1 to 6.2), ocular (OR 3.4, 95% CI 1.2 to 9.6) and bradycardic (OR 2.2, 95% CI 1.1 to 4.3) adverse effects. A trend toward increased odds of pulmonary toxicity was noted (OR 2.0, 95% CI 0.9 to 5.3), but this did not reach statistical significance (p = 0.07). The unadjusted total incidence of drug discontinuation was 22.9% in the amiodarone group and 15.4% in the placebo group. The odds of discontinuing the drug in the amiodarone group was approximately 1.5 times that of the placebo group (OR 1.52, 95% CI 1.2 to 1.9) (p = 0.003). CONCLUSIONS: Compared with placebo, there is a higher likelihood of experiencing several amiodarone-related adverse effects with exposure to low daily doses of the drug. Thus, although low dose amiodarone may be well tolerated, it is not free of adverse effects.
Amiodarone↗
Myelin proteolipid DM20: evidence for function independent of myelination.
DM20 is a proteolipid protein that has been extensively studied for its role in central nervous system myelination. We demonstrate that DM20 expression is widespread and independent of myelination. In the Schwann cells and neurons of the peripheral nervous system, DM20 is not incorporated into the membrane as it is in the central nervous system (CNS), but remains cytoplasmic. Mutations that severely reduce the amount of DM20 mRNA in CNS myelinating cells have little effect on DM20 expression in nonmyelinating cells of the peripheral nervous system and embryonic CNS. Most importantly, the combination of wild-type DM20 from the endogenous X-linked gene and mutant DM20 expressed from an autosomal transgene results in embryonic lethality. We propose a function for DM20 to explain these diverse findings based on the ability of DM20 to form multimeric complexes, and hypothesize that the DM20 complex participates in intracellular molecular transport.
Animals↗
Alpha interferon gene deletions in post-transplant lymphoma.
Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplant and has been associated with high mortality using conventional chemotherapy. We have investigated 11 cases of PTLD for alterations to the interferon alpha (IFNA) and p16 genes on chromosome 9p using archival material. 4/9 (44%) cases had deletions of the IFNA genes, in contrast to 1/59 (1.7%) cases of intermediate/high-grade de novo NHL drawn from the same geographical region. PTLD may therefore represent a distinct NHL subgroup exhibiting distinct gene pathology.
Chromosomes, Human, Pair 9↗
Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacological properties and agonist regulation.
Metabotropic glutamate receptor (mGluR) agonists induce extensive phosphoinositide (PI) hydrolysis in astrocytes grown in a chemically defined medium with select growth factors. These astrocytes express mGluR5 transcripts, but none of the splice variants of mGluR1, thus permitting the characterization of mGluR5 in a native CNS cell without interference from mGluR1 activity. mGluR5 activation (1) was not associated with stimulation of cyclic AMP formation, (2) showed high sensitivity to the removal of extracellular versus intracellular Ca2+, (3) displayed high coupling efficiency relative to receptor density, and (4) induced PI hydrolysis that was suppressed by phorbol esters with low potency. The rank order of agonist potency was similar to that observed in mGluR1 and mGluR5 transfected cells. The phenylglycine antagonists tested were effective in blocking responses to 1-aminocyclopentane-1S,3R-dicarboxylic acid, but not to glutamate. Prolonged exposure to agonists induced a two-phase desensitization of mGluR5 function, an initial phase (completed by 1 h and plateaus for another 3 h) and a late phase (progressive decrease to approximately 30% of control levels by 24 h). Only the latter phase was associated with receptor down-regulation. Desensitization of mGluR5 function did not involve receptor internalization or phosphorylation mediated by protein kinase C or A; it was purely homologous, and reversible. Resensitization after short agonist treatment did not require prior receptor sequestration. Recovery after prolonged agonist exposure required new protein synthesis, but the restoration of function was more rapid than normalization of receptor protein levels, indicating that regulation also involves other components of the transduction system. The protracted desensitization of mGluR5 in astrocytes suggests that the functions mediated by this receptor are maintained under a variety of conditions ranging from repetitive stimulation to injury responses.
Animals↗
[MR tomography studies of myocardial function and perfusion after myocardial infarct].
PURPOSE: With the advent of fast pulse sequences, MR imaging of myocardial function and perfusion in ischaemic heart disease has become possible. Prior studies examined either myocardial perfusion or systolic wall motion. We intended to establish an examination procedure to simultaneously investigate regional myocardial motility and perfusion in patients 7-14 days after myocardial infarction. METHODS: A Turbo-FLASH 2D sequence was optimised to maximise image contrast between normal and malperfused myocardium after Gd-injection using a calculation model basing on the Bloch equation. Calculated values for trigger delay TD, inversion time TI and flip angle alpha were confirmed in a Gd-phantom and healthy volunteers. Subsequently, myocardial motility was studied (cine FLASH 2D sequence) and in slice positions with reduced wall thickening first pass and post contrast studies after 2-10 minutes were performed using the optimised Turbo-FLASH sequence. RESULTS: First pass SI-differences of normal compared to malperfused myocardium vary in relation to TD, TI and alpha in a relevant degree. Reduced myocardial motility was found with a sensitivity of 81% and specificity of 96%. Pathological perfusion patterns were detectable in all of these patients. CONCLUSIONS: A combined examination of motility and perfusion is possible by means of MRI and information about the status of postinfarct myocardium can be obtained.
Adult↗