Reliable detection of bilateral activation in human primary somatosensory cortex by unilateral median nerve stimulation

In non-human primates, a bilateral representation of unilaterally presented somatosensory information can be found at the lowest level of cortical processing as indicated by the presence of neurons with bilateral receptive fields in the hand region of primary somatosensory (SI) cortex. In humans, such bilateral activation of SI is considered controversial due to highly variable detection rates for the much weaker ipsilateral response across different studies (ranging from 3% to 100%). Second-order blind identification (SOBI) is a blind source separation algorithm that has been successfully used to isolate neuronal signals from functionally distinct brain regions, including the left- and right-SI. SOBI-aided extraction of left- and right-SI responses to median nerve stimulation from high-density EEG has been previously validated against the fMRI and MEG literature. Here, we applied SOBI to EEG data and examined whether relatively weaker ipsilateral activations could be reliably detected across subjects. In single subject analysis, statistically significant somatosensory evoked potentials (SEPs) in response to unilateral stimulation were detected from both SI contralateral to and SI ipsilateral to the side of stimulation. Furthermore, these ipsilateral responses were observed in both the left and right hemispheres of all 10 subjects studied. Together these results demonstrate that unilateral stimulation of the median nerve, whether applied to the left or right wrist, can activate both the left- and right-SI, raising the possibility that in humans, unilateral sensory input may be bilaterally represented at the lowest level of cortical processing.     

High-resolution manometry and impedance-pH/manometry: valuable tools in clinical and investigational esophagology

Both high-resolution manometry (HRM) and impedance-pH/manometry monitoring have established themselves as research tools and both are now emerging in the clinical arena. Solid-state HRM capable of simultaneously monitoring the entire pressure profile from the pharynx to the stomach along with pressure topography plotting represents an evolution in esophageal manometry. Two strengths of HRM with pressure topography plots compared with conventional manometric recordings are (1) accurately delineating and tracking the movement of functionally defined contractile elements of the esophagus and its sphincters, and (2) easily distinguishing between luminal pressurization attributable to spastic contractions and that resultant from a trapped bolus in a dysfunctional esophagus. Making these distinctions objectifies the identification of achalasia, distal esophageal spasm, functional obstruction, and subtypes thereof. Ambulatory intraluminal impedance pH monitoring has opened our eyes to the trafficking of much more than acid reflux through the esophageal lumen. It is clear that acid reflux as identified by a conventional pH electrode represents only a subset of reflux events with many more reflux episodes being composed of less acidic and gaseous mixtures. This has prompted many investigations into the genesis of refractory reflux symptoms. However, with both technologies, the challenge has been to make sense of the vastly expanded datasets. At the very least, HRM is a major technological tweak on conventional manometry, and impedance pH monitoring yields information above and beyond that gained from conventional pH monitoring studies. Ultimately, however, both technologies will be strengthened as outcome studies evaluating their utilization become available.     

Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis

BACKGROUND & AIMS: The mechanism for development of primary biliary cirrhosis (PBC) remains enigmatic, but molecular mimicry has been implicated because of well-known cross-reactivity of human mitochondrial autoantigens and equivalent bacterial antigens. Virtually all patients with PBC have antimitochondrial autoantibodies (AMA), but, interestingly, approximately 50% also manifest antinuclear antibodies (ANA). METHODS: To determine whether generation of ANA are due to molecular mimicry of mitochondrial peptides, we established 6 T-cell clones selected by a peptide corresponding to the E2 subunit of mitochondrial pyruvate dehydrogenase complex and analyzed for reactivity to mimicry peptides derived from mitochondrial and nuclear autoantigens, including control sequences. RESULTS: For mitochondrial autoantigens, 1 peptide from the E2 subunit of the pyruvate dehydrogenase complex, 1 peptide from the E2 subunit of the oxo-glutarate dehydrogenase complex, 1 peptide from the E2 subunit of the branched-chain 2-oxoacid dehydrogenase complex, and 1 peptide from the E3-binding protein cross-reacted with these T-cell clones. For the nuclear autoantigens, 5 peptides from gp210 and 1 from Sp100 cross-reacted with these clones. Furthermore, 1 of 3 T-cell clones selected by recombinant gp210 protein reacted with a mimicry peptide corresponding to amino acids 188-201 of gp210, indicating that this part of the protein is a naturally processed immunodominant T-cell epitope. CONCLUSIONS: These results demonstrate molecular mimicry between mitochondrial and nuclear autoantigens in PBC and that a mimicry peptide may become an immunodominant T-cell epitope. These data have significance not only for PBC but also for the production of ANA in other disease processes.     

Macrophage migration inhibitory factor promotes intestinal tumorigenesis

BACKGROUND & AIMS: The cytokine macrophage migration inhibitory factor (MIF) is expressed throughout the human gastrointestinal tract. Recently, protumorigenic activity of MIF has been described in several cancer models. Therefore, we investigated the expression and function of MIF during the early stages of intestinal tumorigenesis. METHODS: MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. MIF function was investigated by using VACO-235 human colorectal adenoma cells in vitro and by testing the effect of genetic deletion of Mif on ApcMin/+ mouse intestinal tumorigenesis. RESULTS: MIF expression and tautomerase activity were increased in human and ApcMin/+ mouse intestinal adenomas compared with adjacent normal mucosa. Up-regulation of MIF occurred mainly in epithelial cells (associated with an increasing grade of dysplasia), but also in stromal plasma cells. Exogenous MIF inhibited apoptosis and promoted anchorage-independent growth of VACO-235 cells (maximal at 100 ng/mL). Homozygous deletion of Mif was associated with a reduction in the number and size of ApcMin/+ mouse adenomas (P = .025 for the difference in large [>7-mm] tumors) and decreased angiogenesis (43% decrease in mean tumor microvessel density), but there was no alteration in epithelial cell apoptosis or proliferation. CONCLUSIONS: MIF expression is increased in sporadic human colorectal adenomas, and exogenous MIF drives tumorigenic behavior of epithelial cells in vitro. Mif also promotes intestinal tumorigenesis (predominantly via angiogenesis) in the ApcMin/+ mouse. Therefore, MIF is a potential colorectal cancer chemoprevention target.     

Epidermoid cyst in intrapancreatic accessory spleen: A systematic review

Background/Objectives

Due to its rarity, epidermoid cyst in intrapancreatic accessory spleen (ECIPAS) is still a diagnostic dilemma during clinical practice. The aim of this review was to summarize the epidemiologic features and management of ECIPAS.

Safety of sputum induction during exacerbations of COPD

Sputum induction (SI) is considered to be a safe tool for assessing airway inflammation in stable patients with COPD, but little is known about its safety during exacerbations. We therefore assessed the safety of SI during COPD exacerbations. SI data from 44 COPD patients were assessed both in the stable phase and during exacerbation. The median FEV1 for the stable phase and exacerbation were 61% predicted (interquartile range [IQR], 49 to 74% predicted) and 51% predicted (IQR, 45 to 60% predicted), respectively. The median decrease in FEV(1) with SI during an exacerbation was 0.27 L (IQR, 0.17 to 0.40 L) vs 0.28 L (IQR, 0.22 to 0.44 L) during the stable phase (p = 0.03). The patients experienced the associated dyspnea well; no other adverse events occurred. All FEV1 values returned to within 90% of their initial value within 30 min. A larger decrease in FEV1 due to SI during an exacerbation was associated with the following parameters in the stable phase of disease: lower total sputum cell count (r = -0.37; p = 0.01); higher percentage of eosinophils (r = 0.33; p = 0.04); and a larger decrease in FEV1 after SI (r = 0.39; p = 0.03). In a multivariate analysis, the only independent association was with the larger decrease in FEV1 in the stable phase. We concluded that SI can be safely carried out in patients with mild-to-moderate COPD who experience an exacerbation, and this occurs with no greater risk than in stable patients with COPD.     

Thyroid hormone improves the mechanical performance of the post-infarcted diabetic myocardium: A response associated with up-regulation of Akt/mTOR and AMPK activation

Objective

Thyroid hormone (TH) is shown to be protective against cardiac and pancreatic injury. Thus, this study explored the potential effects of TH treatment on the functional status of the postinfarcted diabetic myocardium. Diabetic patients have worse prognosis after acute myocardial infarction (AMI).

Materials/Methods

AMI was induced by left coronary ligation in rats previously treated with 35 mg/kg streptozotocin (STZ), (DM-AMI). TH treatment was initiated at 2 weeks after AMI and continued for 6 weeks (DM-AMI + TH), while sham-operated animals served as control (DM-SHAM).

Results

TH treatment increased cardiac mass, improved wall stress and favorably changed cardiac geometry. TH significantly increased echocardiographic left ventricular ejection fraction (LVEF%): [54.2 (6.5) for DM-AMI + TH vs 37 (2.0) for DM-AMI, p < 0.05]. TH treatment resulted in significantly increased insulin and decreased glucose levels in serum. The ratios of phosphorylated (p)-Akt/total Akt and p-mTOR/total mTOR were increased 2.0 fold and 2.7 fold in DM-AMI + TH vs DM-AMI respectively, p < 0.05. Furthermore, the ratio of p-AMPK/total AMPK was found to be increased 1.6 fold in DM-AMI + TH vs DM-AMI, p < 0.05.

Conclusion

TH treatment improved the mechanical performance of the post-infarcted myocardium in rats with STZ-induced diabetes, an effect which was associated with Akt/mTOR and AMPK activation.     

Somatotopic organization of corticospinal and corticotrigeminal neurons in the rat

The method of retrograde axonal transport of horseradish peroxidase was employed to examine the topographic organization of corticospinal and corticotrigeminal neurons in the rat. In both the first somatic sensory (SI) area and the motor (MI) area of the cortex these labeled corticofugal neurons, all of which are found in layer V, are grouped in a well organized, somatotopic pattern. Corticospinal projections which extend to lumbar levels of the spinal cord originate only from neuronal somata located in the hindlimb representation of SI and MI. Those neurons projecting to the cervical enlargement have somata mainly in the forelimb representation of SI and MI and the ventrolateral part of the trunk representation within SI. Cortical projections to the rostral cervical spinal segments appear to originate mainly from the neck and posterior head representations of SI and MI, though this conclusion is clearest for SI. Finally, neurons located exclusively within the head, muzzle, and vibrissal representation of SI project to the spinal trigeminal complex. Corticofugal neurons near the frontal pole and in an area of cortex ventrolateral to SI also project to the spinal cord. The areas involved are probably homologous to the supplementary motor (MII) and second somatic sensory (SII) areas respectively. The corticospinal and corticotrigeminal projections from these areas also appear to be organized in a somatotopic manner.It is concluded that in the rat, as in other species, the corticospinal and corticotrigeminal neurons in the sensorimotor cortex are arranged somatotopically. The somatotopic pattern found correlates remarkably well with that determined by single unit, evoked potential and cortical stimulation techniques.     

Maturation of pyramidal cell form in relation to developing afferent and efferent connections of rat somatic sensory cortex.

Golgi and axonal labeling methods were used to examine the maturation of pyramidal cells in layers III and V of the rat somatic sensory cortex. The material came from animals late in the gestation period, postnatal, ranging from 0 to 43 days of age and at maturity. Special attention was paid to the period (0–7 days of age) during which it is known that thalamic and callosal fibers grow into the cortex. It is shown that the basic features of the pyramidal cell form are established before the long afferent fibers arrive in layers III and V and before the large number of synapses are established in these layers. Nevertheless, considerable dendritic growth and spine formation occurs after the afferent fibers establish an adult-like pattern of distribution. It is also shown that even at 1 day of age, the axons of pyramidal cells in all layers have reached the vicinity of targets such as the striatum, thalamus, brainstem, spinal cord and contralateral cortex.At 0–1 day the immature pyramidal cells are essentially bipolar in the upper cortical plate, but in the developing infragranular layers they have a few short, almost spine-free, basal dendrites and, rarely, a few oblique branches of the apical dendrite. The apical dendrite extends to the pial surface and the dendritic branches end in growth cones. The dendrites of cells in all layers increase in size and complexity of branching over the first postnatal week; the maturation of dendrites in layer V leads that of dendrites in the supragranular layers by about 2–3 days. As maturation proceeds, basal dendrites acquire secondary and tertiary branches and more oblique branches appear on the apical dendrite. Dendritic spines appear after 4 days of age but remain sparse up to 7–8 days. At 14 days of age, the spine density is much higher than in 7-day-old animals but remains at a much lower density than in 4-week-old, 6-week-old, or adult animals. By 7–14 days, the difference in maturity between superficial (layer III) and deep (layer V) pyramidal cells is difficult to discern qualitatively. All the pyramidal cells now have relatively complex, highly branched dendritic trees when compared to younger cells, but the dendritic tree is still immature in terms of the number, length and complexity of branching of the apical and basal dendritic systems.It can be concluded that the growth of the long axon of cortical pyramidal neurons precedes the acquisition of afferent connections and when these afferent fibers arrive in the cortex the dendritic tree of the pyramidal cell is still highly immature. Thus it remains possible that the finer modeling of the dendritic tree and the formation of spines may be affected by extrinsic influences such as the afferent fibers.