Recent advances in objectifying pain using neuroimaging techniques.

The pursuit of a physiological indicator of noxious stimulation is desirable as it has the potential to provide mechanistic information regarding acute pain and may ultimately improve pain management strategies. Currently, there are no specific neurophysiological markers of pain to evaluate treatments. Recent attempts to identify neural correlates of pain have focused on different neuroimaging modalities. The purpose of this review is to discuss common neuroimaging techniques and findings thus far.

Evolutionary transition of dental formula in Late Cretaceous eutherian mammals.

Kulbeckia kulbecke, stem placental mammal from the Late Cretaceous of Uzbekistan, shows a transitional stage of evolution in the dental formula from five to four premolars. A non-replaced dP3/dp3 may occur as individual variation. In other specimens, the lower premolars are crowded with no space for development of dp3. As is evident from the CT scanning of one juvenile specimen, the development of dp3 started in a late ontogenetic stage and was confined to the pulp cavity of the developing p2. This dp3 would have been resorbed in a later ontogenetic stage, as the roots of p2 formed. The initial stage of reduction of the third premolar can be traced to stem therians (Juramaia and Eomaia), which have both dP3 and P3 present in the adult dentition. Further delay in the development of dP3/dp3 led to the loss of the permanent P3/p3 (a possible synapomorphy for Eutheria). The dP3/dp3 was present during most of the adult stages in the Late Cretaceous stem placentals Zhelestidae and Gypsonictops. This tooth is totally absent in basal taxa of Placentalia, which normally have at most four premolars.

Prolonged myelination in human neocortical evolution.

Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelin-related proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.

An efficient material search for room-temperature topological magnons.

Topologically protected magnon surface states are highly desirable as an ideal platform to engineer low-dissipation spintronics devices. However, theoretical prediction of topological magnons in strongly correlated materials proves to be challenging because the ab initio density functional theory calculations fail to reliably predict magnetic interactions in correlated materials. Here, we present a symmetry-based approach, which predicts topological magnons in magnetically ordered crystals, upon applying external perturbations such as magnetic/electric fields and/or mechanical strains. We apply this approach to carry out an efficient search for magnetic materials in the Bilbao Crystallographic Server, where, among 198 compounds with an over 300-K transition temperature, we identify 12 magnetic insulators that support room-temperature topological magnons. They feature Weyl magnons with surface magnon arcs and magnon axion insulators with either chiral surface or hinge magnon modes, offering a route to realize energy-efficient devices based on protected surface magnons.

Improved acquisition of contact heat evoked potentials with increased heating ramp.

Contact heat evoked potentials (CHEPs) represent an objective and non-invasive measure to investigate the integrity of the nociceptive neuraxis. The clinical value of CHEPs is mostly reflected in improved diagnosis of peripheral neuropathies and spinal lesions. One of the limitations of conventional contact heat stimulation is the relatively slow heating ramp (70 °C/s). This is thought to create a problem of desynchronized evoked responses in the brain, particularly after stimulation in the feet. Recent technological advancements allow for an increased heating ramp of contact heat stimulation, however, to what extent these improve the acquisition of evoked potentials is still unknown. In the current study, 30 healthy subjects were stimulated with contact heat at the hand and foot with four different heating ramps (i.e., 150 °C/s, 200 °C/s, 250 °C/s, and 300 °C/s) to a peak temperature of 60 °C. We examined changes in amplitude, latency, and signal-to-noise ratio (SNR) of the vertex (N2-P2) waveforms. Faster heating ramps decreased CHEP latency for hand and foot stimulation (hand: F = 18.41, p < 0.001; foot: F = 4.19, p = 0.009). Following stimulation of the foot only, faster heating ramps increased SNR (F = 3.32, p = 0.024) and N2 amplitude (F = 4.38, p = 0.007). Our findings suggest that clinical applications of CHEPs should consider adopting faster heating ramps up to 250 °C/s. The improved acquisition of CHEPs might consequently reduce false negative results in clinical cohorts. From a physiological perspective, our results demonstrate the importance of peripherally synchronizing afferents recruitment to satisfactorily acquire CHEPs.

CrxPt1-xTe2 (x ≤ 0.45): A Family of Air-Stable and Exfoliatable van der Waals Ferromagnets.

The development of thermally robust, air-stable, exfoliatable two-dimensional van der Waals ferromagnetic materials with high transition temperatures is of great importance. Here, we establish a family of magnetic alloys, CrxPt1-xTe2 (x ≤ 0.45), that combines the stability of the late transition metal dichalcogenide PtTe2 with magnetism from Cr. These materials are easily grown in crystal form from the melt, are stable in ambient conditions, and have among the highest concentrations of magnetic element substitution in transition metal dichalcogenide alloys. The highest Cr-substituted material, Cr0.45Pt0.55Te2, exhibits ferromagnetic behavior below 220 K, and the easy axis is along the c-axis of the material, as determined using a combination of neutron diffraction and magnetic susceptibility measurements. These materials are metallic, with appreciable magnetoresistance below the Curie temperature. Single-crystal and powder diffraction measurements indicate Cr readily alloys onto the Pt site and does not sit in the van der Waals space, allowing these materials to be readily exfoliated to the few-layer regime. In summary, this air-stable, exfoliatable, high transition temperature ferromagnet shows great potential as building block for future 2D devices.

Metabolite activity in the anterior cingulate cortex during a painful stimulus using functional MRS.

To understand neurochemical brain responses to pain, proton magnetic resonance spectroscopy (1H-MRS) is used in humans in vivo to examine various metabolites. Recent MRS investigations have adopted a functional approach, where acquisitions of MRS are performed over time to track task-related changes. Previous studies suggest glutamate is of primary interest, as it may play a role during cortical processing of noxious stimuli. The objective of this study was to examine the metabolic effect (i.e., glutamate) in the anterior cingulate cortex during noxious stimulation using fMRS. The analysis addressed changes in glutamate and glutamate + glutamine (Glx) associated with the onset of pain, and the degree by which fluctuations in metabolites corresponded with continuous pain outcomes. Results suggest healthy participants undergoing tonic noxious stimulation demonstrated increased concentrations of glutamate and Glx at the onset of pain. Subsequent reports of pain were not accompanied by corresponding changes in glutamate of Glx concentrations. An exploratory analysis on sex revealed large effect size changes in glutamate at pain onset in female participants, compared with medium-sized effects in male participants. We propose a role for glutamate in the ACC related to the detection of a noxious stimulus.

Recurrent paralogy in the evolution of archaeal chaperonins.

Chaperonins are multisubunit double-ring complexes that mediate the folding of nascent proteins [1] [2]. In bacteria, chaperonins are homo-oligomeric and are composed of seven-membered rings. Eukaryotic and most archaeal chaperonin rings are eight-membered and exhibit varying degrees of hetero-oligomerism [3] [4]. We have cloned and sequenced seven new genes encoding chaperonin subunits from the crenarchaeotes Sulfolobus solfataricus, S. acidocaldarius, S. shibatae and Desulfurococcus mobilis. Although some archaeal genomes possess a single chaperonin gene, most have two. We describe a third chaperonin-encoding gene (TF55-gamma) from two Sulfolobus species; phylogenetic analyses indicate that the gene duplication producing TF55-gamma occurred within crenarchaeal evolution. The presence of TF55-gamma in Sulfolobus correlates with their unique nine-membered chaperonin rings. Duplicate genes (paralogs) for chaperonins within archaeal genomes very often resemble each other more than they resemble chaperonin genes from other archaea. Our phylogenetic analyses suggest multiple independent gene duplications - at least seven among the archaea examined. The persistence of paralogous genes for chaperonin subunits in multiple archaeal lineages may involve a process of co-evolution, where chaperonin subunit heterogeneity changes independently of selection on function.

Transporting silence: design of carriers for siRNA to angiogenic endothelium.

The recently developed siRNA oligonucleotides are an attractive alternative to antisense as a therapeutic modality because of their robust, gene selective silencing of drug target protein expression. To achieve therapeutic success, however, several hurdles must be overcome including rapid clearance, nuclease degradation, and inefficient intracellular localization. In this presentation, we discuss design strategies for development of self-assembling nanoscale carriers for neovasculature targeted delivery of siRNA inhibiting tumor or ocular angiogenesis.

Antihypertensive ureidopiperidines.

The synthesis of a series of 1-aralkyl-4-ureidopiperidines is reported. These compounds are related to the benzamidopiperidines exemplified by indoramin. Some of the ureidopiperidines are more potent antihypertensive agents than their benzamidopiperidine counterparts. Two examples, 1-(2-thenoyl)-3-[1-[2-(3-indolyl)ethyl]piperid-4-yl]urea and 1-(2-thenoyl)-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperid-4-yl]urea (19 and 58), emerged as the most potent antihypertensive agents in this series.

Design of an antithrombotic-antihypertensive agent (Wy 27569). Synthesis and evaluation of a series of 2-heteroaryl-substituted dihydropyridines.

An approach to the design of potential combined antithrombotic-antihypertensive agents is described. A series of 1,4-dihydropyridines bearing a 1H-imidazol-1-yl or pyrid-3-yl substituted side chain in the 2-position were synthesized and tested for antihypertensive activity in spontaneously hypertensive rats and for inhibition of TXA2 synthetase in rabbit platelets, in vitro. 1,4-Dihydro-2-(1H-imidazol-1-ylmethyl)-6-methyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-ethyl 5-methyl diester (1) was shown to be similar in potency to nitrendipine as an antihypertensive agent. Compound 1 inhibited TXA2 synthetase in rabbit and human platelets in vitro and reduced plasma TXB2 levels in rats at antihypertensive dose levels. The reductions in thromboxane production observed in vivo and in vitro were accompanied by enhanced levels of 6-KPGF1 alpha, reflecting diversion of the arachidonic acid cascade toward prostacyclin synthesis.

Naloxone and spinal fluid drainage as adjuncts in the surgical treatment of thoracoabdominal and thoracic aneurysms.

Forty-seven patients who were treated for thoracoabdominal or thoracic aneurysms over a 5 1/2-year period were analyzed for neurologic deficit risk. Patients were divided into two groups for analysis. Twenty-four patients, who were treated from January 1984 to December 1986, did not undergo spinal fluid drainage or naloxone administration (group A). Twenty-three patients, who were treated from January 1987 to August 1989, had spinal fluid drainage (group B); 12 patients in this group also received naloxone as an intravenous drip at 1 microgram/kg/hr for 48 hours after surgery. Permanent neurologic deficits occurred in seven (29%) group A patients but in only one (4%) group B patient, who did not receive naloxone (p less than 0.03). The first two group B patients to receive naloxone showed complete reversal of neurologic deficits on waking from anesthesia. This significant reduction in neurologic deficit was associated with an increased 1-year survival rate (72% in group A, 91% in group B). We conclude that the use of naloxone and spinal fluid drainage reduces the incidence of neurologic deficit that is associated with repair of thoracoabdominal and thoracic aortic aneurysms. This reduction in neurologic deficit is associated with improved survival in the long term. The observed reversal of postoperative neurologic deficits with naloxone implicates opiates as a major factor in the pathophysiology of spinal cord ischemia.

Effects of age and exercise on physiological dead space during simulated dives at 2.8 ATA.

Physiological dead space (Vds), end-tidal CO(2) (Pet(CO(2))), and arterial CO(2) (Pa(CO(2))) were measured at 1 and 2.8 ATA in a dry hyperbaric chamber in 10 older (58-74 yr) and 10 younger (19-39 yr) air-breathing subjects during rest and two levels of upright exercise on a cycle ergometer. At pressure, Vd (liters btps) increased from 0.34 +/- 0.09 (mean +/- SD of all subjects for normally distributed data, median +/- interquartile range otherwise) to 0.40 +/- 0.09 (P = 0.0060) at rest, 0.35 +/- 0.13 to 0.45 +/- 0.11 (P = 0.0003) during light exercise, and 0.38 +/- 0.17 to 0.45 +/- 0.13 (P = 0.0497) during heavier exercise. During these conditions, Pa(CO(2)) (Torr) increased from 33.8 +/- 4.2 to 35.7 +/- 4.4 (P = 0.0059), 35.3 +/- 3.2 to 39.4 +/- 3.1 (P < 0.0001), and 29.6 +/- 5.6 to 37.4 +/- 6.5 (P < 0.0001), respectively. During exercise, Pet(CO(2)) overestimated Pa(CO(2)), although the absolute difference was less at pressure. Capnography poorly estimated Pa(CO(2)) during exercise at 1 and 2.8 ATA because of wide variability. Older subjects had higher Vd at 1 ATA but similar changes in Vd, Pa(CO(2)), and Pet(CO(2)) at pressure. These results are consistent with an effect of increased gas density.

Serum theophylline profile with once-daily theophylline (Uniphyl) following conversion from intravenous theophylline in adult asthmatic patients.

Although guidelines are available for conversion from intravenous (IV) theophylline to twice-daily, oral, controlled-release theophylline, the optimal method for conversion to Uniphyl, a chronotherapeutically formulated, once-daily theophylline preparation, has not been previously evaluated. The present study was designed to prospectively evaluate a method for converting patients from IV theophylline to Uniphyl, to formulate simple, practical dosage recommendations for use in clinical practice. Ten patients with acute exacerbation of asthma receiving IV theophylline for > or = 48 hours and with steady state serum theophylline concentrations (STCs) between 4.5 and 15.5 mg/L (25 and 86 mumol/L) were enrolled into the study. Patients with STCs > or = 4.5 and < 12 mg/L (> or = 25 and < 66 mumol/L) and those with STCs > or = 12 and < or = 15.5 mg/L (> or = 66 and < or = 86 mumol/L) received their first Uniphyl dose immediately following termination of IV theophylline (No Time Lapse [NTL] group) and after a 4-hour delay (Time Lapse [TL] group), respectively. The differences in the area under the curve values between Uniphyl dosing and IV theophylline were 11% in the NTL group (1214.6 +/- 247.9 mumol/h.L-1 vs 1370.4 +/- 148.1 mumol/h.L-1, 95% confidence interval, 74% to 103%; P = 0.068) and 10% in the TL group (1959.4 +/- 165.1 mumol/h.L-1 vs 1784.6 +/- 119.4 mumol/h.L-1, 95% confidence interval, 103% to 117%; P = 0.013).(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of vision caused by expansion of intraocular perfluoropropane (C(3)F(8)) gas during nitrous oxide anesthesia.

PURPOSE: To report visual loss associated with nitrous oxide anesthesia in patients with intraocular perfluoropropane (C(3)F(8)) gas. DESIGN: Observational case series. METHODS: Three patients are described who lost vision in the eye with intraocular gas after subsequent nitrous oxide general anesthesia. RESULTS: Three patients, aged 75, 80, and 73 years, with intraocular C(3)F(8) gas in three eyes underwent nitrous oxide general anesthesia in three different medical centers for conditions unrelated to their ophthalmic surgery, ranging from 10 days to 1 month after their vitreoretinal procedure. All three patients suffered visual loss due to presumed central retinal artery occlusion caused by expansion of the intraocular gas by nitrous oxide during general anesthesia. In two patients, there was no recovery of light perception. In one patient, there was moderate recovery of vision. CONCLUSIONS: Identification of patients with intraocular gas is critical when planning nitrous oxide anesthesia. This may be achieved by the use of a simple intraocular gas identification bracelet issued to patients at the time of their vitreoretinal procedure.

Asphyxial suicide by propane inhalation and plastic bag suffocation.

A 26-year-old male committed suicide by inducing asphyxia using a combination of plastic bag suffocation and propane-gas inhalation. This method has been reported in the literature, but it remains unusual. Autopsy findings were consistent with a hypoxic event, and blood, brain, and lung tissue tested positive for propane by gas chromatography. Propane, while possessing some narcotic properties, causes death primarily by displacing oxygen in the atmosphere with resultant asphyxia.

Developmental changes in the spatial organization of neurons in the neocortex of humans and common chimpanzees.

In adult humans the prefrontal cortex possesses wider minicolumns and more neuropil space than other cortical regions. These aspects of prefrontal cortex architecture, furthermore, are increased in comparison to chimpanzees and other great apes. In order to determine the developmental appearance of this human cortical specialization, we examined the spatial organization of neurons in four cortical regions (frontal pole [Brodmann's area 10], primary motor [area 4], primary somatosensory [area 3b], and prestriate visual cortex [area 18]) in chimpanzees and humans from birth to approximately the time of adolescence (11 years of age). Horizontal spacing distance (HSD) and gray level ratio (GLR) of layer III neurons were measured in Nissl-stained sections. In both human and chimpanzee area 10, HSD was significantly higher in the postweaning specimens compared to the preweaning ones. No significant age-related differences were seen in the other regions in either species. In concert with other recent studies, the current findings suggest that there is a relatively slower maturation of area 10 in both humans and chimpanzees as compared to other cortical regions, and that further refinement of the spatial organization of neurons within this prefrontal area in humans takes place after the postweaning periods included here.

Neuropil distribution in the cerebral cortex differs between humans and chimpanzees.

Increased connectivity of high-order association regions in the neocortex has been proposed as a defining feature of human brain evolution. At present, however, there are limited comparative data to examine this claim fully. We tested the hypothesis that the distribution of neuropil across areas of the neocortex of humans differs from that of one of our closest living relatives, the common chimpanzee. The neuropil provides a proxy measure of total connectivity within a local region because it is composed mostly of dendrites, axons, and synapses. Using image analysis techniques, we quantified the neuropil fraction from both hemispheres in six cytoarchitectonically defined regions including frontopolar cortex (area 10), Broca's area (area 45), frontoinsular cortex (area FI), primary motor cortex (area 4), primary auditory cortex (area 41/42), and the planum temporale (area 22). Our results demonstrate that humans exhibit a unique distribution of neuropil in the neocortex compared to chimpanzees. In particular, the human frontopolar cortex and the frontoinsular cortex had a significantly higher neuropil fraction than the other areas. In chimpanzees these prefrontal regions did not display significantly more neuropil, but the primary auditory cortex had a lower neuropil fraction than other areas. Our results support the conclusion that enhanced connectivity in the prefrontal cortex accompanied the evolution of the human brain. These species differences in neuropil distribution may offer insight into the neural basis of human cognition, reflecting enhancement of the integrative capacity of the prefrontal cortex.

Brain collections at the National Museum of Health and Medicine.

Owing in large part to the foresight and efforts of Wally Welker, the National Museum of Health and Medicine has become a major repository for collections of brain specimens vital to the study of neurobehavioral evolution. From its origins in the Armed Forces Institute of Pathology, with the collection of largely pathological specimens assembled by Paul Yakovlev, the museum has added to its resources four additional extensive collections, largely consisting of specimens acquired specifically for comparative and evolutionary studies: Welker's collection from the University of Wisconsin-Madison, John I. Johnson's collection from Michigan State University, the Adolf Meyer Collection from the Johns Hopkins University, and the Elizabeth Crosby collections from the University of Michigan. We describe here the history and contents of each of these five collections, to inform the scientific field of the extent and details of these remarkable resources.