Proliferative leukoplakia: Proposed new clinical diagnostic criteria.

OBJECTIVE: We aimed to characterize proliferative verrucous leukoplakia (PVL) from a clinical and histopathological standpoint and suggest an updated classification. SUBJECTS AND METHODS: Records of patients seen at three oral medicine centers with a clinical diagnosis of PVL were reviewed for clinical and histopathological features and malignant transformation (MT). RESULTS: There were 42 patients (median age: 69 years [range: 36-88]; 35 females). 12.2% were current smokers. Family history of cancer was present in 43.7% of patients. Partial demarcation of lesion margins was present in 31.3% of lesions, followed by verrucous (27.5%), smooth (22.7%) erythematous (22.3%), and fissured (18.3%) appearance. Large and contiguous and multisite and non-contiguous lesions comprised 57.1% (24/42) and 35.7% (15/42) of PVL cases, respectively. 19.1% had prominent erythema (erythroleukoplakia). The most common histopathological diagnosis at first visit was hyperkeratosis without dysplasia (22/42; 56.4%). MT occurred in 71.4% patients after a median of 37 months [range: 1-210] from initial visit; erythroleukoplakia exhibited MT in 100% of cases. CONCLUSION: The generic term "proliferative leukoplakia (PL)" may be more appropriate than PVL because 18.3% were fissured and 22.7% erythematous. We also propose the term proliferative erythroleukoplakia to more accurately describe the subset of PL with prominent erythema, which had the highest MT rate.

Highcor: a novel data-driven regressor identification method for BOLD fMRI.

A data-driven regressor selection technique for reducing physiological noise in BOLD fMRI is presented that capitalizes on additional information contained in the phase of the signal time-course. This method, termed highcor, identifies a set of suspect voxels by selecting based on high temporal correlation between the magnitude and phase components of the time-course. Temporal regressors are generated from principal component analysis of this voxel set. Regressor spectral content is investigated with high temporal resolution datasets, and filtering performance is demonstrated. The technique is benchmarked against compcor, an increasingly popular data driven technique. Highcor was found to select a unique set of physiological noise source voxels, and identification of confound and physiologically related signals was robust even at slow temporal sampling rates. Filtering using regressors derived from compcor and highcor voxels resulted in reductions in overall temporal standard deviation in cortical areas of 16.1%±3.1%, and 18.1%±3.8%, (mean±sd.) as measured over 36 BOLD fMRI datasets that featured an anti-saccade task. An approach combining both methods resulted in further reductions of temporal standard deviations by 31.4%±3.8%. In these regions, mean temporal SNR values were improved from 38.7±3.4 to 47.7±3.7 (cc), 49.2±2.2 (hc), and 57.8±2.3 (hc+cc). tSNR increases from data-driven filtering translated into some associated improvements in overall detection of task in the sample datasets.

Effect of fructans, prebiotics and fibres on the human gut microbiome assessed by 16S rRNA-based approaches: a review.

The inherent and diverse capacity of dietary fibres, nondigestible oligosaccharides (NDOs) and prebiotics to modify the gut microbiota and markedly influence health status of the host has attracted rising interest. Research and collective initiatives to determine the composition and diversity of the human gut microbiota have increased over the past decade due to great advances in high-throughput technologies, particularly the 16S ribosomal RNA (rRNA) sequencing. Here we reviewed the application of 16S rRNA-based molecular technologies, both community wide (sequencing and phylogenetic microarrays) and targeted methodologies (quantitative PCR, fluorescent in situ hybridisation) to study the effect of chicory inulin-type fructans, NDOs and specific added fibres, such as resistant starches, on the human intestinal microbiota. Overall, such technologies facilitated the monitoring of microbiota shifts due to prebiotic/fibre consumption, though there are limited community-wide sequencing studies so far. Molecular studies confirmed the selective bifidogenic effect of fructans and galactooligosaccharides (GOS) in human intervention studies. Fructans only occasionally decreased relative abundance of Bacteroidetes or stimulated other groups. The sequencing studies for various resistant starches, polydextrose and beta-glucan showed broader effects with more and different types of gut microbial species being enhanced, often including phylotypes of Ruminococcaceae. There was substantial variation in terms of magnitude of response and in individual responses to a specific fibre or NDO which may be due to numerous factors, such as initial presence and relative abundance of a microbial type, diet, genetics of the host, and intervention parameters, such as intervention duration and fibre dose. The field will clearly benefit from a more systematic approach that will support defining the impact of prebiotics and fibres on the gut microbiome, identify biomarkers that link gut microbes to health, and address the personalised response of an individual's microbiota to prebiotics and dietary fibres.

Dissociating pain from its anticipation in the human brain.

The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging in healthy humans was applied to dissociate neural activation patterns associated with acute pain and its anticipation. Expectation of pain activated sites within the medial frontal lobe, insular cortex, and cerebellum distinct from, but close to, locations mediating pain experience itself. Anticipation of pain can in its own right cause mood changes and behavioral adaptations that exacerbate the suffering experienced by chronic pain patients. Selective manipulations of activity at these sites may offer therapeutic possibilities for treating chronic pain.

Comparison of Multiple Sclerosis Cortical Lesion Types Detected by Multicontrast 3T and 7T MRI.

BACKGROUND AND PURPOSE: Our aims were the following: 1) to compare multicontrast cortical lesion detection using 3T and 7T MR imaging, 2) to compare cortical lesion type frequency in relapsing-remitting and secondary-progressive MS, and 3) to assess whether detectability is related to the magnetization transfer ratio, an imaging marker sensitive to myelin content. MATERIALS AND METHODS: Multicontrast 3T and 7T MR images from 10 participants with relapsing-remitting MS and 10 with secondary-progressive MS. We used the following 3T contrast sequences: 3D-T1-weighted, quantitative T1, FLAIR, magnetization-transfer, and 2D proton-density- and T2-weighted. We used the following 7T contrast sequences: 3D-T1-weighted, quantitative T1, and 2D-T2*-weighted. RESULTS: Cortical lesion counts at 7T were the following: 720 total cortical lesions, 420 leukocortical lesions (58%), 27 intracortical lesions (4%), and 273 subpial lesions (38%). Cortical lesion counts at 3T were the following: 424 total cortical, 393 leukocortical (93%), zero intracortical, and 31 subpial (7%) lesions. Total, intracortical, and subpial 3T lesion counts were significantly lower than the 7T counts (P < .002). Leukocortical lesion counts were not significantly different between scanners. Total and leukocortical lesion counts were significantly higher in secondary-progressive MS, at 3T and 7T (P ≤ .02). Subpial lesions were significantly higher in secondary-progressive MS at 7T (P = .006). The magnetization transfer ratio values of leukocortical lesions visible on both scanners were significantly lower than the magnetization transfer ratio values of leukocortical lesions visible only at 3T. No significant difference was found in magnetization transfer ratio values between subpial lesions visible only at 7T and subpial lesions visible on both 3T and 7T. CONCLUSIONS: Detection of leukocortical lesions at 3T is comparable with that at 7T MR imaging. Imaging at 3T is less sensitive to intracortical and subpial lesions. Leukocortical lesions not visible on 7T T2*-weighted MRI may be associated with less demyelination than those that are visible. Detectability of subpial lesions does not appear to be related to the degree of demyelination.

Functional MRI of oropharyngeal air-pulse stimulation.

Although the posterior oral cavity and oropharynx play a major role in swallowing, their central representation is poorly understood. High-field functional magnetic resonance imaging of the brain was used to study the central processing of brief air-pulses, delivered to the peritonsillar region of the lateral oropharynx, in six healthy adults. Bilateral air-pulse stimulation was associated with the activation of a bilateral network including the primary somatosensory cortex and the thalamus, classic motor areas (primary motor cortex, supplementary motor area, cingulate motor areas), and polymodal areas (including the insula and frontal cortex). These results suggest that oropharyngeal stimulation can activate a bilaterally distributed cortical network that overlaps cortical regions previously implicated in oral and pharyngeal sensorimotor functions such as tongue movement, mastication, and swallowing. The present study also demonstrates the utility of air-pulse stimulation in investigating oropharyngeal sensorimotor processing in functional brain imaging experiments.

Morphology-Specific Discrimination between MS White Matter Lesions and Benign White Matter Hyperintensities Using Ultra-High-Field MRI.

BACKGROUND AND PURPOSE: Recently published North American Imaging in Multiple Sclerosis guidelines call for derivation of a specific radiologic definition of MS WM lesions and mimics. The purpose of this study was to use SWI and magnetization-prepared FLAIR images for sensitive differentiation of MS from benign WM lesions using the morphologic characteristics of WM lesions. MATERIALS AND METHODS: Seventeen patients with relapsing-remitting MS and 18 healthy control subjects were enrolled retrospectively. For each subject, FLAIR and multiecho gradient-echo images were acquired using 7T MR imaging. Optimized postprocessing was used to generate single-slice SWI of cerebral veins. SWI/FLAIR images were registered, and 3 trained readers performed lesion assessment. Morphology, location of lesions, and the time required for assessment were recorded. Analyses were performed on 3 different pools: 1) lesions of >3 mm, 2) nonconfluent lesions of >3 mm, and 3) nonconfluent lesions of >3 mm with no or a single central vein. RESULTS: The SWI/FLAIR acquisition and processing protocol enabled effective assessment of central veins and hypointense rims in WM lesions. Assessment of nonconfluent lesions with ≥1 central vein enabled the most specific and sensitive differentiation of patients with MS from controls. A threshold of 67% perivenous WM lesions separated patients with MS from controls with a sensitivity of 94% and specificity of 100%. Lesion assessment took an average of 12 minutes 10 seconds and 4 minutes 33 seconds for patients with MS and control subjects, respectively. CONCLUSIONS: Nonconfluent lesions of >3 mm with ≥1 central vein were the most sensitive and specific differentiators between patients with MS and control subjects.

The effects of visual object priming on brain activation before and after recognition.

BACKGROUND: Recognizing an object is improved by recent experience with that object even if one cannot recall seeing the object. This perceptual facilitation as a result of previous experience is called priming. In neuroimaging studies, priming is often associated with a decrease in activation in brain regions involved in object recognition. It is thought that this occurs because priming causes a sharpening of object representations which leads to more efficient processing and, consequently, a reduction in neural activity. Recent evidence has suggested, however, that the apparent effect of priming on brain activation may vary as a function of whether the neural activity is measured before or after recognition has taken place. RESULTS: Using a gradual 'unmasking' technique, we presented primed and non-primed objects to subjects, and measured activation time courses using high-field functional magnetic resonance imaging (fMRI). As the objects were slowly revealed, but before recognition had occurred, activation increased from baseline level to a peak that corresponded in time to the subjects' behavioural recognition responses. The activation peak for primed objects occurred sooner than the peak for non-primed objects, and subjects responded sooner when presented with a primed object than with a non-primed object. During this pre-recognition phase, primed objects produced more activation than non-primed objects. After recognition, activation declined rapidly for both primed and non-primed objects, but now activation was lower for the primed objects. CONCLUSIONS: Priming did not produce a general decrease in activation in the brain regions involved in object recognition but, instead, produced a shift in the time of peak activation that corresponded to the shift in time seen in the subjects' behavioural recognition performance.

An fMRI study of the selective activation of human extrastriate form vision areas by radial and concentric gratings.

The ventral form vision pathway of the primate brain comprises a sequence of areas that include V1, V2, V4 and the inferior temporal cortex (IT) [1]. Although contour extraction in the V1 area and responses to complex images, such as faces, in the IT have been studied extensively, much less is known about shape extraction at intermediate cortical levels such as V4. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that the human V4 is more strongly activated by concentric and radial patterns than by conventional sinusoidal gratings. This is consistent with global pooling of local V1 orientations to extract concentric and radial shape information in V4. Furthermore, concentric patterns were found to be effective in activating the fusiform face area. These findings support recent psychophysical [2,3] and physiological [4,5] data indicating that analysis of concentric and radial structure represents an important aspect of processing at intermediate levels of form vision.

Differences in perceived shape from shading correlate with activity in early visual areas.

The perception of shape from shading depends on the orientation of the shading gradient [1] [2] [3] [4]. Displays composed of elements with vertically oriented shading gradients of opposite polarity produce a strong and stable percept of 'concave' and 'convex' elements. If the shading gradients are rotated 90 degrees , the depth percept is reduced and appears much more ambiguous. Results from psychophysical [1] [2] [3] [4] [5] [6], neuropsychological [7] and computational studies [8] [9] suggest that the perception of shape from shading engages specific mechanisms in early cortical visual areas. In a three-dimensional functional magnetic resonance imaging (fMRI) study at 1.5 Tesla using a three-dimensional, interleaved-echoplanar imaging technique and a surface radio frequency (RF) coil placed under the visual cortex, we investigated the activity in these early visual areas associated with viewing shape from shading displays at two different orientations. We found significantly greater activation in area V1 and neighbouring low-level visual areas of cortex when subjects viewed displays that led to weak and unstable depth percepts than when they viewed displays that led to strong and stable depth percepts.

Initial Investigation into Microbleeds and White Matter Signal Changes following Radiotherapy for Low-Grade and Benign Brain Tumors Using Ultra-High-Field MRI Techniques.

BACKGROUND AND PURPOSE: External beam radiation therapy is a common treatment for many brain neoplasms. While external beam radiation therapy adheres to dose limits to protect the uninvolved brain, areas of high dose to normal tissue still occur. Patients treated with chemoradiotherapy can have adverse effects such as microbleeds and radiation necrosis, but few studies exist of patients treated without chemotherapy. MATERIALS AND METHODS: Ten patients were treated for low-grade or benign neoplasms with external beam radiation therapy only and scanned within 12-36 months following treatment with a 7T MR imaging scanner. A multiecho gradient-echo sequence was acquired and postprocessed into SWI, quantitative susceptibility mapping, and apparent transverse relaxation maps. Six patients returned for follow-up imaging approximately 18 months following their first research scan and were imaged with the same techniques. RESULTS: At the first visit, 7/10 patients had microbleeds evident on SWI, quantitative susceptibility mapping, and apparent transverse relaxation. All microbleeds were within a dose region of >45 Gy. Additionally, 4/10 patients had asymptomatic WM signal changes evident on standard imaging. Further analysis with our technique revealed that these lesions were venocentric, suggestive of a neuroinflammatory process. CONCLUSIONS: There exists a potential for microbleeds in patients treated with external beam radiation therapy without chemotherapy. This finding is of clinical relevance because it could be a precursor of future neurovascular disease and indicates that additional care should be taken when using therapies such as anticoagulants. Additionally, the appearance of venocentric WM lesions could be suggestive of a neuroinflammatory mechanism that has been suggested in diseases such as MS. Both findings merit further investigation in a larger population set.

Imaging function in the working brain with fMRI.

The intrinsic flexibility of functional magnetic resonance imaging has allowed ever more innovative neuroscience applications. New acquisition and analysis techniques have contributed to improvements in detection sensitivity, as well as spatial and temporal resolution. Furthermore, by considering the dynamic evolution of the active brain areas in a network, computational models are making the first steps towards linking brain and mind.

Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation.

OBJECTIVE: The neuronal circuitry underlying posttraumatic stress disorder (PTSD) was studied in traumatized subjects with and without PTSD. METHOD: Traumatized subjects with (N=9) and without (N=9) PTSD were studied by using the script-driven symptom provocation paradigm adapted to functional magnetic resonance imaging at a 4-T field strength. RESULTS: PTSD subjects showed significantly less activation of the thalamus, the anterior cingulate gyrus (Brodmann's area 32), and the medial frontal gyrus (Brodmann's area 10/11) than did the comparison subjects. CONCLUSIONS: The findings suggest anterior cingulate, frontal, and thalamic involvement in the neuronal circuitry underlying PTSD.

Human forebrain activation by visceral stimuli.

Visceral function is essential for survival. Discreet regions of the human brain controlling visceral function have been postulated from animal studies (Cechetto and Saper [1987] J. Comp. Neurol. 262:27-45) and suspected from lethal cardiac arrythmias (Cechetto [1994] Integr. Physiol. Behv. Sci. 29:362-373). However, these visceral sites remain uncharted in the normal human brain. We used 4-Tesla functional magnetic resonance imaging (fMRI) to identify changes in activity in discrete regions of the human brain previously identified in animal studies to be involved in visceral control. Five male subjects underwent heart rate (HR) and/or blood pressure (BP) altering tests: maximal inspiration (MX), Valsalva's maneuver (VM), and isometric handgrip (HG). Increased neuronal activity was observed during MX, VM, and HG, localized in the insular cortex, in the posterior regions of the thalamus, and in the medial prefrontal cortex. To differentiate special visceral (taste) regions from general visceral (HR, BP) regions in these areas, response to gustatory stimulation was also examined; subjects were administered saline (SAL) and sucrose (SUC) solutions as gustatory stimuli. Gustatory stimulation increased activity in the ventral insular cortex at a more inferior level than the cardiopulmonary stimuli. The observed neural activation is the first demonstration of human brain activity in response to visceral stimulation as measured by fMRI.

A prospective study of cognitive impairment in ALS.

OBJECTIVE: To characterize prospectively the cognitive profile in ALS. METHODS: Clinically definite ALS patients (11 men, 2 women), age 39.9 to 74.0 years (mean age, 54.2 +/- 9.6 years; mean disease duration, 21.1 +/- 10.5 months) underwent neuropsychologic, language, and speech testing followed by MR 1H spectroscopy (4 T). Five spousal control subjects completed an identical protocol. Eight ALS patients participated in follow-up studies at a 6-month interval. RESULTS: Relative to control subjects, ALS patients showed mild impairment in word generation, recognition memory (faces), and motor-free visual perception. Bulbar-onset patients showed greater impairment in a number of measures (working memory, problem solving/cognitive flexibility, visual perception, and recognition memory for words and faces), and cognitive impairment appeared more progressive over time. ALS patients demonstrated anomia on a confrontation naming test, with no significant problems following commands or repeating. Speech motor performance scores and intelligibility scores were not significantly different. No significant declines in forced vital capacity, forced expiratory volume, or peak expiratory flow rates were observed. Although normal at initial testing (T1), MR 1H spectroscopy demonstrated a reduction of the N-acetylaspartate/creatine (NAA/Cr) ratio in the nondominant precentral motor strip across the two testing intervals. In contrast, the NAA/Cr ratio obtained from the anterior cingulate gyrus at T1 was already reduced in bulbar-onset patients (p < 0.001), whereas no deficits were observed in limb-onset individuals in the same region. CONCLUSIONS: Bulbar-onset ALS patients with cognitive impairments and neuronal loss in the anterior cingulate gyrus subsequently developed more profound neuropsychological dysfunction whereas both language and speech capabilities remained relatively preserved. Of note, the absence of bulbar signs did not predict an absence of cognitive decline.

Carcinoma of the urinary bladder category T3NxMo treated by the combination of radium implant and external irradiation: second report.

Forty-one patients with bladder cancer, T3NxMo, with a diameter not exceeding 5 cm, were treated by 3 times 350 rad external irradiation, radium implant at reduced dose, and an additional 3000 rad external irradiation ("Radium 55%"). Survival is excellent where there is a high or medium degree of differentiation without vascular invasion in the biopsy specimen; prognosis is poor if a low degree of differentiation is combined with vascular invasion. The future therapeutic approach will be adapted to this finding.

Cancer of the urinary bladder category T2, T3, (NxMo) treated by interstitial radium implant: second report.

Three-hundred-twenty-eight patients with bladder cancer category T2NxMo and 63 patients with category T3NxMo have been treated by 3 times 3.5 Gy external irradiation followed by a radium implant. Overall 5- and 10-year survival in the T2 category are 56%. In the T3 category they are 39% and 13%, respectively. The intercurrent death (i.e. without evidence of bladder malignancy) corrected actuarial survival percentage in the T2 category is 75% at 5 years and 69% at 10 years. The corresponding percentages in the T3 category are 62% and 59%. Prognosis is worsened by the following factors: more than 1 diagnostic transurethral resection, a pathological intravenous pyelography, non-papillary structure and poor degree of differentiation of the growth. Prognosis in category T3, as compared with category T2, is worse because of the prevalence of bad prognosticators in this T3 category. Therapeutic adaptation to these findings might improve prognosis in the future.

Carcinoma of the urinary bladder T3NxMo treated by preoperative irradiation followed by simple cystectomy.

One hundred eighty-three patients with bladder cancer category T3NxMo (the diameter of the primary exceeding 5 cm), were treated by preoperative 40 Gy and simple cystectomy. Using only pretreatment information, the group with the best prognosis was characterized by a T3A-growth with a normal intravenous pyelography, with about a 75% cure rate. Before cystectomy, after irradiation the combination of a clinically assessed radiation-downstaged growth (T40GY less than 3) with normal urography, predicted the best chance of cure at about 80%. After cystectomy was performed, the best prognostic group could be most correctly identified: those patients with both microscopic downstaging of the primary ("P" less than 3) and no vascular invasion in the cystectomy specimen (CV-) combined with normal urography had an 81% chance of cure. This most favorable group constitutes 45% of all patients.

Functional brain mapping using magnetic resonance imaging. Signal changes accompanying visual stimulation.

Easily detectable (5%-20%) transient increases in the intensity of water proton magnetic resonance (MR) signals in human primary visual cortex were observed during visual stimulation in gradient echo images at 4-T field strength. The signal intensity increases were predominantly restricted to areas containing gray matter and were used to produce high-spatial-resolution human functional brain maps. Time dependence of the functional brain maps also was monitored during visual stimulation using images acquired every approximately 5 seconds; these images with high spatial and temporal resolution demonstrated that photic stimulation first resulted in signal increases in a large area of the visual cortex followed by a reduction in the size of the area, and that signal intensity increases in the gray matter were time dependent. Reducing the image acquisition echo times reduced the amplitude of the fractional signal change, suggesting that it is produced by a change in T2 or T2*. The amplitude, sign, and echo time dependence of these intrinsic signal changes are consistent with the idea that neural activation increases regional cerebral with the idea that neural activation increases regional cerebral blood flow (rCBF) with a concomitant increase in venous blood oxygenation.

Reversal of natural resistance to bouvardin (NSC 259968) in sarcoma 180 cells in vitro and in vivo by verapamil.

Reversal of natural resistance to bouvardin (NSC 259968) has been attained in vitro and in vivo, by the calcium influx blocker verapamil in sarcoma 180 cells insensitive to bouvardin. Verapamil increased the in vitro lethality of the tumor cells following exposure with cells for 1 and 3 h as a result of the cytotoxic effect of bouvardin. Similar results were observed in vivo when the tumor cells were exposed to verapamil and then treated with bouvardin, showing a significant percent increase in the lifespan to 30% and 45%. This suggested that this calcium channel blocker had interacted with tumor cell membrane to modulate the response of the cells, and make them more amenable to the drug action.