Synapses are continually regulated by chemical modulators and by their own activity. We tested the specificity of regulation in two excitatory pathways of the neocortex: thalamocortical (TC) synapses, which mediate specific inputs, and intracortical (IC) synapses, which mediate the recombination of cortical information. Frequency-sensitive depression was much stronger in TC synapses than in IC synapses. The two synapse types were differentially sensitive to presynaptic neuromodulators: only IC synapses were suppressed by activation of GABA(B) receptors, only TC synapses were enhanced by nicotinic acetylcholine receptors, and muscarinic acetylcholine receptors suppressed both synapse types. Modulators also differentially altered the frequency sensitivity of the synapses. Our results suggest a mechanism by which the relative strength and dynamics of input and associational pathways of neocortex are regulated during changes in behavioral state.

Thalamocortical (TC) synapses carry information into the neocortex, but they are far outnumbered by excitatory intracortical (IC) synapses. We measured the synaptic properties that determine the efficacy of TC and IC axons converging onto spiny neurons of layer 4 in the mouse somatosensory cortex. Quantal events from TC and IC synapses were indistinguishable. However, TC axons had, on average, about 3 times more release sites than IC axons, and the mean release probability at TC synapses was about 1.5 times higher than that at IC synapses. Differences of innervation ratio and release probability make the average TC connection several times more effective than the average IC connection, and may allow small numbers of TC axons to dominate the activity of cortical layer 4 cells during sensory inflow.

We explored differences in the properties of convergent afferent inputs to single neurons in the barrel area of the neocortex. Thalamocortical slices were prepared from mature mice. Recordings were made from neurons in layer V, and either thalamocortical afferents or horizontal intracortical axons were stimulated. Monosynaptic EPSPs from both sources had latencies shorter than 1.8 msec and low shape variance. Disynaptic thalamocortical IPSPs had latencies longer than 1.8 msec. All neuronal types, as defined by intrinsic firing patterns, received both thalamocortical and intracortical monosynaptic input. The shape parameters (rate of rise and half-width) of monosynaptic EPSPs from the two inputs did not differ significantly. The rate of rise of EPSPs varied considerably across cells, but the rates of rise of thalamocortical and intracortical EPSPs onto single cells were strongly correlated. The relative thresholds for activation of synaptic excitation and inhibition were strikingly different between the two tracts: thalamocortical stimulation induced GABAA-dependent IPSPs at stimulus intensities equal to or less than those required for evoking EPSPs in 35% (24 of 68) of the cells. In contrast, the threshold response to intracortical stimulation was always an EPSP, and only stronger stimuli could generate di- or polysynaptic IPSPs. We suggest that postsynaptic factors may tend to equalize the waveforms of EPSPs from thalamocortical and intracortical synapses onto single neurons. A major difference between the two convergent tracts is that the thalamocortical pathway much more effectively activates feedforward inhibitory circuits than does the horizontal intracortical pathway.

Importance: Transnasal fiberoptic laryngoscopy (TFL) has been used to guide various in-office procedures for the past 3 decades. Publications on in-office laryngeal biopsy have concurred that this procedure is safe, feasible, and easy to perform. However, the accuracy of inoffice biopsy via TFL has not yet been established. The aim of this study was to examine this issue.Objective: To compare pathologic results obtained via in-office TFL with those of subsequent direct laryngoscopy to assess the accuracy of TFL as a diagnostic tool.Design: Prospective cohort study. Setting: Tertiary reference medical center.Participants: One-hundred two patients with suspicious laryngeal lesions.Intervention: All patients underwent in-office biopsies. Main Outcome Measures:All patients with malignant lesions were referred to appropriate services for treatment, and those with a diagnosis of a benign lesion or carcinoma in situ were referred for direct laryngoscopy for definitive diagnosis. The results of the pathologic testing on specimens from in-office and direct laryngoscopy were compared.Results: Adequate tissue for diagnostic purposes was obtained in 96 of 102 in-office TFL biopsies (94.1%). The biopsy results revealed invasive carcinoma in 34 patients (35.4%), carcinoma in situ in 17 patients (17.7%), and benign lesions in 45 patients (46.9%). All patients with benign lesions and carcinoma in situ were referred for biopsy of samples obtained using direct laryngoscopy, to which 57 patients agreed. The final pathologic results identified from the biopsies on direct laryngoscopy revealed that there was an underestimation of the TFL results in 30 of 91 patients (false-negative rate, 33.0%) and an overestimation in 1 patient (false-positive rate, 1.1%). The sensitivity of TFL biopsy compared with that of direct laryngoscopy biopsy was 69.2% and the specificity was 96.1%. Conclusions and Relevance:Transnasal fiberoptic laryngoscopy yielded low sensitivity in assessing suspicious lesions of the larynx. These results may indicate that direct laryngoscopy represents the definitive pathologic diagnostic procedure whenever the pathologic results of an in-office TFL procedure are interpreted as benign or as carcinoma in situ.

Given the appropriate doses, curcumin exhibits radio-sensitizing effects on SCC cells in vitro.

Patch-clamp recording has revolutionized the study of ion channels, transporters, and the electrical activity of small cells. Vital to this method is formation of a tight seal between glass recording pipette and cell membrane. To better understand seal formation and improve practical application of this technique, we examine the effects of divalent ions, protons, ionic strength, and membrane proteins on adhesion of membrane to glass and on seal resistance using both patch-clamp recording and atomic force microscopy. We find that H(+), Ca(2+), and Mg(2+) increase adhesion force between glass and membrane (lipid and cellular), decrease the time required to form a tight seal, and increase seal resistance. In the absence of H(+) (10(-10) M) and divalent cations (<10(-8) M), adhesion forces are greatly reduced and tight seals are not formed. H(+) (10(-7) M) promotes seal formation in the absence of divalent cations. A positive correlation between adhesion force and seal formation indicates that high resistance seals are associated with increased adhesion between membrane and glass. A similar ionic dependence of the adhesion of lipid membranes and cell membranes to glass indicates that lipid membranes without proteins are sufficient for the action of ions on adhesion.

The usage of a neuronavigation system is safe and may be beneficial for optimal positioning and trajectory of ventricular catheters in children with small ventricles or an abnormal ventricular anatomy.

Extracellular vesicles (EVs) are heterogamous lipid bilayer-enclosed membranous structures secreted by cells. They are comprised of apoptotic bodies, microvesicles, and exosomes, and carry a range of nucleic acids and proteins that are necessary for cell-to-cell communication via interaction on the cells surface. They initiate intracellular signaling pathways or the transference of cargo molecules, which elicit pleiotropic responses in recipient cells in physiological processes, as well as pathological processes, such as cancer. It is therefore important to understand the molecular means by which EVs are taken up into cells. Accordingly, this review summarizes the underlying mechanisms involved in EV targeting and uptake. The primary method of entry by EVs appears to be endocytosis, where clathrin-mediated, caveolae-dependent, macropinocytotic, phagocytotic, and lipid raft-mediated uptake have been variously described as being prevalent. EV uptake mechanisms may depend on proteins and lipids found on the surfaces of both vesicles and target cells. As EVs have been shown to contribute to cancer growth and progression, further exploration and targeting of the gateways utilized by EVs to internalize into tumor cells may assist in the prevention or deceleration of cancer pathogenesis.