Global Nav1.7 Knockout Mice Recapitulate the Phenotype of Human Congenital Indifference to Pain

Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund’s adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.     

Pain Perception Is Increased in Congenital but Not Late Onset Blindness

There is now ample evidence that blind individuals outperform sighted individuals in various tasks involving the non-visual senses. In line with these results, we recently showed that visual deprivation from birth leads to an increased sensitivity to pain. As many studies have shown that congenitally and late blind individuals show differences in their degree of compensatory plasticity, we here address the question whether late blind individuals also show hypersensitivity to nociceptive stimulation. We therefore compared pain thresholds and responses to supra-threshold nociceptive stimuli in congenitally blind, late blind and normally sighted volunteers. Participants also filled in questionnaires measuring attention and anxiety towards pain in everyday life. Results show that late blind participants have pain thresholds and ratings of supra-threshold heat nociceptive stimuli similar to the normally sighted, whereas congenitally blind participants are hypersensitive to nociceptive thermal stimuli. Furthermore, results of the pain questionnaires did not allow to discriminate late blind from normal sighted participants, whereas congenitally blind individuals had a different pattern of responses. Taken together, these results suggest that enhanced sensitivity to pain following visual deprivation is likely due to neuroplastic changes related to the early loss of vision.     

Golden Eagle Indifference to Heli-Skiing and Military Helicopters in Northern Utah

Abstract: In 2006-2007, during Wasatch Powderbird Guides (WPG) permit renewal for heli-skiing in the Tri-Canyon Area (TCA) of the Wasatch Mountains, Utah, USA, we recorded 303 helicopter passes between 0 m and 3,000 m (horizontal distance) near ≥30 individual golden eagles (Aquila chrysaetos) in 22 nesting territories, through passive observation and active experimentation with civilian and military (Apache AH-64) helicopters. Flight profiles included 800-m, 400-m, 200-m, and 100-m flybys (horizontal distance from cliff nest on parallel course), as well as approaches and popouts where helicopters flew toward, or popped out from behind, adult-occupied cliff nests (0 m, horizontal distance). Between 1981 and 2007, during the only 8 years when nesting in the TCA was confirmed by presence of chicks, WPG annually flew 108–2,836 helicopter flights in the same drainages on 10–37 days between 15 December and 15 April, with no effect on early courtship, nest repair, or subsequent nesting success. Total WPG operating days (x̄ = 62.4) and helicopter hours (x̄ = 210.6) fluctuated annually but did not increase 1974–2007 (Cox-Stuart trend test, P = 0.371, 0.393, respectively). Apache helicopter testing (227 passes) did not reduce golden eagle nesting success or productivity rates within the same year (t_{111, 96} = 0.495, 0.782, P = 0.622, 0.436, respectively), or rates of renewed nesting activity the following year, compared with 81–101 non-manipulated nesting territories. We recorded no response during 66% and only watching during 30% of Apache passes at 0-800 m from nesting golden eagles. No other reactions occurred until after hatching when ≤4 golden eagles accounted for 5 flatten and 3 fly behaviors at 3 nest sites. No responding pairs failed to fledge young because of testing. Limited fly responses suggested helicopters only precipitated an imminent departure, rather than causing startled, avoidance reactions. Responsiveness between test weeks 1 and 2 decreased (X²₂ = 32.167, P ≤ 0.001). Apache helicopters were twice as loud as WPG helicopters at comparable distances. Sound decreased with distance, most rapidly when flights were perpendicular to cliffs or ridges. Eagle ambient behaviors and watching the helicopter occurred randomly throughout recorded sound levels during helicopter testing (76.7–108.8 decibels, unweighted). Much helicopter sound energy is below golden eagles' auditory threshold, thus reducing potential impacts. Neither our observations nor our testing indicated special management restrictions are required for helicopters flying near nesting golden eagles in northern Utah. Our results underscore the necessity for circumstance-specific research, as well as enlightened resource management to accommodate unexpected results.     

On Indifference Zone Selection with a Preference Threshold

This paper discusses a selection criterion that generalizes the well-known concept of indifference zone selection through a preference threshold. A population is preferred to another population if the difference in the sums of observed values exceeds a given nonnegative threshold value. We present an argument for this selection rule by modelling preference by imprecise previsions. We aim at guidelines to design a selection experiment, which is characterized by two numbers: the number of necessary observations per population, and the preference threshold. Next to the probability of correct selection we also need a second specification. In this paper we consider a probability of false selection that is strongly related to the minimum probability of correct selection. Based on this model the outcome of an experiment may be ‘no selection’, at least not based on strong preference of a single population. The ideas are presented through a simple selection problem for normal populations with common known variance. Although the theory has a frequentist nature, the derivation and justification of the selection rule through imprecise previsions relies on Bayesian foundations, and via this route we gain more insight into the selection criterion.     

学会承受痛夺和残忍

人和自然之间的关系,出现在镜头中最为触目惊心的情节，莫过于卢广的画面。同样拍摄金矿，巴西人萨尔加多的画面为世界摄影图库对金矿的定义，留下了经典的一笔。卢广的画面，则为西藏金矿的开采，留下了不可或缺的影响。人和自然环境之间的恩恩怨怨．在镜头中逐层展开．责任感的驱使，让他为这个世界展开了道德的准线和良心的力量。或许只需要简单地换一个角度，卢广会是一个出色的风光摄影家．会快乐地穿行于美妙的光影形色之间。然而他却选择了和“苦难”同行，和刻骨铭心的“残忍”同行。所以他比其他的摄影家走得更为艰难，也走得更为自信。他的镜头并不是在批判，或者像某些人说的，专门揭露世界的“阴暗面”，而是像他自己说的那样，他仅仅是做到保持一颗良心，背负一种责任，让自己的镜头“不说谎”。     

学会承受痛苦和残忍

人和自然之间的关系,出现在镜头中最为触目惊心的情节,莫过于卢广的画面。同样拍摄金矿,巴西人萨尔加多的画面为世界摄影图库对金矿的定义,留下了经典的一笔。卢广的画面,则为西藏金矿的开采,留下了不可或缺的影响。人和自然环境之间的恩恩怨怨,在镜头中逐层展开,责任感的驱使,让他为这个世界展开了道德的准线和良心的力量。或许只需要简单地换一个角度,卢广会是一个出色的风光摄影家,会快乐地穿行于美妙的光影形色之间。然而他却选择了和“苦难”同行,和刻骨铭心的“残忍”同行。所以他比其他的摄影家走得更为艰难,也走得更为自信。他的镜头并不是在批判,或者像某些人说的,专门揭露世界的“阴暗面”,而是像他自己说的那样,他仅仅是做到保持一颗良心,背负一种责任,让自己的镜头“不说谎”。     

Oral and Craniofacial Manifestations and Two Novel Missense Mutations of the NTRK1 Gene Identified in the Patient with Congenital Insensitivity to Pain with Anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare inherited disorder of the peripheral nervous system resulting from mutations in neurotrophic tyrosine kinase receptor 1 gene (NTRK1), which encodes the high-affinity nerve growth factor receptor TRKA. Here, we investigated the oral and craniofacial manifestations of a Chinese patient affected by autosomal-recessive CIPA and identified compound heterozygosity in the NTRK1 gene. The affected boy has multisystemic disorder with lack of reaction to pain stimuli accompanied by self-mutilation behavior, the inability to sweat leading to defective thermoregulation, and mental retardation. Oral and craniofacial manifestations included a large number of missing teeth, nasal malformation, submucous cleft palate, severe soft tissue injuries, dental caries and malocclusion. Histopathological evaluation of the skin sample revealed severe peripheral nerve fiber loss as well as mild loss and absent innervation of sweat glands. Ultrastructural and morphometric studies of a shed tooth revealed dental abnormalities, including hypomineralization, dentin hypoplasia, cementogenesis defects and a dysplastic periodontal ligament. Genetic analysis revealed a compound heterozygosity- c.1561T>C and c.2057G>A in the NTRK1 gene. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with CIPA and provides additional insight for clinical and molecular diagnosis.     

Indifference of potato anther culture to colchicine and genetic similarity among anther-derived monoploid regenerants determined by RAPD analysis

Effects of colchicine on androgenesis of diploid potato (Solanum phureja Juz. & Buk.) and ploidy of anther-derived plants were examined in three experiments. In the first, no significant difference was found for mean embryos per anther of an interspecific potato clone after application of five colchicine treatments (0, 25, 50, 100 and 200 mg l^-1) for 24 h to freshly excised anthers containing late uninucleate microspores. The same colchicine treatments were applied to six hybrid potato families in the second experiment. Families differed for number of embryos per anther and embryo regeneration frequency; however, androgenic response did not differ significantly among colchicine treatments. The 312 regenerated plants included 233 (75%) monoploids. The third experiment examined durations (0, 90 s vacuum infiltration, 24, 48 and 72 h) of high colchicine treatment (200 mg l^-1) on anther culture of seedlings representing one family. Mean embryos per anther, though not statistically significant, ranged from 0.96 to 1.90 for 48 h colchicine and 90 s vacuum infiltration, respectively. There were 126 plants regenerated of which 62% were monoploid. Frequency of monoploid plants regenerated from colchicine treatments did not differ significantly. RAPD analysis was conducted on 26 anther-derived monoploids of one family, based on common flasks of origin. The 13 decamer primers revealed 54 polymorphic loci. These were used to characterize the monoploids genetically. From one flask, two pairs of monoploids among six examined were genetically indistinguishable. Examination of a second and third flask revealed, six of seven and three of seven monoploids that were genetically indistinguishable. These data suggest the regeneration of genetic clones within flasks and may indicate the occurrence of secondary embryogenesis during anther culture. This revised version was published online in June 2006 with corrections to the Cover Date.     

Pain perception in relation to emotional learning

Noninvasive brain imaging has established the participation of the cortex in pain perception and identified a long list of brain structures involved. More recent studies show the interaction between clinical chronic pain conditions and the reorganization of the brain functionally, anatomically, and chemically. Mechanisms underlying this reorganization hint to essential links between pain, especially its affective component with emotional learning and memory. This review is a discussion of the rationale and evidence for the interaction between these modalities, emphasizing underlying mechanisms.     

Congenital Anomalies and Congenital Adrenal Hyperplasia

Among 74 patients with congenital adrenal hyperplasia observed at Childrens Hospital, Los Angeles, in a 25-year period, 36 had the simple virilizing type and 38 the salt-losing type. During the same time, seven children with virilizing adrenal tumors were observed at the hospital.While virilization and dehydration were the most common presenting symptoms, some of the children first came to medical attention because of other symptoms, and 11 of them died before adrenal hyperplasia had been diagnosed. Twenty-eight additional congenital cardiovascular, genitourinary, and gastrointestinal anomalies were found in 16 of these 74 children.With proper management, the patients tolerated such stresses as surgical operation and infections without difficulty.     

Congenital cataract linked to the Y chromosome]

A possible Y linked form of congenital cataract is reported, but an autosomal dominant mode of inheritance cannot be ruled out.