Simulating activations with cytoarchitecture

Cytoarchitectonic delineation of areas in post-mortem human brains provides the precise location of these areas. It has been possible to study the size and location of areas between post-mortem brains with multi-subject cytoarchitectonic data. If the structure–function relationship is assumed to be a one-to-one mapping for the purposes of inter-subject variability, then functional areas in the cortex will also adhere to the structure, and therefore, the location and size of cytoarchitectonic areas in the brain. Thus, it is possible to use the cytoarchitectonic data as being representative of the size and location of functional activations. Under this assumption, we simulated activations in cytoarchitectonic areas from ten post-mortem brains in this study. We then treated these data as we would a normal PET experiment. The purpose of this study is to demonstrate a standard PET image analysis on a simulated ten-subject PET study using cytoarchitecture to localize the activations. By doing so, we simulate activations with real inter-subject variability with the size and location of each area. Significant activations were obtained for activations simulated in areas 3a and 3b. A voxel-wise conjunction between simulated data and experimental data was made to better determine the underlying areas activated by the experimental tasks. This study presents a novel technique for demonstrating the effect of standard image analysis on the location and size of simulated activations as determined by cytoarchitectonic data from multiple subjects. Furthermore, this technique has been applied to better determine the underlying areas activated in an experiment.     

Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma

In southern Vietnam, a four-year-old boy presented with severe diarrhea, followed by seizures, coma, and death. The cerebrospinal fluid contained 1 white cell per cubic millimeter, normal glucose levels, and increased levels of protein (0.81 g per liter). The diagnosis of avian influenza A (H5N1) was established by isolation of the virus from cerebrospinal fluid, fecal, throat, and serum specimens. The patient's nine-year-old sister had died from a similar syndrome two weeks earlier. In both siblings, the clinical diagnosis was acute encephalitis. Neither patient had respiratory symptoms at presentation. These cases suggest that the spectrum of influenza H5N1 is wider than previously thought.     

Cell signalling-mediating insulin increase of mRNA expression for cationic amino acid transporters-1 and -2 and membrane hyperpolarization in human umbilical vein endothelial cells

Insulin induces vasodilatation in human subjects and increases l-arginine transport and NO synthesis in human umbilical vein endothelial cells (HUVEC). Cell signalling events associated with insulin effects on activity and mRNA expression of the human cationic amino acid transporters 1 (hCAT-1) and 2B (hCAT-2B) are unknown. l-Arginine transport and eNOS activity were determined in HUVEC exposed to insulin. mRNA levels for hCAT-1, hCAT-2B and eNOS were quantitated by real time RT-PCR and endothelial NO synthase (eNOS) protein was identified by Western blot analysis. Intracellular Ca²⁺, l-arginine and l-citrulline levels, l-[³H]citrulline formation from l-[³H]arginine, cGMP formation, nitrite level, ATP release and membrane potential were determined. Insulin increased l-arginine transport and the mRNA levels for hCAT-1 and hCAT-2B and eNOS expression and activity. Insulin also induced membrane hyperpolarization and increased intracellular Ca²⁺, l-[³H]citrulline, cGMP and nitrite formation. Insulin-mediated stimulation of the l-arginine/NO pathway is thus associated with increased hCAT-1 and hCAT-2B mRNA, and eNOS expression, via mechanisms involving membrane hyperpolarization, mitogen-activated protein kinases p42 and p44, phosphatidylinositol 3-kinase, NO and protein kinase C. We have characterized a cell signalling pathway by which hyperinsulinaemia could lead to vasodilatation in human subjects, and which could have implications in patients in whom plasma insulin levels are altered, such as in diabetes mellitus.     

Persistent tubular conduction in vacuolated amphibian skeletal muscle following osmotic shock

The transverse (T-)tubules primarily function in conducting the action potentials that initiate excitation– contraction coupling in skeletal muscle but may additionally subserve longer-term roles in volume regulation, membrane fusion and other trafficking processes. Osmotic shock thus both electrically detaches the T-tubules from surface membrane (‘detubulation’) and produces tubular vacuolation. The present experiments separated these effects. An established, reference osmotic shock protocol that exposed muscles to Ca²⁺/Mg²⁺-Ringer and gradual cooling to 10°C after 18 min in glycerol–Ringer accomplished significant detubulation (77.5 ± 13.15%, mean ± SEM; n = 4). In contrast, a test protocol conducted entirely at room temperature using Mg²⁺-rather than Ca²⁺/Mg²⁺-Ringer yielded reduced (P < 0.05, post hoc Duncan's multiple range test) detubulation indices (1.67 ± 1.67%, n = 6) statistically indistinguishable from findings in fibres spared osmotic shock. Yet both osmotic shocks caused a formation of closed vacuoles, demonstrated by Sulphorhodamine B trapping, that occupied statistically similar fractions of total fibre volume (reference procedure: 14.38 ± 2.7%, n = 6; test procedure: 13.36 ± 2.00%, n = 22) in turn higher than determinations in control fibres (P < 0.05). The findings reconcile reports associating detubulation with vacuolation in osmotically shocked muscle [S. Nik-Zainal et al. (1999) J Muscle Res Cell Motil 20: 45–53; K.N. Khan et al. (2000) J Muscle Res Cell Motil 21: 79–90] with the persistence of tubular electrical activity in extensively vacuolated amphibian fibres following fatigue [J. Lannergren and H. Westerblad (1987) Acta Physiol Scand 129: 311–318; J. Lannergren et al. (1999) J Muscle Res Cell Motil 20: 19–32]. Furthermore test protocols produced higher densities of open vacuoles (13.38 ± 2.33%, n = 9) than did reference protocols (6.66 ± 1.63%, n = 20) contrary to their possible involvement in the electrophysiological changes. Abolition of tubular electrophysiological activity thus either follows or is independent of tubular vacuolation whilst sharing some of its underlying osmotic mechanisms. This revised version was published online in July 2006 with corrections to the Cover Date.     

Role of the pathologist in the diagnosis of hereditary non-polyposis colorectal cancer

The aim of this paper is to indicate how the pathologist may suspect a diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) on the basis of histological criteria and patient age alone. A single morphological feature, namely the presence of intra-epithelial lymphocytes (tumor infiltrating lymphocytes), identifies the majority of colorectal cancers (CRC) with the DNA microsatellite instability-high phenotype. A number of pathological criteria can help to distinguish HNPCC from sporadic MSI-H CRC, though age below 60 years is an important pointer towards HNPCC. Immunohistochemistry to demonstrate loss of expression of DNA mismatch repair genes serves as a highly reliable test of mismatch repair deficiency if antibodies to hMLH1, hMSH2, hMSH6 and hPMS2 are employed.     

Testing the Habituation-Based Model of Exposures for Child and Adolescent Anxiety

Exposure has been identified as key to effective treatment of youth anxiety. However, the precise theoretical mechanisms of exposure are a matter of debate. Emotional processing theory emphasizes the need for fear activation during exposure and its habituation both within and across exposures. Despite the popularity of the theory to explain exposure, it has not been tested with anxious youth. To determine whether emotional processing theory parameters predict anxiety severity, coping abilities, and global functioning after cognitive-behavioral treatment. The present study examined 72 youth (M_age = 10.50 years; 45% female; 87.5% non-Hispanic Caucasian) diagnosed with an anxiety disorder and who received family or individual CBT. Three exposure habituation variables—initial fear activation (peak anxiety), within-session habituation, and between-session habituation—were assessed using Subjective Units of Distress and examined as predictors of outcome at posttreatment and at 1-year follow-up. Outcomes were measured using the Coping Questionnaire, Multidimensional Anxiety Scale for Children, Revised Children’s Manifest Anxiety Scale, Children’s Global Assessment Scale, and clinician severity ratings on the Anxiety Disorder Interview Schedule. Emotional processing theory variables did not predict any anxiety outcomes at posttreatment or follow-up with one exception: Initial fear activation predicted less anxiety at follow-up among youth without GAD. In addition, within- and between-session habituation were not associated with one another. Between-session habituation was not associated with initial fear activation. These findings suggest a limited role of habituation within cognitive-behavioral therapy for anxiety in youth. An alternative to emotional processing theory, inhibitory learning theory, is discussed.     

Immunohistochemical Localization of p53 in Human Thyroid Neoplasms: Correlation with Biological Behavior

Molecular analyses of thyroid tumors have documented mutations in the tumor suppressor p53 gene almost exclusively in anaplastic carcinomas. In contrast, immunohistochemistry has localized p53 in differentiated papillary and follicular thyroid cancers. To establish the significance of p53 immunolocalization in these lesions, 78 thyroid tumors of follicular derivation were examined. All tumors were classified by strict criteria and the extent of tumor was determined morphologically. Immunohistochemical staining for p53 was performed on paraffin sections of formalin-fixed tumor tissue. The results of staining were correlated with diagnosis, tumor extent and clinical outcome. Immunopositivity for p53 was diffuse and strong in all five anaplastic carcinomas examined. There was no staining in five of six follicular adenomas. Four of nine follicular carcinomas had some degree of nuclear staining, but this was focal; all nine tumors were confined to the thyroid at the time of examination. Of 49 papillary carcinomas, 26 were intrathyroidal, and 7 of these were occult; there was no p53 positivity in any occult lesion and only 5 of the 19 palpable lesions stained. In contrast, among 23 papillary carcinomas with extrathyroidal extension or metastases, only 9 were negative for p53 immunoreactivity. Five of seven tall cell papillary carcinomas and one of two insular carcinomas had p53 immunopositivity and this correlated with aggressive behavior. These results support the tumorigenic role of p53 mutations postulated for anaplastic thyroid carcinomas and indicate that localization of p53 by immunohistochemistry is a useful prognostic index of clinical behavior in differentiated thyroid carcinomas of follicular cell derivation.     

Effect of patient sex, clinician sex, and sex role on the diagnosis of Antisocial Personality Disorder: models of underpathologizing and overpathologizing biases

This study examined the influence of patient sex and clinician sex and sex role for a case, meeting minimum diagnostic criteria for Antisocial Personality Disorder, in which patient sex was varied. The purpose was to provide an in-depth evaluation of the process by which patient sex and characteristics of clinicians may contribute to bias in personality disorder diagnoses. Psychologists (N = 167) read two cases, including the target case, and provided symptom ratings and diagnoses. A sex-unspecified condition served as a baseline to assess for over- and underpathologizing bias, and diagnoses based on the symptom ratings were compared to assigned diagnoses. Clinician sex role was assessed using the Bem Sex Role Inventory-Short Form. Results revealed that bias occurred when the patient's sex (female) was inconsistent with the gender weighting of the symptoms in the case (masculine), but the direction of the bias was consistent with sex roles (underdiagnosis of sex-role-inconsistent diagnoses, overdiagnosis of sex-role-consistent diagnoses). Path models of over- and underdiagnostic bias were developed using structural equation modeling. Patient sex had a direct effect on diagnostic ratings whereas clinician sex role had an indirect effect through symptom ratings.     

Central melanocortin receptor agonist reduces spontaneous and scheduled meal size but does not augment duodenal preload-induced feeding inhibition

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague-Dawley rats following central intracerebroventricular administration of MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.