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Cerebral white matter: technical development and clinical applications of effective magnetization transfer (MT) power concepts for high-power, thin-section, quantitative MT examinations.

PURPOSE: To evaluate white matter disorders with magnetization transfer (MT) techniques. MATERIALS AND METHODS: In 46 healthy volunteers and 46 clinical patients, MT Z spectra were obtained with various continuous-wave-equivalent MT powers (B1CW) and frequency offsets. RESULTS: With B1CW of 270 Hz and 4,000-Hz frequency offset, the MT ratio of normal callosal white matter was 59.2% +/- 1.5 (standard deviation), with less than 5% contribution from direct saturation and spin locking. A small statistically significant (P < .01) regional variation in normal white matter was seen. Plaques in MS patients had a broad (or wide) range of MT ratios; normal appearing white matter had a slightly reduced MT ratio. Vasogenic edema had a minimal effect on MT ratio, and radiation necrosis showed prominent reductions in MT ratio. CONCLUSION: High MT power techniques can expand the dynamic range of MT ratios, maintain a relatively pure MT effect, and be used effectively in MT imaging to evaluate white matter disorders.

Brain↗

The effect of dynamic receptor clustering on the sensitivity of biochemical signaling.

Lateral clustering has emerged as a general mechanism used by many cellular receptors to control their responses to critical changes in the external environment. Here we derive a general mathematical framework to characterize the effect of receptor clustering on the sensitivity and dynamic range of biochemical signaling. In particular, we apply the theory to the bacterial chemosensory system and show that it can integrate a large body of experimental observations and provide a unified explanation to many aspects of chemotaxis. The principles of dynamic receptor clustering and signal amplification incorporated into this theory may underlie the design of many cellular networks.

Bacterial Proteins↗

[Importance of Helicobacter pylori in the pathogenesis of gastric cancer. Experimental models in rodents].

UNLABELLED: We found that the seroprevalence in Cancer Institute of H. pylori infection was significantly more frequent in gastric cancer than in age- and gender-matched controls. This study suggested an epidemiological link between H. pylori infection and gastric cancer. H. pylori exhibits a complex system of enzymes which serve a range of functions. Toxic effects are produced by urease (UR), phospholipase (PL) and alcohol dehydrogenase (ADH). We embarked on an exploration of the enzyme activities of H. pylori infected patients using a TLC-autoradioluminography. This method has a wide dynamic range and could offer an analytical technique for studying a radioactive compound and its enzymes in H. pylori infected mucosa. Biopsies samples taken from 21 gastric cancer patients and 95 controls were studied. Although high activity of UR indicates well the presence of H. pylori impairment, activities of ADH and PL reflects more the chronicity of mucosal damage in both groups. Clearly, the enzyme profile showed in our study reflects the "physiological" adaptations behind chronic injured mucosal changes but its relation to gastric cancer and H. pylori needs further study. There is an urgent need to understand the carcinogenesis process using animal models. We performed previous study for to explore the effect of H. pylori infection on N- methyl-N-nitrosourea-induced (MNU) gastric carcinogenesis in mice C57BL/6 mice were administered broth culture of H. pylori and given MNU in drinking water. In terms of the incidence of neoplasms development was increase in the MNU group pre-infected with H. pylori. That findings showed that C57BL/6 mice-infected model is well suited for investigating the bacteria promoter effect in the gastric carcinogenesis. Finally another rodent model study (still in process) showed rapid development of hyperplastic gastritis with gastric erosions in H. pylori-infected MTH1 knockout mice. We sought to further evaluate MTH1 knockout mice as potential test animal for carcinogenesis. CONCLUSION: It is suggested that H. pylori infection is an important risk factor for the development of gastric cancer. The possibility that this organism acts etiologically, exerting its effect over long period of time, is biologically plausible. However, the role of H. pylori per se in that process is still a matter of discussion. The various enzymes of H. pylori discussed in this paper support colonization, and are perhaps important for epithelial damage, they could contribute to the stimulation and modulation of the chronic inflammatory response, but its relation to gastric cancer and H. pylori needs further study. Finally H. pylori in C57BL/6 and knockout mice showed excellent colonization at two months and six months after infection there was adenomatous, hyperplastic and ulcerative changes. Those findings showed that both mice-infected models are well suited for investigating the bacteria promoter effect in the gastric carcinogenesis.

Adenocarcinoma↗

Unusual inheritance patterns due to dynamic mutation in fragile X syndrome.

Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to dynamic mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for dynamic mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the premutation range. Dynamic mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of dynamic mutation diseases.

Alleles↗

Recruitment and discharge patterns of single motor units during speech production.

Recruitment and discharge patterns of single motor units (MUs) in the anterior belly of digastric were studied during speech in three subjects, using electrodes facilitating selective recording at high force levels. Fixed recruitment order was observed in over 99% of all comparisons. Later recruited units invariably possessed muscle action potentials of higher amplitude, suggesting that units were activated in accordance with the "size principle." Additional evidence for this was that later recruited units, of a set of three studied during speech, motor unit training, and isometric force ramps, showed greater sensitivity to input, and greater dynamic range than earlier recruited units. Units in this set were much more sensitive to rapid changes in input associated with speech gestures than to static activation even at high force levels. Several significant relations between discharge characteristics and aspects of movement dynamics were observed, including relations between (1) recruitment interval (MU1 to MU3) and latency of mandibular lowering, (2) onset of initial discharge of MU1 and relative mechanical advantage of the mandible, (3) number of MUs active and velocity and displacement of the mandible, and (4) discharge rate of MU3 and velocity and displacement of the mandible.

Action Potentials↗

The Theodore Bücher lecture. Investigating signal transduction with genetically encoded fluorescent probes.

Ca2+ and cAMP are ubiquitous second messengers in eukaryotes and control numerous physiological responses ranging from fertilization to cell death induction. To distinguish between these different responses, their subtle regulation in time, space and amplitude is needed. Therefore, the characterization of the signalling process requires measurement of second messengers with tools of precise localization, high dynamic range and as little disturbance of cell physiology as possible. Recently, fluorescent proteins of marine jellyfish have given rise to a set of genetically encoded biosensors which fulfil these criteria and which have already led to important new insights into the subcellular handling of Ca2+ and cAMP. The use of these probes in combination with new microscopical methods such as two-photon microscopy now enables researchers to study second messenger signalling in intact tissues. In this review, the genetically encoded measurement probes and their origin are briefly introduced and some recent insights into the spatio-temporal complexity of both Ca2+ and cAMP signalling obtained with these tools are discussed.

Aequorin↗

Encoding of acoustic stimulus intensity by inferior collicular neurons of the big brown bat, Eptesicus fuscus.

Using bats as a model system, we studied the isointensity and isofrequency discharge rate functions of inferior collicular (IC) neurons under free field stimulation conditions in order to understand how the midbrain auditory neurons encode stimulus intensity. For each encountered IC neuron, the best frequency (BF), minimum threshold (MT), tuning curve and intensity rate function for the BF were first determined. Then at a fixed stimulus intensity, the number of impulses was measured for several frequencies which were incrementally chosen across the entire range of the neuron's tuning curve. Such an isointensity discharge rate function was determined for at least three different intensities above each neuron's MT. A series of isofrequency discharge rate functions were also obtained by determining the intensity rate function for each of several frequencies chosen. Among 110 intensity rate functions measured at the BF of each IC neuron, 98 (89%) were non-monotonic and 12 (11%) were monotonic. The profiles of the intensity rate functions measured at several chosen frequencies for each neuron varied greatly. Thus, within the same series of isofrequency intensity rate functions, a neuron showed both monotonic and non-monotonic functions when measured at different frequencies. Similarly, the profile of each intensity rate curve within a series of isointensity rate functions might also vary with stimulus intensity. The isointensity discharge rate functions of most IC neurons (62 neurons, 61%) was triangular shaped reaching a peak value when stimulated with BF. The remaining (39 neurons, 39%) IC neurons had isointensity functions in which different curves peaked at different stimulus frequencies. In some extreme cases, some curves had two peaks or fluctuated within a moderate range of discharge rate throughout the whole range of stimulus frequency. Our studies suggest that encoding of a wide range of acoustic stimulus intensity in the IC involves more than the discharge rate of any one individual IC neuron. Different populations of IC neurons with different BFs will have to work coordinately in order to overcome the limitation of the dynamic range of individual neurons and to solve the ambiguity created by the same discharge rate of each individual neuron to different combinations of frequency and intensity within its auditory response area.

Acoustic Stimulation↗

Processing of sinusoidally amplitude modulated signals in the nuclei of the lateral lemniscus of the big brown bat, Eptesicus fuscus.

Changes in amplitude are a characteristic feature of most natural sounds, including the biosonar signals used by bats for echolocation. Previous evidence suggests that the nuclei of the lateral lemniscus play an important role in processing timing information that is essential for target range determination in echolocation. Neurons that respond to unmodulated tones with a sustained discharge are found in the dorsal nucleus (DNLL), intermediate nucleus (INLL) and multipolar cell division of the ventral nucleus (VNLLm). These neurons provide a graded response over a broad dynamic range of intensities, and would be expected to provide information about the amplitude envelope of a modulated signal. Neurons that respond only at the onset of a tone make up a small proportion of cells in DNLL, INLL and VNLLm, but are the only type found in the columnar division of the ventral nucleus (VNLLc). Onset neurons in VNLLc maintain a constant latency across a wide range of stimulus frequencies and intensities, thus providing a precise marker for when a sound begins. To determine how these different functional classes of cells respond to amplitude changes, we presented sinusoidally amplitude modulated (SAM) signals monaurally to awake, restrained bats and recorded the responses of single neurons extracellularly. There were clear differences in the ability of neurons in the different cell groups to respond to SAM. In the VNLLm, INLL and DNLL, 90% of neurons responded to SAM with a synchronous discharge. Neurons in the VNLLc responded poorly or not at all to SAM signals. This finding was unexpected given the precise onset responses of VNLLc neurons to unmodulated tones and their ability to respond synchronously to sinusoidally frequency modulated (SFM) signals. Among neurons that responded synchronously to SAM, synchronization as a function of modulation rate described either a bandpass or a lowpass function, with the majority of bandpass functions in neurons that responded to unmodulated tones with a sustained discharge. The maximal modulation rates that elicited synchronous responses were similar for the different cell groups, ranging from 320 Hz in VNLLm to 230 Hz in DNLL. The range of best modulation rates was greater for SAM than for SFM; this was also true of the range of maximal modulation rates at which synchronous discharge occurred. There was little correlation between a neuron's best modulation rate or maximal modulation rate for SAM signals and those for SFM signals, suggesting that responsiveness to amplitude and frequency modulations depends on different neural processing mechanisms.

Acoustic Stimulation↗

High-frequency air-conduction and electric bone-conduction audiometry. Age and sex variations.

208 subjects representing both sexes and five age groups (15-70 years) were examined to obtain age-related threshold values for high-frequency (HF) electric bone-conduction (EBC) audiometry. The measurements also included conventional pure-tone audiometry and air-conduction (AC) HF (8-18 kHz) audiometry. The measured EBC thresholds were comparable to the values obtained with AC audiometers, and were equal to ISO standards at the frequencies of 0.5-6 kHz. The 15- and 20-year-old groups' EBC thresholds at 8 kHz were equivalent to thresholds of 15-year-old people from a cross-sectional material in Northern Finland. Thresholds deteriorated as a function of age, particularly in the HF range. The males had poorer thresholds than the females, especially in the age groups of 40 and 60 years. This could be attributed mainly to their greater noise exposure. The EBC method is quite practical and reliable for routine clinical measurements, but the dynamic range of the audiometer limits its use to relatively young subjects.

Adolescent↗

Functional properties of spinomesencephalic tract (SMT) cells in the upper cervical spinal cord of the cat.

Response and receptive field properties were evaluated for 62 spinomesencephalic tract cells in the upper cervical spinal cord (C1-C3) of cats anesthetized with sodium pentobarbital and alpha-chloralose. Recordings were made from cells in laminae I-VIII and X contralateral to antidromic stimulating electrodes positioned in the rostral, caudal and intercollicular region of the midbrain. The mean antidromic threshold for all cells was 185 +/- 132 microA, and conduction velocities ranged from 2.3 to 38.6 m/sec. Twelve cells were backfired from both midbrain and diencephalic stimulation sites. Receptive fields ranged from simple, i.e., ipsilateral forelimb or face, to complex, i.e., excitatory and/or inhibitory responses from large portions of the body. Peripheral receptive fields included muscles, joints, cornea, dura, forelimbs, hind limbs, tail, and/or testicles. Five functional classes of cells were observed: (a) wide dynamic range (14 cells); (b) high threshold (2 cells): (c) low threshold (4 cells); (d) deep/tap (11 cells); and (e) non-responsive (31 cells). Eight cells were evaluated for responses to different doses (5-150 micrograms) of intravenous (i.v.) serotonin. Two of the 8 cells exhibited excitatory effects, whereas 2 cells classified as deep/tap and 4 cells classified as non-responsive were not affected. The results of this study have shown the upper cervical component of the spinomesencephalic tract is made up of a heterogenous population of cells involved in the integration of varied inputs from large portions of the body. It is proposed that the large population of SMT cells in the upper cervical spinal cord may be involved in pain mechanisms, especially those related to the affective consequences of acute and chronic pain.

Animals↗

A high-frequency pulsed-wave Doppler ultrasound system for the detection and imaging of blood flow in the microcirculation.

Previous work with a 40-MHz continuous-wave Doppler ultrasound system has demonstrated the potential of high-frequency Doppler ultrasound (HFD), operating in the frequency range 20-200 MHz, to detect blood flow in the microcirculation. This paper describes a directional, pulsed-wave high-frequency Doppler ultrasound (PW HFD) system that was designed and constructed further to investigate this potential. The PW HFD system electronics have a dynamic range of > 80 dB, a noise floor of 250 nV, a directional isolation of 45 dB and operate over the frequency range 1-200 MHz. The system is tested using a focused PVDF transducer that is tuned for maximum sensitivity at 50 MHz, has a -6 dB lateral beamwidth of 70 microns and -6 dB depth-of-focus of 0.90 mm. This permits the practical use of sample volumes with dimensions 70 microns laterally by 90-900 microns axially. The PW HFD system can operate in duplex mode by either sharing the Doppler transducer or using a second PVDF transducer for imaging. Tests with string and capillary flow phantoms demonstrate that the PW HFD system is capable of detecting velocities on the order of the blood velocities found in the capillaries (0.5 mm/s) and arterioles (5 mm/s) with suitable velocity (30-300 microns/s) and temporal (15-100 ms) resolutions. In vivo measurements demonstrate that PW HFD can detect and measure blood velocities of less than 5 mm/s in arterioles and venules with diameters as small as 20 microns and 35 microns, respectively, using a sample volume of only 70 microns laterally by 150 microns axially. Preliminary experiments with high-frequency colour Doppler (HFCD) and high-frequency power Doppler (HFPD) imaging are also presented.

Animals↗

Auditory temporal processing: responses to sinusoidally amplitude-modulated tones in the inferior colliculus.

Time-varying envelopes are a common feature of acoustic communication signals like human speech and induce a variety of percepts in human listeners. We studied the responses of 109 single neurons in the inferior colliculus (IC) of the anesthetized Mongolian gerbil to contralaterally presented sinusoidally amplitude-modulated (SAM) tones with a wide range of parameters. Modulation transfer functions (MTFs) based on average spike rate (rMTFs) showed regions of enhancement and suppression, where spike rates increased or decreased respectively as stimulus modulation depth increased. Specifically, almost all IC rMTFs could be described by some combination of a primary and a secondary region of enhancement and an intervening region of suppression, with these regions present to varying degrees in individual rMTFs. rMTF characteristics of most neurons were dependent on sound pressure level (SPL). rMTFs in most neurons with "onset" or "onset-sustained" peri-stimulus time histograms (PSTHs) in response to brief pure tones showed only a peaked primary region of enhancement. The region of suppression tended to occur in neurons with "sustained" or "pauser" PSTHs, and usually emerged at higher SPLs. The secondary region of enhancement was only found in eight neurons. The lowest modulation frequency at which the spike rate reached a clear peak ("best modulation frequency" or BMF) was measured. All but two mean BMFs lay between 0 and 100 Hz. Fifty percent of the 49 neurons tested over at least a 20-dB range of SPLs showed a BMF variation larger than 66% of their mean BMF. MTFs based on vector strength (tMTFs) showed a variety of patterns; although mostly similar to those reported from the cochlear nucleus, tMTFs of IC neurons showed higher maximum values, smaller dynamic range with depth, and a lower high-frequency limit for significant phase locking. Systematic and large increases in phase-lead commonly occurred as SPL increased. rMTFs measured at multiple carrier frequencies (F(c)s) showed that the suppressive region was not the result of sideband inhibition. There was no systematic relationship between BMF and F(c) of stimulation in the cells studied, even at low carrier frequencies. The results suggest various possible mechanisms that could create IC MTFs, and strongly support the idea that inhibitory inputs shape the rMTF by sharpening regions of enhancement and creating a suppressive region. The paucity of BMFs above 100 Hz argues against simple rate-coding schemes for pitch. Finally, any labeled line or topographic representation of modulation frequency is unlikely to be independent of SPL.

Acoustic Stimulation↗

Tuning characteristics of cochlear nucleus units in response to electrical stimulation of the cochlea.

The responses of single units in the ventral cochlear nucleus of acute anesthetized guinea pigs were studied with continuous sinusoidal electrical stimuli presented through a multi-electrode implant in the scala tympani. Implants had two or four electrodes along the axis of the scala with 1 mm separations. Best frequencies were consistently in the 100 Hz range (50-250 Hz) with thresholds of about 0.063 mA peak-to-peak. Tuning curves were usually symmetrical with slopes of 3-4 dB/octave, both below and above the best frequency. The relative sharpness of the tuning curves, as measured by Q10dB, averaged 0.2. Dynamic ranges as determined by the intensity-rate functions for the various frequencies were 2-15 dB. No significant difference was found between tuning characteristics of units in response to stimulation via the apical or basal pair of implant electrodes. The findings suggest some limitations on the applicability of independent stimulating channels in multi-electrode implants.

Acoustic Stimulation↗

The development of auditory function in the cochlea of the mongolian gerbil.

Cochlear microphonic (CM) potentials were recorded throughout the development of auditory function in the Mongolian gerbil. CM responses were first recorded at 12 days after birth (DAB), with thresholds exceeding 103 dB SPL. CM thresholds subsequently improved rapidly in a parallel fashion across the responsive frequency range, achieving adult levels by 18 DAB. There was no evidence from CM thresholds of a preferential rate of maturation for either the high or low frequency ranges. CM responses to suptrathreshold stimulation were also studied throughout development. At all responsive ages, CM input-output functions increased logarithmically to a saturating maximum value and then declined. Maximum CM responses increased continuously throughout development in a parallel fashion across all frequencies. The dynamic range of the CM input-output functions (the intensity interval from CM threshold to maximum CM value) also developed in a parallel manner across frequencies, but reached mature assymptotic values by 16 DAB. The results suggest that throughout the adult CM frequency range cochlear hair cell function develops simultaneously.

Age Factors↗

Two measures of insulin sensitivity provided similar information in a U.S. population.

BACKGROUND AND OBJECTIVE: Two methods for measuring insulin sensitivity, fasting plasma insulin (FPI) and homeostasis model assessment (HOMA) have been proposed for use in large epidemiological research and clinical practice. This project describes the range of observed values of the HOMA and FPI in a large sample of the U.S. population. METHODS: We used fasting plasma glucose and insulin values from the Third National Health and Nutrition Survey (NHANES III) to identify the FPI and HOMA values. For both FPI and HOMA, higher values indicate lower insulin sensitivity. RESULTS: Among 6,511 participants without treated diabetes mellitus, FPI ranged from 1.8 to 175.8 microU/mL, with 25th percentile=6.7, median=9.3, 75th percentile=13.3, and mean+/-1 SD=11.2+/-7.5; HOMA ranged from 0.3 to 52.6 (mmol)(microU)/L(2), with 25th percentile=1.5, median=2.2, 75th percentile=3.3, and mean+/-SD=2.8+/-2.4. CONCLUSION: These findings describe the spectrum of insulin sensitivity and may be useful in helping physicians develop a clinical understanding of the dynamic range of both FPI and HOMA measures.

Adult↗

Inter-laboratory comparison of qualitative and quantitative detection of hepatitis C (HCV) virus RNA in diagnostic virology: a multicentre study (MS) in Italy.

BACKGROUND: The importance of the standardisation of nucleic acid amplification technology (NAT) assays for the detection of hepatitis C virus RNA is well known today, as many studies carried out in different European countries attest. The results of a previous study performed in Italy (J. Clin. Virol. 1 (2003) 83) by the Italian Society of Clinical Microbiology (AMCLI) showed that the use of external reference standards and of multicentre collaborative studies significantly improves laboratory performance for the qualitative evaluation of HCV RNA. OBJECTIVES: the AMCLI organised a new study on the standardisation of both the qualitative and the quantitative evaluation of HCV RNA with NAT in order to improve the implementation of the diagnostic methods for HCV RNA detection. STUDY DESIGN: seventeen diagnostic centres of major Italian Hospitals participated in this quality control study. The study consisted of testing three panels, each made up of 10 coded samples including negative and positive samples. Positive samples contained four levels of HCV RNA (genotype 1). RESULTS AND CONCLUSION: Seven out of 510 qualitative results obtained were incorrect (1.4%), two false negative and five false positive. The results gave a sensitivity of 99.5% and a specificity of 95.8%. Regarding quantitative tests, the geometric mean (GM) and standard deviation (S.D.) could be calculated only for the three highest HCV RNA levels. The percentage of results within the range of GM +/- 0.5 log(10) varied from 91% to 100%. Some laboratories had some difficulty in the exact quantification of the lowest (3.00 log IU/ml) as well as of the highest viral levels (6.35 log IU/ml) values, very near to the limits of the dynamic range of the assays. The comparison of the results of this study with that previously carried out one confirms that a regular participation in external quality assessment (EQA) assures the achievement of a high proficiency level in the diagnosis of HCV infection.

Hepacivirus↗

Voice profiles and standard voice profile of untrained children.

Voice profiles were taken of 277 healthy children between the ages of 5 and 14 years. The measured phonetograms were grouped according to sex and years of age. In each group, the means and standard deviations of maximal and minimal volume of each frequency were calculated. The median was used to establish the upper and lower limits of the voice range of each group. No age-dependent changes of the group voice profiles were shown in the groups of 7 to 10 year olds. Out of that emerged a standard childhood voice profile of the untrained voice. After age 10, an increase of the dynamic range over the lowest frequencies was found. Because of the voice changes in puberty, a profile for 13- and 14-year-old boys could not be established.

Adolescent↗

Contrast-detail detectability analysis: comparison of a digital spot mammography system and an analog screen-film mammography system.

RATIONALE AND OBJECTIVES: The authors compared the contrast-detail detectability properties of an optically coupled charge-coupled device (CCD) digital mammography system with those of a conventional analog screen-film mammography system. METHODS: A proprietary contrast-detail phantom was imaged with both systems. Twelve observers viewed analog and digital images obtained at seven different mean glandular doses. Contrast-detail-dose curves were generated on the basis of the readers' visual perceptions. Interobserver errors were also calculated. In addition, the authors applied a theoretical model for lesion detectability to calculate and compare the digital and analog mammography systems. RESULTS: The readers' contrast-detail detectability was significantly superior with the digital system in the detail and contrast ranges evaluated (P < .001). CONCLUSION: The performance of the readers paralleled the performance predicted by the theoretical model for the two imaging systems. The following features account for the superior performance of the digital mammography system: (a) higher quantum efficiency of the phosphor, (b) wider dynamic range, (c) better contrast transfer characteristics, and, most important, (d) greater photon flux at the phosphor entrance.

Contrast Sensitivity↗