FDG-PET/MRI with high-resolution DWI characterises the distinct phenotypes of endometrial cancer.

AIM: To evaluate the capability of integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET)/magnetic resonance imaging (MRI) to characterise the distinct phenotypes of endometrial cancer. MATERIALS AND METHODS: Thirty-one patients with endometrial cancer (23 with type I, including 17 G1 and six G2 endometrioid adenocarcinomas, and eight with type II, including three G3 endometrioid adenocarcinomas, two carcinosarcomas, and three serous carcinomas) underwent pretreatment FDG-PET/MRI with simultaneous reduced field-of-view diffusion-weighted imaging (DWI). The standardised uptake value (SUV), apparent diffusion coefficient (ADC), and SUV-to-ADC ratio were compared between low-risk (type I and stage I and negative for lymph-vascular space invasion [LVSI]) and high-risk cancers. The diagnostic accuracy for discriminating the cancer phenotypes was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The SUV was not significantly different between low-risk and high-risk endometrial cancers. High-risk cancers had a significantly lower ADC (756±232×10-6) and a greater SUV-to-ADC ratio (21.7±7.7×109) than low-risk cancers (937±154×10-6, p<0.05 and 13.1±4.1×109, p<0.005, respectively). On comparison of the area under the ROC curves (AUCs), the SUV-to-ADC ratio demonstrated the greatest diagnostic accuracy (ratio 0.83, ADC 0.72, and SUV 0.66). The AUCs for the ratios were significantly higher than those for the SUV values (p<0.05). The optimal SUV-to-ADC cut-off value of 16.9×109 for predicting high-risk cancer revealed a sensitivity of 73%, specificity of 81%, and accuracy of 77%, which was significantly higher than the accuracy for SUV. CONCLUSION: The SUV-to-ADC ratio obtained using integrated FDG-PET/MRI with high-resolution DWI reflects tumour aggressiveness including LVSI, and will be useful for lesion characterisation to decide on an appropriate therapeutic strategy for endometrial cancer.

The ideal strategy for cervical cancer screening in Japan: Result from the Fukui Cervical Cancer Screening Study.

INTRODUCTION: The aims of the Fukui Cervical Cancer Screening (FCCS) study are to determine the frequency of women with high-risk HPV (hrHPV), whether HPV16 or HPV18 (HPV16/18), in the Japanese cancer screening population for the first time and to identify the best strategy for cervical cancer screening in Japan. METHODS: This study enrolled 7584 women aged ≥25 years who were undergoing routine screening. All women underwent LBC and cobas HPV tests. Women with abnormal cytology, whether hrHPV positive or negative; women with hrHPV positivity with either normal or abnormal cytology; and women randomly selected from women with normal cytology and negative hrHPV negative were referred for colposcopy. RESULTS: The prevalences of hrHPV positivity and HPV16/18 positivity were 6.8% and 1.7%, respectively. The baseline data from the FCCS study showed that the combination of HPV tests and cytology was more sensitive than cytology with respect to the detection of intraepithelial neoplasia grade 2 or worse. However, the specificity (94.1%) of the co-testing strategy that required all women with abnormal cytology or hrHPV positivity to be referred for colposcopy was much lower than that (97.8%) of cytology. The sensitivity and specificity of the co-testing strategy that required only women with abnormal cytology or HPV16/18 positivity to undergo colposcopy were 85.5% and 97.0%, respectively. CONCLUSION: The baseline data from the FCCS study suggest that a cervical cancer screening strategy in which only women with abnormal cytology or HPV16/18 positivity undergo colposcopy offers a more balanced sensitivity and specificity than other strategies.

Local sensitivity to stimulus orientation and spatial frequency within the receptive fields of neurons in visual area 2 of macaque monkeys.

We used dynamic dense noise stimuli and local spectral reverse correlation methods to reveal the local sensitivities of neurons in visual area 2 (V2) of macaque monkeys to orientation and spatial frequency within their receptive fields. This minimized the potentially confounding assumptions that are inherent in stimulus selections. The majority of neurons exhibited a relatively high degree of homogeneity for the preferred orientations and spatial frequencies in the spatial matrix of facilitatory subfields. However, about 20% of all neurons showed maximum orientation differences between neighboring subfields that were greater than 25 deg. The neurons preferring horizontal or vertical orientations showed less inhomogeneity in space than the neurons preferring oblique orientations. Over 50% of all units also exhibited suppressive profiles, and those were more heterogeneous than facilitatory profiles. The preferred orientation and spatial frequency of suppressive profiles differed substantially from those of facilitatory profiles, and the neurons with suppressive subfields had greater orientation selectivity than those without suppressive subfields. The peak suppression occurred with longer delays than the peak facilitation. These results suggest that the receptive field profiles of the majority of V2 neurons reflect the orderly convergence of V1 inputs over space, but that a subset of V2 neurons exhibit more complex response profiles having both suppressive and facilitatory subfields. These V2 neurons with heterogeneous subfield profiles could play an important role in the initial processing of complex stimulus features.

Neuronal responses in visual area V2 (V2) of macaque monkeys with strabismic amblyopia.

Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia.

Inhibition of transforming growth factor-beta signalling attenuates interleukin (IL)-18 plus IL-2-induced interstitial lung disease in mice.

Interstitial lung disease (ILD) is an intractable disease induced by various factors in humans. However, there is no universally effective treatment for ILD. In this study, we investigated the role of transforming growth factor (TGF)-beta signalling in the pathogenesis of ILD by using model mice. Injection of interleukin (IL)-18 plus IL-2 in C57BL6 (B6) mice resulted in acute ILD by infiltration of natural killer (NK) cells and a significant increase of TGF-beta mRNA in the lung. To examine the pathogenetic role of TGF-beta in ILD mice, we used SB-431542 (4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]-benzamide), which is a potent and selective inhibitor of TGF-beta receptor I (TbetaRI), also known as activin receptor-like kinase 5 (ALK5). Treatment of B6-ILD mice with SB-431542 resulted in improvement of ILD, delay in mortality, reduction of the expression of interferon (IFN)-gamma and IL-6 in the lungs. The same treatment also decreased significantly the percentage of natural killer (NK) cells in the lungs (P < 0.05) and mRNA expression levels of certain chemokines such as CCL2, CCL3, CCL4, CCL5 and CXCL10 in B6-ILD. These findings were confirmed by IL-18 plus IL-2 treatment of Smad3-deficient (Smad3(-/-)) mice (P < 0.05). Our results showed that inhibition of TGF-beta signalling reduced the percentage of NK cells and the expression of certain chemokines in the lungs, resulting in improvement of ILD. The findings suggest that TGF-beta signalling may play an important role in the pathogenesis of IL-18 plus IL-2-induced ILD in mice.

Laser microdissection-based analysis of cytokine balance in the kidneys of patients with lupus nephritis.

To determine the cytokine balance in patients with lupus nephritis (LN), we analysed kidney-infiltrating T cells. Renal biopsy samples from 15 systemic lupus erythematosus (SLE) patients were used. In accordance with the classification of International Society of Nephrology/Renal Pathology Society, they were categorized into Class III, Class III+V (Class III-predominant group, n = 4), Class IV, Class IV+V (Class IV-predominant group, n = 7) and Class V (n = 4) groups. The single-cell samples of both the glomelular and interstitial infiltrating cells were captured by laser-microdissection. The glomerular and interstitial infiltrating T cells produced interleukin (IL)-2, IL-4, IL-10, IL-13 and IL-17 cytokines in the Class III-predominant, Class IV-predominant and Class V groups. Interferon-gamma was detected only in the glomeruli of the Class III-predominant and Class V group samples. The expression level of IL-17 was correlated closely with clinical parameters such as haematuria, blood urea nitrogen level, SLE Disease Activity Index scores in both glomeruli and interstitium, urine protein level in glomeruli and serum creatinine and creatinine clearance levels in interstitium. This suggests that the glomerular infiltrating T cells might act as T helper type 1 (Th1), Th2 and Th17 cells while the interstitial infiltrating T cells, act as Th2 and Th17 cells in the Class III-predominant and Class V groups. In contrast, both the glomerular and interstitial infiltrating T cells might act as Th2 and Th17 cells in the Class IV-predominant group. The cytokine balances may be dependent upon the classification of renal pathology, and IL-17 might play a critical role in SLE development.

Siamese cats: abnormal responses of retinal ganglion cells.

Comparison of optic tract recordings in Siamese and ordinary cats reveals that Siamese cats have a significantly lower percentage of Y-cells than of X-cells. In addition, Siamese cats show depressed responses to a contrast-reversal stimulus, a result that supports the lower spatial contrast sensitivity demonstrated behaviorally by these animals. Both physiological findings suggest neurophysiological anomalies in the Siamese retina.

Reorganization of retinotopic cortical maps in adult mammals after lesions of the retina.

The organization of the visual cortex has been considered to be highly stable in adult mammals. However, 5 degrees to 10 degrees lesions of the retina in the contralateral eye markedly altered the systematic representations of the retina in primary and secondary visual cortex when matched inputs from the ipsilateral eye were also removed. Cortical neurons that normally have receptive fields in the lesioned region of the retina acquired new receptive fields in portions of the retina surrounding the lesions. The capacity for such changes may be important for normal adjustments of sensory systems to environmental contingencies and for recoveries from brain damage.

Reexamination of photoreceptor-bipolar connectivity patterns in carp retina: HRP-EM and Golgi-EM studies.

On- and off-center bipolar cells were identified in the carp retina by means of intracellular recording, intracellular injection of HRP, and Golgi silver-chromate impregnation. Light and electron microscopy revealed that these functionally different bipolar cells make synaptic contacts with both rods and cones, and that both on- and off-center cells can be further divided into two subtypes (I and II) according to the relationship between the position of their dendritic processes and the synaptic ribbons in the photoreceptor terminal. The type I on-center bipolar cell is characterized by a large cell body, a thick primary dendrite, and a big swelling of the axon terminal in the innermost part of the inner plexiform layer (IPL). Dendritic processes of this cell type make predominantly ribbon contacts with rods and nonribbon contacts with cones. The type II on-center cell, having a large dendritic tree in the outer plexiform layer and a large ramification of the axon terminal extending over the inner part of the IPL makes mostly nonribbon contacts with rods and cones. Many of these type II cell processes, however, terminate very close to cone synaptic ribbons. The type I off-center cell shows two varieties in the axon terminal structure; a large terminal swelling or a large flat ramification of the terminal in the outermost part of the IPL. These cells make predominantly ribbon contacts with rods and cones. Usually, but not always, the process of a type I off-center cell runs parallel to the synaptic ridge apex of cones. The type II off-center cell, showing a large ramification of the axon terminal extending over the outer half of the IPL, makes mainly nonribbon contacts with rods and cones. The results from the HRP-EM study generally agree with those from the Golgi-EM study. A few discrepancies between the results obtained with these two techniques are noted and their implication is discussed.

Receptive field properties of simple and complex striate neurons in Siamese cats.

Responses of striate cortical cells in Midwestern Siamese cats to moving slits and stationary flashed spots were recorded and compared to similar data in common cat controls obtained under identical experimental conditions. Over 90% of the neurons sampled had receptive fields within 10 degrees of the area centralis. The proportion of binocularly excited cells in Siamese striate cortex was less than that found in the control cats, but more than has previously been reported, and was inversely related to the extent of convergent misalignment exhibited by each animal. Those striate neurons which could be driven by either eye had normal binocular receptive fields and demonstrated normal binocular interaction effects except facilitation. Receptive field dimensions (length, width, area) were significantly larger in Siamese than in common cats. For the simple cells, strabismic Siamese cats had larger receptive fields than orthophoric Siamese cats. Average spontaneous activity in Siamese cats was significantly higher than in the controls. However, similar encounter rates of simple, complex, and hypercomplex units were observed in both Siamese and common cats, and peak responses were not different. Velocity preference in complex Siamese units was shifted to slower velocities compared to common cat complex cells. A loss of direction selectivity was also revealed in the Siamese simple and complex neurons. Finally, sharpness of orientation tuning was dramatically reduced in Siamese complex cells, and this reduction was directly related to the extent of convergent squint exhibited by each animal. The results are discussed in terms of developmental anomalies and neurophysiological retinal abnormalities in Siamese cats.

Effects of convergent strabismus on the development of physiologically identified retinogeniculate axons in cats.

We have studied the effects of surgically induced convergent strabismus (esotropia) on the morphological development of retinogeniculate X and Y axon arbors in cats. Single axons were recorded in the lateral geniculate nucleus or in the optic tract adjacent to the nucleus, classified physiologically, and injected intracellularly with horseradish peroxidase. The arbors of recovered axons were compared with X and Y axon arbors from normally reared adult cats. Our data demonstrate that while X axon arbors are relatively normal, the arbors of Y axons are profoundly affected by rearing with strabismus. Y axons, whether originating from the deviated or the nondeviated eye, have substantially smaller arbors and fewer boutons in the A-laminae of the lateral geniculate nucleus compared to Y axons in normal cats. The C-lamina terminations of contralaterally projecting Y axons in the strabismic cats are unaffected. These results suggest that the postnatal development of retinogeniculate Y axon arbors in the A-laminae is strongly influenced by abnormalities in postnatal visual experience. Furthermore, the present data suggest that, in addition to intraocular competitive interactions between X and Y axons previously proposed to account for the effects of other rearing conditions, interactions between afferents from the two eyes must also be involved in the development of at least Y axons.

Abnormal orientation bias of LGN neurons in strabismic cats.

The reduced visual sensitivity of strabismic amblyopes is often accentuated when they view vertical as opposed to horizontal gratings ("vertical effect"). Earlier attempts to show neurophysiological correlates of the vertical effect in strabismic cats have yielded controversial findings. We now report the results of experiments in the lateral geniculate nucleus (LGN) that clearly demonstrate the reduced sensitivity of X-cells in strabismic cats to vertical gratings as compared to horizontal ones. We conclude that the neural basis for the vertical effect is present at least at the level of the LGN.

Effect of onset age of strabismus on the binocular responses of neurons in the monkey visual cortex.

PURPOSE: By 6 weeks of age, neurons in the monkey's primary visual cortex acquire qualitatively adult-like binocular response properties and behaviorally stereopsis emerges. In this study, it was determined whether the onset of strabismus has a more severe impact on cortical binocularity before or after this critical developmental age. METHODS: Infant monkeys were fit with a light-weight helmet which held a total of 27 diopters of base-in prisms in front of their two eyes for a fixed period of two weeks. For one group of infant monkeys, prism-rearing began at 2 weeks of age and for a second group, the onset was at 6 weeks of age. Immediately after the rearing period, i.e., at 4 weeks and 8 weeks of age, respectively, extracellular single-unit recording methods were used to determine the nature and severity of alterations in the binocular response properties of V1 neurons. Dichoptic sinewave gratings were used as visual stimuli. RESULTS: In comparison to normal age-matched infants, V1 neurons in both strabismic groups exhibited reductions in sensitivity to interocular spatial phase disparities (disparity sensitivity) and a higher prevalence of binocular inhibitory interactions (binocular suppression). However, the reduction in disparity sensitivity and the magnitude of binocular suppression were much greater in the late (6-8 weeks) than the early (2- 4 weeks) onset group. CONCLUSIONS: Discordant binocular signals due to brief periods of early strabismus have more serious effects on the development of binocular properties of V1 neurons if they occur shortly after rather than before the emergence of stereopsis (i.e., when the binocular connections are relatively more mature but the visual cortex still shows a high degree of plasticity).

Binocular cross-orientation suppression in the primary visual cortex (V1) of infant rhesus monkeys.

PURPOSE: To better understand the course of cortical maturation during early development, the phenomenon of binocular cross-orientation suppression in neurons of the primary visual cortex (V1) in young infant monkeys was investigated. METHODS: Extracellular single-unit recordings were made in anesthetized and paralyzed monkeys ranging in age between 6 days and 8 weeks. Orthogonally oriented, dichoptic sine-wave gratings were used as visual stimuli. RESULTS: V1 neurons in young infant monkeys showed a higher prevalence and greater magnitude of binocular cross-orientation suppression than in adult monkeys. Binocular suppression decreased and reached an adult level between 4 and 8 weeks of age, the presumed onset-age for stereopsis in monkeys. CONCLUSIONS: During the first 4 weeks of life, the functional connections that are necessary for initiating binocular cross-orientation suppression exist in the monkey primary visual cortex. This finding is consistent with the view that before the abrupt onset of stereopsis, human infants may detect the differences between interocularly iso-oriented gratings and orthogonal gratings.

Nasotemporal directional bias of V1 neurons in young infant monkeys.

PURPOSE: Optokinetic nystagmus (OKN) in young infants typically shows a temporal-to-nasal asymmetry under monocular viewing conditions. The neural basis for this asymmetry has been a matter of debate. One idea is that the OKN asymmetry reflects a similar asymmetry in the directional sensitivity of primary visual cortical (V1) neurons. An alternative hypothesis is that the OKN asymmetry is due to an immaturity in the ability of cortical neurons to influence the activity of subcortical structures that directly control OKN. We addressed this issue by studying the directional sensitivity of V1 neurons in young infant monkeys. METHODS: The neuronal activity of V1 units was recorded from anesthetized and paralyzed rhesus monkeys ranging in age from 6 days to 8 weeks using standard extracellular single-unit recording methods. For comparison, V1 units from normal adult monkeys were also studied. Using drifting sinusoidal gratings of the optimal spatial frequency and a moderate contrast, we measured the responsiveness of individual units to 24 directions of stimulus movement. The preferred stimulus direction and the magnitude of the directional response bias were determined by a vector summation method. RESULTS: No clear signs of nasotemporal asymmetries in direction tuning were found in our cell population from infant monkeys. However, the overall directional sensitivity and the peak monocular response amplitudes of these units were significantly lower, and binocular suppression was greater during the first 4 weeks of life than in adults. CONCLUSIONS: The OKN asymmetry in young infants may be more closely associated with the lower overall directional sensitivity and the subnormal responsiveness of V1 neurons rather than with an obvious asymmetry in the directional properties of V1 neurons.

The role of visual experience in the cortical topographic map reorganization following retinal lesions.

The mature visual cortex is capable of reorganizing its functional connections in response to retinal injuries. Although this phenomenon is well established, there are a number of unresolved issues. This paper will review some of the more critical aspects of adult plasticity including those based on our most recent findings. Our preliminary data indicate that a large-scale reorganization of cortical maps following retinal injuries may require an increase in synaptic strengths at key cortical sites promoted by long-term, repeated use.

Posterior mediastinal endodermal sinus (yolk sac) tumor in a female patient.

Primary endodermal sinus tumor (yolk sac tumor) of the mediastinum is uncommon. Most patients are young and male, and the great majority of tumors are found in the anterior mediastinum. We report a case of primary posterior mediastinal endodermal sinus tumor occurring in a female patient. Surgical excision was performed and three courses of combination chemotherapy were subsequently given. The serum alpha-fetoprotein level returned to normal.

Dopaminergic amacrine cells in the retina of Japanese dace.

The morphological and physiological identification of the cells in the inner retina of Japanese dace was made by means of intracellular single cell recording and dye injection techniques. Our flat mounts and physiological classification revealed that 97 out of 102 sample cells were amacrine cells except for 3 transient neurons possibly being ganglion cells. Only two cells were identified as interplexiform cells. The double-labeling histochemical technique showed that 17 cells including the two interplexiform cells are dopaminergic neurons. Therefore, 15 of 97 amacrine cells in dace retina were dopaminergic cells, a finding which is different from the previously published data.

Spectral opponency of on-type ganglion cells and the blue preference of Rana pipiens.

Spectrally opponent processes of ON-type retinal ganglion cells and the blue preference behavior were identified by parallel physiological and behavioral experiments in Rana pipiens. Spectral opponency of retinal ON-units was measured by recording from optic nerve terminals in the anterior thalamus, while the retina was stimulated by combinations of monochromatic stimuli. Spectral opponency of the blue preference was determined in a Y-maze, using similar combinations of monochromatic stimuli. The opponent processes of the ON-units and blue preference are similar in the spectral ranges of excitatory and inhibitory effects. In both cases the spectral opponency can be described as short wavelength excitation and long wavelength inhibition. The data suggest that the short wavelength excitation is based, at least in part, on the green rod (P432) channel, while the long wavelength inhibition is caused, at least in part, by stimulation of the principal and/or single cone (P580) channel. A model is presented to show how receptor interactions may encode this spectrally opponent process. The results support the hypothesis that the blue preference is dependent on information supplied to the anterior thalamus by ON-type retinal ganglion cells.

Properties of X- and Y-type retinal ganglion cells in Siamese cats.

There is ample evidence that the visual system of the Siamese cat is different from common cats. These abnormalities suggest possible retinal origins, although no documentation exists. In the present study, single unit recordings were made from 91 misrouted and 209 normally-routed optic tract fibers in Siamese cats. Electrophysiological responses of the misrouted fibers did not differ from those found in the normally-routed fibers of the Siamese cat with the exception of depressed responses to contrast reversal stimuli. X/Y classification of units and experiments on receptive field center sizes, intensity-response functions, and responses to flicker failed to demonstrate significant differences between the misrouted and normally-routed fibers in Siamese cats. These results were not affected by different degrees of interocular misalignment exhibited by the Siamese cat studied. Response properties of retinal ganglion cells in Siamese cats, however, were found to be quite abnormal when compared with common cats. Only 14% (42/300) of all units studied were Y-cells in Siamese cats in comparison to 35% (60/170) in common cats. The percentage of Y-units also was correlated with the severity of interocular misalignment in Siamese cats, i.e. the greater the misalignment of the eyes, the lower the percentage of Y-cells. Experiments on response to contrast reversal stimuli, intensity-response functions and responses to flicker revealed that the ganglion cells in Siamese cats are not as responsive as those in common cats.