Measuring disease in dermatology: studies of objective and subjective methods

Itch lies second only to disturbance of body image as a reported symptom in dermatology. This study started by concentrating on improving the measurement of itch. Itch has a paired physical response, scratch. The pairing can be exploited: preliminary work by this unit had validated the use of wrist-worn movement-measuring machines called ‘accelerometers’ to measure itch-related movement (scratch and rub). The first part of this research developed use of these machines. Simple accelerometers (‘Actiwatch Plus’) were used to observe the pattern of variation of itch over clusters of nights and in different conditions. The accelerometer scores were able to identify controls’ scores from those with itchy disease. Considerable variation (56%) was discovered in objective score between subject and considerable variation was noted (46%) even within subject. More complex accelerometers, (‘DigiTrac’) which could potentially specifically identify itch-related movement on the basis of frequency of action derived from Fast Fourier Transform (FFT), were validated against the ‘gold standard’ measurement of itch-related movement, directly observed movement (via infra red video recording). It was necessary to characterise the ‘frequency of action’ of itch on video and, as an aside, the characteristics of human itch-related movement were compared to other mammals’ itch-related movement ‘frequency of action’. The ‘frequency of action’ and video data was used to enrich the DigiTrac readouts to improve specificity of itch-related movement detection. During the accelerometer studies, an unexpected finding came to light: objective score of itch was not related to subjective score. To try to explain the lack of relationship, a 42 day longitudinal study of atopic dermatitis patients’ subjective and objective scores was undertaken. The results demonstrated autocorrelation for subjective scores, but not for the objective scores but still did not fully explain the lack of relationship. In an effort to explain the disconnect between subjective and objective scores a second tranche of experiments and the second part of this research interrogated whether the methods with which we measure disease as a whole in dermatology are robust. One study investigated whether the way patients are asked about subjective symptoms in general was resistant to the effects of focusing and framing bias. The results were reassuring as they suggested that the commonly used and recommended symptom scoring systems were robust in the face of bias. In order to assess whether perspective or perception of disease explained the disconnect, a study was designed in collaboration with the Edinburgh College of Art. A series of computer-generated images of different psoriasis severities were created and used to assess how doctors and patients assessed disease-extent. This study showed that, whilst each group had a naturally divergent opinion of extent of disease, by scoring disease using the models it was possible to unify the perspective and perception of extent. Finally, an exploratory study to reduce recall bias to a minimum, in case this had caused the disconnect between objective and subjective, was undertaken. This employed a novel questionnaire, the Day Reconstruction Method

Pattern-Sensitive Epilepsy. I: A Demonstration of a Spatial Frequency Selective Epileptic Response to Gratings

Rare individuals suffer epileptic seizures when they view certain images, particularly stripes. Contrast-threshold functions (the ability to see faint stripes of various widths) were determined for two pattern-sensitive brothers, and the epileptogenicity of various patterns was assessed for one of them. Sine wave grating contrast-detection thresholds for the two subjects were essentially normal, with lowest thresholds at approximately 2 cycles/ degree (c/deg). Epileptiform discharges occurred maximally at 5 c/deg with a 1-octave 50% bandwidth. Pattern epileptogenicity was increased by the addition of a third harmonic sine wave grating to its fundamental, but was unaffected by the phase relation of the two gratings. The frequency selectivity of epileptic responsiveness was quantitatively similar to a “spatial frequency channel.” Inhibitory interactions were not present. The findings suggest relations between the phenomena of pattern-sensitive epilepsy and hypothesized spatial frequency channels which merit further exploration. RESUMEN De manera excepcional, hay personas que pueden tener ataques epilÉpticos cuando ven ciertas imÁgenes, particularmente rayas. Se determinaron los umbrales para contrastes (la capacidad de ver rayas de diversas anchuras y muy tenues) en dos hermanos sensibles a patrones y se estableciÓ la epileptogeneidad de di versos patrones en uno de ellos. Los umbrales para contrastes fueron esencialmente normales en los dos sujetos cuando se utilizeÓ una rejilla hecha con ondas sinusoidales, siendo el umbral inferior unos 2 ciclos/ grado (c/deg). Descargas epileptiformes tuvieron lugar de modo mÁximo a 5 c/deg con una amplitud de banda del 50% de una octava. la capacidad epileptogÉnica del partÓn aumentÓ cuando se aÑadiÓ una tercera sinusoide armÓnica a la rejilla base pero esa capacidad no se viÓ alterada por la relaciÓn de fase entre las dos rejillas. La selectividad de la frecuencia de la respuesta epileptogÉnica fue cuantitativamente similar al “canal de frecuencia espacial”. No se observaron interacciones inhibitorias. Los hallazgos sugieren que hay relaciones entre la epilepsyÍa secundaria a patrones visuales y los hipotÉticos canales de frecuencia espacial, lo cual merece mÁs investigaciÓn.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65270/1/j.1528-1157.1980.tb04075.x.pd

Histamine-induced itch and its relationship with pain

Itch is one of the major complications of skin diseases. Although there are various substances that induce itch or pruritus, it is evident that histamine is the best known endogenous agent that evokes itch. Even though histamine-induced itch has been studied for some time, the underlying mechanism of itch is just beginning to emerge. Although various downstream signaling pathways of histamine receptors have been revealed, more studies are required to determine the cause of histamine-induced itch. It appears that itch and pain involve different neuronal pathways. Pain generally inhibits itch, which indicates an inter-communication between the two. Complex interactions between itch and pain may be expected based on reports on disease states and opioids. In this review, we discuss the molecular mechanism and the pharmacological aspects of histamine-induced itch. Especially, the underlying mechanism of TRPV1 (an anti-pruritus target) has been determined to some extent

Hyperammonemic Coma—Barking Up the Wrong Tree

Hepatic encephalopathy and myxedema coma share clinical features: coma, ascites, anemia, impaired liver functions, and a “metabolic” electroencephalogram (EEG). Hyperammonemia, a hallmark of hepatic encephalopathy, has also been described in hypothyroidism. Differentiation between the 2 conditions, recognition of their possible coexistence, and the consequent therapeutic implications are of utmost importance. We describe a case of an 82-year-old woman with a history of mild chronic liver disease who presented with hyperammonemic coma unresponsive to conventional therapy. Further investigation disclosed severe hypothyroidism. Thyroid hormone replacement resulted in gain of consciousness and normalization of hyperammonemia. In patients with an elevated ammonia level, altered mental status, and liver disease, who do not have a clear inciting event for liver disease decompensation, overwhelming evidence of hepatic decompensation, or who do not respond to appropriate therapy for hepatic encephalopathy, hypothyroidism should be considered and evaluated

DNA barcoding and a precise morphological comparison revealed a cryptic species in the Nippolachnus piri complex (Hemiptera: Aphididae: Lachninae)

Nippolachnus is a small Palaearctic-Oriental genus of very characteristic aphids that live on the leaves of woody Rosaceae. One species, N. piri, has hitherto been regarded to be widely distributed and relatively polyphagous. Members of this genus are considered to be easy to recognize due to the absence of the ocular tubercle and triommatidia on the head. We conducted research on the morphology and generic characters of Nippolachnus piri complex using scanning electron microscopy (for the first time) and DNA barcoding. We analyzed N. piri populations on Pyrus and other plants (Eriobotrya, Rhaphiolepis and Sorbus) in Japan and the Republic of Korea. Specifically, a high genetic divergence value was found between the N. piri populations associated with different host plants. SEM investigation of the head capsule revealed that a triommatidium is present under the compound eye, despite their lack of an ocular tubercle. We propose Nippolachnus micromeli Shinji, 1924 stat. nov. as a cryptic species in the N. piri complex based on a morphological comparison, DNA barcoding and different host-plant associations. Illustrations and descriptions of studied species are given. Morphological keys to the apterae and alatae of all known species of the genus Nippolachnus are also provided

Transmitters and Pathways Mediating Inhibition of Spinal Itch-Signaling Neurons by Scratching and Other Counterstimuli

Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABAA and GABAB antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished) by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli

A novel widespread cryptic species and phylogeographic patterns within several giant clam species (Cardiidae: Tridacna) from the Indo-Pacific Ocean

Giant clams (genus Tridacna) are iconic coral reef animals of the Indian and Pacific Oceans, easily recognizable by their massive shells and vibrantly colored mantle tissue. Most Tridacna species are listed by CITES and the IUCN Redlist, as their populations have been extensively harvested and depleted in many regions. Here, we survey Tridacna crocea and Tridacna maxima from the eastern Indian and western Pacific Oceans for mitochondrial (COI and 16S) and nuclear (ITS) sequence variation and consolidate these data with previous published results using phylogenetic analyses. We find deep intraspecific differentiation within both T. crocea and T. maxima. In T. crocea we describe a previously undocumented phylogeographic division to the east of Cenderawasih Bay (northwest New Guinea), whereas for T. maxima the previously described, distinctive lineage of Cenderawasih Bay can be seen to also typify western Pacific populations. Furthermore, we find an undescribed, monophyletic group that is evolutionarily distinct from named Tridacna species at both mitochondrial and nuclear loci. This cryptic taxon is geographically widespread with a range extent that minimally includes much of the central Indo-Pacific region. Our results reinforce the emerging paradigm that cryptic species are common among marine invertebrates, even for conspicuous and culturally significant taxa. Additionally, our results add to identified locations of genetic differentiation across the central Indo-Pacific and highlight how phylogeographic patterns may differ even between closely related and co-distributed species

Human Umbilical Cord Blood Treatment in a Mouse Model of ALS: Optimization of Cell Dose

Amyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (10(6) cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10x10(6), 25x10(6) and 50x10(6), were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice.Our results showed that a cell dose of 25x10(6) cells significantly increased lifespan of mice by 20-25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25x10(6) cells, although prevalent human Th1 cytokines were indicated in mice with 50x10(6) cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25x10(6) (mainly) and 10x10(6) cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25x10(6) cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25x10(6) cells.These results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response

Stridulations Reveal Cryptic Speciation in Neotropical Sympatric Ants

The taxonomic challenge posed by cryptic species underlines the importance of using multiple criteria in species delimitation. In the current paper we tested the use of acoustic analysis as a tool to assess the real diversity in a cryptic species complex of Neotropical ants. In order to understand the potential of acoustics and to improve consistency in the conclusions by comparing different approaches, phylogenetic relationships of all the morphs considered were assessed by the analysis of a fragment of the mitochondrial DNA cytochrome b. We observed that each of the cryptic morph studied presents a morphologically distinct stridulatory organ and that all sympatric morphs produce distinctive stridulations. This is the first evidence of such a degree of specialization in the acoustic organ and signals in ants, which suggests that stridulations may be among the cues used by these ants during inter-specific interactions. Mitochondrial DNA variation corroborated the acoustic differences observed, confirming acoustics as a helpful tool to determine cryptic species in this group of ants, and possibly in stridulating ants in general. Congruent morphological, acoustic and genetic results constitute sufficient evidence to propose each morph studied here as a valid new species, suggesting that P. apicalis is a complex of at least 6 to 9 species, even if they present different levels of divergence. Finally, our results highlight that ant stridulations may be much more informative than hitherto thought, as much for ant communication as for integrative taxonomists