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PubMed2001

The benefits of multibit chaotic sigma delta modulation.

Sigma delta modulation is a popular technique for high-resolution analog-to-digital conversion and digital-to-analog conversion. We investigate chaotic phenomena in multibit first-order sigma-delta modulators. Particular attention is placed on the occurrence of periodic orbits or limit cycles. These may result in idle tones audible to the listener when sigma-delta modulation is used for audio signal processing. One suggested method of eliminating idle tones is the operation of a sigma delta modulator in the chaotic regime. Unfortunately, chaotic modulation of a first order sigma delta modulator is a poor system for signal processing. We show that minor variations on a traditional first order sigma-delta modulator, together with a multibit implementation, may be used to produce an effective, stable chaotic modulator that accurately encodes the input and helps remove the presence of idle tones. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed2005

Circadian modulation of complex learning in diurnal and nocturnal Aplysia.

Understanding modulation of memory, as well as the mechanisms underlying memory formation, has become a key issue in neuroscience research. Previously, we found that the formation of long-term, but not short-term, memory for a nonassociative form of learning, sensitization, was modulated by the circadian clock in the diurnal Aplysia californica. To define the scope of circadian modulation of memory, we examined an associative operant learning paradigm, learning that food is inedible (LFI). Significantly greater long-term memory of LFI occurred when A. californica were trained and tested during the subjective day, compared with animals trained and tested in the subjective night. In contrast, animals displayed similar levels of short-term memory for LFI when trained in either the subjective day or night. Circadian modulation of long-term memory for LFI was dependent on the time of training, rather than the time of testing. To broaden our investigation of circadian modulation of memory, we extended our studies to a nocturnal species, Aplysia fasciata. Contrary to the significant memory observed during the day with the diurnal A. californica, A. fasciata showed no long-term memory for LFI when trained during the day. However, A. fasciata demonstrated significant long-term memory when trained and tested during the night. Thus, the circadian clock modulates memory formation in phase with the animals' activity period. The results from our studies of circadian modulation of long-term sensitization and LFI suggest that circadian modulation of memory formation may be a general phenomenon with potentially widespread implications for many types of long-term learning.

Animals↗
PubMed2005

An evolutionary constraint: strongly disfavored class of change in DNA sequence during divergence of cis-regulatory modules.

The DNA of functional cis-regulatory modules displays extensive sequence conservation in comparisons of genomes from modestly distant species. Patches of sequence that are several hundred base pairs in length within these modules are often seen to be 80-95% identical, although the flanking sequence cannot even be aligned. However, it is unlikely that base pairs located between the transcription factor target sites of cis-regulatory modules have sequence-dependent function, and the mechanism that constrains evolutionary change within cis-regulatory modules is incompletely understood. We chose five functionally characterized cis-regulatory modules from the Strongylocentrotus purpuratus (sea urchin) genome and obtained orthologous regulatory and flanking sequences from a bacterial artificial chromosome genome library of a congener, Strongylocentrotus franciscanus. As expected, single-nucleotide substitutions and small indels occur freely at many positions within the regulatory modules of these two species, as they do outside the regulatory modules. However, large indels (>20 bp) are statistically almost absent within the regulatory modules, although they are common in flanking intergenic or intronic sequence. The result helps to explain the patterns of evolutionary sequence divergence characteristic of cis-regulatory DNA.

Animals↗
PubMed1989

Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

We have shown previously that reserpine is an effective "modulator" of P-glycoprotein-associated multidrug resistance (MDR). In addition to enhancing drug cytotoxicity in our multidrug-resistant human leukemia cell line, CEM/VLB100, reserpine strongly competes with a photoactivatible analog of vinblastine, N-(p-azido-3-[125I]iodosalicyl)-N'-(beta-aminoethyl)vindesine, for binding to P-glycoprotein. We also demonstrated previously that there are three substructural domains present in many compounds that modulate P-glycoprotein-associated MDR: a basic nitrogen atom and two planar aromatic rings. In the present study, we wished to test more rigorously the hypothesis that not only are these domains necessary for modulators of MDR but also they must exist in an appropriate conformation. Reserpine is a modulator of MDR in which these domains are present in a well-defined conformation. Accordingly, we prepared eight compounds that vary the spatial orientation of these domains, using either naturally occurring reserpine or yohimbine as chemical templates. When tested for their ability to enhance the cytotoxic activity of natural product antitumor drugs in CEM/VLB100 cells, five compounds that retained the pendant benzoyl function in an appropriate spatial orientation all modulated MDR. By contrast, compounds lacking this moiety failed to do so. These active modulators competed strongly with the 125I-labeled vinblastine analog for binding to P-glycoprotein in plasma membrane vesicles prepared from these cells. Conformational analysis using molecular mechanics revealed the structural similarities of the active modulators. Our results support the hypothesis that the relative disposition of aromatic rings and basic nitrogen atom is important for modulators of P-glycoprotein-associated MDR, and they suggest a ligand-receptor relationship for these agents. These results also provide direction for the definition of an MDR "pharmacophore."

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B.

Hereditary deficiency of factor IXa (fIXa), a key enzyme in blood coagulation, causes hemophilia B, a severe X chromosome-linked bleeding disorder afflicting 1 in 30,000 males; clinical studies have identified nearly 500 deleterious variants. The x-ray structure of porcine fIXa described here shows the atomic origins of the disease, while the spatial distribution of mutation sites suggests a structural model for factor X activation by phospholipid-bound fIXa and cofactor VIIIa. The 3.0-A-resolution diffraction data clearly show the structures of the serine proteinase module and the two preceding epidermal growth factor (EGF)-like modules; the N-terminal Gla module is partially disordered. The catalytic module, with covalent inhibitor D-Phe-1I-Pro-2I-Arg-3I chloromethyl ketone, most closely resembles fXa but differs significantly at several positions. Particularly noteworthy is the strained conformation of Glu-388, a residue strictly conserved in known fIXa sequences but conserved as Gly among other trypsin-like serine proteinases. Flexibility apparent in electron density together with modeling studies suggests that this may cause incomplete active site formation, even after zymogen, and hence the low catalytic activity of fIXa. The principal axes of the oblong EGF-like domains define an angle of 110 degrees, stabilized by a strictly conserved and fIX-specific interdomain salt bridge. The disorder of the Gla module, whose hydrophobic helix is apparent in electron density, can be attributed to the absence of calcium in the crystals; we have modeled the Gla module in its calcium form by using prothrombin fragment 1. The arched module arrangement agrees with fluorescence energy transfer experiments. Most hemophilic mutation sites of surface fIX residues occur on the concave surface of the bent molecule and suggest a plausible model for the membrane-bound ternary fIXa-FVIIIa-fX complex structure: fIXa and an equivalently arranged fX arch across an underlying fVIIIa subdomain from opposite sides; the stabilizing fVIIIa interactions force the catalytic modules together, completing fIXa active site formation and catalytic enhancement.

Amino Acid Chloromethyl Ketones↗
PubMed1996

Intron positions correlate with module boundaries in ancient proteins.

We analyze the three-dimensional structure of proteins by a computer program that finds regions of sequence that contain module boundaries, defining a module as a segment of polypeptide chain bounded in space by a specific given distance. The program defines a set of "linker regions" that have the property that if an intron were to be placed into each linker region, the protein would be dissected into a set of modules all less than the specified diameter. We test a set of 32 proteins, all of ancient origin, and a corresponding set of 570 intron positions, to ask if there is a statistically significant excess of intron positions within the linker regions. For 28-A modules, a standard size used historically, we find such an excess, with P < 0.003. This correlation is neither due to a compositional or sequence bias in the linker regions nor to a surface bias in intron positions. Furthermore, a subset of 20 introns, which can be putatively identified as old, lies even more explicitly within the linker regions, with P < 0.0003. Thus, there is a strong correlation between intron positions and three-dimensional structural elements of ancient proteins as expected by the introns-early approach. We then study a range of module diameters and show that, as the diameter varies, significant peaks of correlation appear for module diameters centered at 21.7, 27.6, and 32.9 A. These preferred module diameters roughly correspond to predicted exon sizes of 15, 22, and 30 residues. Thus, there are significant correlations between introns, modules, and a quantized pattern of the lengths of polypeptide chains, which is the prediction of the "Exon Theory of Genes."

Algorithms↗
PubMed2003

Enhanced CD4 down-modulation by late stage HIV-1 nef alleles is associated with increased Env incorporation and viral replication.

Three viral proteins participate in the down-modulation of CD4 in human immunodeficiency virus type 1 (HIV-1)-infected cells. The underlying mechanisms have been extensively investigated. However, the physiological relevance of this phenomenon remains poorly understood. To address the role of CD4 down-modulation in HIV-1 pathogenesis in vivo, we have characterized the functional properties of nef alleles isolated from seven HIV-1-infected patients at either the stage of AIDS (late alleles) or during the asymptomatic phase of infection (early alleles). HIV-1 variants carrying these nef alleles showed striking differences in CD4 down-modulation, virus infectivity, and replication properties. Infection of T cells with late strains resulted in production of viral particles with enhanced infectivity, as compared with variants carrying early nef alleles. These differences in infectivity were observed only when viruses were produced in cells with high levels of the viral receptor, suggesting a functional link between CD4 levels and the ability of Nef to down-modulate CD4 and to enhance viral infectivity. Similarly, late nef alleles were substantially more active than early nef genes in stimulating HIV-1 replication in high CD4-positive cells, including primary lymphocytes, but not in cells expressing low levels of the CD4 receptor. Single-round assays showed that differences in infectivity between late and early strains are largely reduced when evaluated in target cells with high levels of CD4, suggesting that the inhibitory effect occurs at the entry step. Supporting this, enhanced CD4 down-modulation by late nef alleles was associated with higher levels of envelope incorporation into viral particles, a phenomenon that likely accounted for the augmented infectivity. Our data suggest a mechanistic link between the Nef-mediated CD4 down-modulation and the enhancement of replication in CD4-positive lymphocytes. As progression to disease occurs, HIV-1 Nef variants with enhanced ability to down-modulate CD4 are selected. These strains efficiently overcome the deleterious effects of CD4 and replicate more aggressively in CD4-positive primary lymphocytes. These results highlight the importance of the virus-induced CD4 down-modulation in HIV-1 pathogenesis.

Alleles↗
PubMed2006

NMR structure of the R-module: a parallel beta-roll subunit from an Azotobacter vinelandii mannuronan C-5 epimerase.

In the bacterium Azotobacter vinelandii, a family of seven secreted and calcium-dependent mannuronan C-5 epimerases (AlgE1-7) has been identified. These epimerases are responsible for the epimerization of beta-d-mannuronic acid to alpha-l-guluronic acid in alginate polymers. The epimerases consist of two types of structural modules, designated A (one or two copies) and R (one to seven copies). The structure of the catalytically active A-module from the smallest epimerase AlgE4 (consisting of AR) has been solved recently. This paper describes the NMR structure of the R-module from AlgE4 and its titration with a substrate analogue and paramagnetic thulium ions. The R-module folds into a right-handed parallel beta-roll. The overall shape of the R-module is an elongated molecule with a positively charged patch that interacts with the substrate. Titration of the R-module with thulium indicated possible calcium binding sites in the loops formed by the nonarepeat sequences in the N-terminal part of the molecule and the importance of calcium binding for the stability of the R-module. Structure calculations showed that calcium ions can be incorporated in these loops without structural violations and changes. Based on the structure and the electrostatic surface potential of both the A- and R-module from AlgE4, a model for the appearance of the whole protein is proposed.

Alginates↗
PubMed2006

Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique low density lipoprotein class A modules.

The relaxin and insulin-like peptide 3 receptors, LGR7 and LGR8, respectively, are unique members of the leucine-rich repeat-containing G-protein-coupled receptor (LGR) family, because they possess an N-terminal motif with homology to the low density lipoprotein class A (LDLa) modules. By characterizing several LGR7 and LGR8 splice variants, we have revealed that the LDLa module directs ligand-activated cAMP signaling. The LGR8-short variant encodes an LGR8 receptor lacking the LDLa module, whereas LGR7-truncate, LGR7-truncate-2, and LGR7-truncate-3 all encode truncated secreted proteins retaining the LGR7 LDLa module. LGR8-short and an engineered LGR7 variant missing its LDLa module, LGR7-short, bound to their respective ligands with high affinity but lost their ability to signal via stimulation of intracellular cAMP accumulation. Conversely, secreted LGR7-truncate protein with the LDLa module was able to block relaxin-induced LGR7 cAMP signaling and did so without compromising the ability of LGR7 to bind to relaxin or be expressed on the cell membrane. Although the LDLa module of LGR7 was N-glycosylated at position Asn-14, an LGR7 N14Q mutant retained relaxin binding affinity and cAMP signaling, implying that glycosylation is not essential for optimal LDLa function. Using real-time PCR, the expression of mouse LGR7-truncate was detected to be high in, and specific to, the uterus of pregnant mice. The differential expression and evolutionary conservation of LGR7-truncate further suggests that it may also play an important role in vivo. This study highlights the essential role of the LDLa module in LGR7 and LGR8 function and introduces a novel model of GPCR regulation.

Animals↗
PubMed2002

Development and evaluation of a computer-assisted learning module on glomerulonephritis for medical students.

An interactive computer-assisted learning (CAL) module on glomerulonephritis, previously identified by fourth-year medical students as a difficult topic, was developed. The module comprised background material, case studies, graphics, animation, video and supporting quizzes with feedback. The impact of the module on student learning was evaluated by comparing the performance of two matched groups of students, only one of which accessed the CAL module, in an online assessment. The analysis examined the effect of having completed a clinical term in renal medicine. A significant improvement in the performance of those students who used the CAL module was demonstrated. Unexpectedly, completing a renal medicine term had no beneficial influence on students' performance. Students who used the CAL module perceived a significant decrease in the difficulty of the topic. It is concluded that the module is an effective learning tool, but important caveats are noted associated with using CAL modules in redesigned medical curricula.

Computer-Assisted Instruction↗
PubMed1996

A novel role for the integrin-binding III-10 module in fibronectin matrix assembly.

Fibronectin matrix assembly is a cell-dependent process which is upregulated in tissues at various times during development and wound repair to support the functions of cell adhesion, migration, and differentiation. Previous studies have demonstrated that the alpha 5 beta 1 integrin and fibronectin's amino terminus and III-1 module are important in fibronectin polymerization. We have recently shown that fibronectin's III-1 module contains a conformationally sensitive binding site for fibronectin's amino terminus (Hocking, D.C., J. Sottile, and P.J. McKeown-Longo. 1994. J. Biol. Chem. 269: 19183-19191). The present study was undertaken to define the relationship between the alpha 5 beta 1 integrin and fibronectin polymerization. Solid phase binding assays using recombinant III-10 and III-1 modules of human plasma fibronectin indicated that the III-10 module contains a conformation-dependent binding site for the III-1 module of fibronectin. Unfolded III-10 could support the formation of a ternary complex containing both III-1 and the amino-terminal 70-kD fragment, suggesting that the III-1 module can support the simultaneous binding of III-10 and 70 kD. Both unfolded III-10 and unfolded III-1 could support fibronectin binding, but only III-10 could promote the formation of disulfide-bonded multimers of fibronectin in the absence of cells. III-10-dependent multimer formation was inhibited by both the anti-III-1 monoclonal antibody, 9D2, and amino-terminal fragments of fibronectin. A fragment of III-10, termed III-10/A, was able to block matrix assembly in fibroblast monolayers. Similar results were obtained using the III-10A/RGE fragment, in which the RGD site had been mutated to RGE, indicating that III-I0/A was blocking matrix assembly by a mechanism distinct from disruption of integrin binding. Texas red-conjugated recombinant III-1,2 localized to beta 1-containing sites of focal adhesions on cells plated on fibronectin or the III-9,10 modules of fibronectin. Monoclonal antibodies against the III-1 or the III-9,10 modules of fibronectin blocked binding of III-1,2 to cells without disrupting focal adhesions. These data suggest that a role of the alpha 5 beta 1 integrin in matrix assembly is to regulate a series of sequential self-interactions which result in the polymerization of fibronectin.

Amino Acid Sequence↗
PubMed2004

KCNE3 truncation mutants reveal a bipartite modulation of KCNQ1 K+ channels.

The five KCNE genes encode a family of type I transmembrane peptides that assemble with KCNQ1 and other voltage-gated K(+) channels, resulting in potassium conducting complexes with varied channel-gating properties. It has been recently proposed that a triplet of amino acids within the transmembrane domain of KCNE1 and KCNE3 confers modulation specificity to the peptide, since swapping of these three residues essentially converts the recipient KCNE into the donor (Melman, Y.F., A. Domenech, S. de la Luna, and T.V. McDonald. 2001. J. Biol. Chem. 276:6439-6444). However, these results are in stark contrast with earlier KCNE1 deletion studies, which demonstrated that a COOH-terminal region, highly conserved between KCNE1 and KCNE3, was responsible for KCNE1 modulation of KCNQ1 (Tapper, A.R., and A.L. George. 2000 J. Gen. Physiol. 116:379-389.). To ascertain whether KCNE3 peptides behave similarly to KCNE1, we examined a panel of NH(2)- and COOH-terminal KCNE3 truncation mutants to directly determine the regions required for assembly with and modulation of KCNQ1 channels. Truncations lacking the majority of their NH(2) terminus, COOH terminus, or mutants harboring both truncations gave rise to KCNQ1 channel complexes with basal activation, a hallmark of KCNE3 modulation. These results demonstrate that the KCNE3 transmembrane domain is sufficient for assembly with and modulation of KCNQ1 channels and suggests a bipartite model for KCNQ1 modulation by KCNE1 and KCNE3 subunits. In this model, the KCNE3 transmembrane domain is active in modulation and overrides the COOH terminus' contribution, whereas the KCNE1 transmembrane domain is passive and reveals COOH-terminal modulation of KCNQ1 channels. We furthermore test the validity of this model by using the active KCNE3 transmembrane domain to functionally rescue a nonconducting, yet assembly and trafficking competent, long QT mutation located in the conserved COOH-terminal region of KCNE1.

Amino Acid Substitution↗
PubMed1999

Temporal resolution requirements for intensity modulated radiation therapy delivered by multileaf collimators.

Intensity modulated radiation therapy may be delivered via dynamic control of a multileaf collimator by defining dynamic leaf trajectories at a series of control points which are spaced at arbitrary intervals throughout an exposure. Leaves move linearly between the positions defined at the control points and hence leaf motion is a linear approximation to the planned trajectories. When many control points are used, very complex modulations can be defined accurately. If too few are used, dose errors are introduced which depend on the complexity of the modulation and the number of control points chosen. Proposed intensity modulations, of varying complexity, have been converted to trajectory plans where the number of equally spaced control points varied between 11 and 99. In each case the fluence map generated by the resulting leaf motions was computed, and this was quantitatively compared with the desired modulation by calculating the root mean square (RMS) error. It is shown that in no case can the RMS error be significantly reduced by increasing the number of control points beyond 50. Guidelines are derived such that compensators and simple modulations may be very accurately delivered with about 20 control points, moderately complex modulations require 30-35 control points and very complex modulations 50 control points. A similar analysis of the step and shoot technique suggests that very accurate deliveries are always achieved with a maximum of 25 equally weighted static fields and reasonable accuracy with 15 fields.

Calibration↗
PubMedDate not supplied

A discriminative model for identifying spatial cis-regulatory modules.

Transcriptional regulation is mediated by the coordinated binding of transcription factors to the upstream regions of genes. In higher eukaryotes, the binding sites of cooperating transcription factors are organized into short sequence units, called cis-regulatory modules. In this paper, we propose a method for identifying modules of transcription factor binding sites in a set of co-regulated genes, using only the raw sequence data as input. Our method is based on a novel probabilistic model that describes the mechanism of cis-regulation, including the binding sites of cooperating transcription factors, the organization of these binding sites into short sequence modules, and the regulation of a gene by its modules. We show that our method is successful in discovering planted modules in simulated data and known modules in yeast. More importantly, we applied our method to a large collection of human gene sets and found 83 significant cis-regulatory modules, which included 36 known motifs and many novel ones. Thus, our results provide one of the first comprehensive compendiums of putative cis-regulatory modules in human.

Binding Sites↗
PubMed2000

Preclinical and clinical development of cyclin-dependent kinase modulators.

In the last decade, the discovery and cloning of the cyclin-dependent kinases (cdks), key regulators of cell cycle progression, have led to the identification of novel modulators of cdk activity. Initial experimental results demonstrated that these cdk modulators are able to block cell cycle progression, induce apoptotic cell death, promote differentiation, inhibit angiogenesis, and modulate transcription. Alteration of cdk activity may occur indirectly by affecting upstream pathways that regulate cdk activity or directly by targeting the cdk holoenzyme. Two direct cdk modulators, flavopiridol and UCN-01, are showing promising results in early clinical trials, in which the drugs reach plasma concentrations that can alter cdk activity in vitro. Although modulation of cdk activity is a well-grounded concept and new cdk modulators are being assessed for clinical testing, important scientific questions remain to be addressed. These questions include whether one or more cdks should be inhibited, how cdk inhibitors should be combined with other chemotherapy agents, and which cdk substrates should be used to assess the biologic effects of these drugs in patients. Thus, modulation of cdk activity is an attractive target for cancer chemotherapy, and several agents that modulate cdk activity are in or are approaching entry into clinical trials.

Alkaloids↗
PubMed1993

Repeat of a helix-turn-helix module in DNA-binding proteins.

Helix-turn-helix motif is one of the common motifs observed in DNA-binding proteins. The motif interacts with DNA double helix and recognizes specific base sequences. It is assumed that the helix-turn-helix motif appears only once in seven prokaryotic transcriptional repressors of which 3-D structures have been determined by X-ray crystallographic studies. These prokaryotic repressors consist of several alpha-helices connected with turns. We report here that these repressors are decomposable into helix-turn-helix modules and their connectors. A module is defined as a compact structural unit with consecutive amino acid residues in a globular protein. Each of the helix-turn-helix motifs in the seven proteins corresponds approximately to a single helix-turn-helix module consisting of approximately 13 amino acids. Identification of modules of seven prokaryotic repressors and comparisons of their tertiary structures led to the conclusion that three of these DNA-binding proteins contain more than one helix-turn-helix module with a structure similar to the helix-turn-helix motif. The difference in module organization of these DNA-binding proteins paves the way for further classification of the DNA-binding proteins with the helix-turn-helix motif. The structural repertoire of these transcriptional regulators was increased through different utilizations in the number of helix-turn-helix and other modules. The difference in DNA base recognition ability in these helix-turn-helix modules is ascribed to a difference in size of a side chain at the fifth residue from Gly, on the turn.

Amino Acid Sequence↗
PubMed2001

Human auditory steady-state responses to tones independently modulated in both frequency and amplitude.

OBJECTIVE: Independent amplitude and frequency modulation (IAFM) of a carrier tone uses two different modulating frequencies, one for amplitude modulation (AM) and one for frequency modulation (FM). This study measured the human steady-state responses to multiple IAFM tones. The first question was whether the IAFM responses could be recorded without attenuation of the AM and FM components. The second question was whether IAFM stimuli would provide a more effective demonstration of responses at intensities near threshold than the responses to AM tones. The third question was whether the responses to multiple IAFM stimuli would relate to the discrimination of words at different intensities. DESIGN: Multiple AM, FM, or IAFM stimuli were presented simultaneously. Responses were recorded between the vertex and the neck and analysed in the frequency domain. The first experiment compared IAFM responses with AM and FM responses. The second experiment compared IAFM responses with AM responses between intensities 20 to 50 dB SPL. The third experiment related the IAFM responses to the discrimination of monosyllabic words at intensities between 20 and 70 dB SPL. RESULTS: Steady-state responses to the individual component of the IAFM stimuli were clearly recognizable although attenuated a little (14%) from the responses to AM or FM alone. Using IAFM stimuli was not different than simply using AM stimuli when trying to recognize responses at low intensities. The number of responses detected during multiple IAFM stimulation and the amplitudes of these responses correlated significantly with word discrimination. CONCLUSIONS: IAFM of a carrier using two different modulating frequencies (one for AM and one for FM) elicits separate AM and FM responses that are relatively independent of each other. These separate responses can be used to detect whether a particular carrier has been processed in the cochlea, but they are not as effective as measuring responses to carriers that have been modulated in both amplitude and frequency at the same modulation frequency (mixed modulation). The detectability of eight different responses (four AM and four FM) to an IAFM stimuli relates well to the ability of subjects to discriminate words. IAFM stimuli therefore show promise as an objective test for assessing suprathreshold hearing.

Adult↗
PubMed2000

Modulation of spinal deformities in patients with neurofibromatosis type 1.

STUDY DESIGN: A consecutive case retrospective chart and radiographic review. OBJECTIVES: To determine the incidence of nine radiographic dystrophic features acquired during the process of modulation, and to analyze the statistical correlation of these acquired dystrophic features with clinical progression of a spinal deformity. SUMMARY OF BACKGROUND DATA: In patients with neurofibromatosis, spinal deformities with seemingly few initial dystrophic features have shown a tendency to acquire dystrophic changes during long-term follow-up periods. Similarly, deformities with dystrophic changes can acquire further dystrophic features. This phenomenon is termed "modulation," a feature unique to spinal deformities in neurofibromatosis. These dystrophic changes may evolve slowly or aggressively, and may spread to other regions as well. METHODS: A review was done of the clinical records, photographs, radiographs, and other imaging studies of 457 patients referred between 1982 and 1995 with the diagnosis of neurofibromatosis Type 1. One hundred twenty-eight patients were diagnosed with a spinal deformity. Ninety-one patients who had a complete set of clinical and radiographic data were included in the study. Location and type of curve as well as the extent of spinal deformity were studied for their effect on the tendency for modulation. Initial spinal radiographs were analyzed for nine radiographic dystrophic features: rib penciling, vertebral rotation, posterior vertebral scalloping, anterior vertebral scalloping, lateral vertebral scalloping, vertebral wedging, spindling of the transverse process, widened interpedicular distance, and enlarged intervertebral foramina. Subsequent radiographs were analyzed critically for evolution, progression, or spread of these features. Correlation of acquisition in these dystrophic features with clinical progression in the spinal deformity, as measured in increments of scoliosis and kyphosis, was analyzed. RESULTS: In 81% of patients with spinal deformity diagnosed before 7 years of age and in 25% of patients with such a diagnosis after 7 years of age, evidence of modulation was observed. Location, side, and extent of the deformity and patient gender did not influence the propensity of the deformity to modulate. Correlation of modulation with clinical progression of the deformity showed rib penciling to be the only singular factor statistically influencing risk of progression. Of the deformities that acquired three or more penciled ribs, 87% showed significant clinical progression. No other radiographic dystrophic feature individually influenced progression. However, when three or more of the dystrophic skeletal features were acquired, the risk of progression reached statistical significance in 85% of patients. CONCLUSIONS: Spinal deformities in patients with neurofibromatosis 1 should be regarded as deformities in evolution. One should resist assigning these evolving deformities to either the dystrophic or nondystrophic end of the spectrum without considering the possibility of modulation across the spectrum. A spinal deformity that develops before 7 years of age should be followed closely for evolving dystrophic features (i.e., modulation). When a curve acquires either three penciled ribs or a combination of three dystrophic features, clinical progression is almost a certainty.

Adolescent↗