[Role of p38MAPK signaling pathway in rats with phantom limb pain].

OBJECTIVE: To investigate the role of p38MAPK signal pathway in spinal cord and dorsal root ganglion (DRG) in rats with phantom limb pain and the effects of specific inhibitors.
 Methods: Healthy adult male SD rats (n=48) were cut off one side of the sciatic under anesthesia to establish a model of phantom limb pain. In addition, the healthy rats were taken as a sham group (group S, n=24). The animals were scored by observing the action of chewing (0=no chewing, 13=the worst chewing) after the operation and were sacrificed on the following day after the operation. The successful model of phantom limb pain were randomly divided into 2 groups: a phantom limb pain group (group P, n=24) and a phantom limb pain plus inhibitor group (group P+I, n=24). SB203580 was given to the rat at 0.8 mg/kg on every Monday until the rats were sacrificed, the rest of the rats received an equal amount of saline. Eight rats from each group were randomly taken for the determination of levels of P-p38MAPK in spinal cord and DRG before administration and on the 4th, 6th, 8th weekend following the administration, respectively.
 Results: In the sham group, no animal developed chewing. Meanwhile, rats in successful model of phantom limb pain group began chewing from the 2nd day after operation with scores at eight to eleven. The chewing scores in the P+I group were reduced after the treatment. Compared with group S, P-p38MAPK levels were elevated in groups of P and P+I (P<0.05 or P<0.01). Compared with group P, P-p38MAPK level was decreased in the group P+I (P<0.05 or P<0.01).
 Conclusion: P38MAPK signal pathway involves in the development of phantom limb pain.

Identification of a novel nonsense mutation of the neurotrophic tyrosine kinase receptor type 1 gene in two siblings with congenital insensitivity to pain with anhidrosis.

Objective To explore the aetiology of congenital insensitivity to pain with anhidrosis (CIPA) in two Chinese siblings with typical CIPA symptoms including insensitivity to pain, inability to sweat, and self-mutilating behaviours. Methods Clinical examination and genetic testing were conducted of all available family members, and the findings were used to create a pedigree. Mutation screening using PCR amplification and DNA Sanger sequencing of the entire neurotrophic tyrosine kinase receptor type 1 gene ( NTRK1) including intron-exon boundaries was used to identify mutations associated with CIPA. Results A novel nonsense mutation (c.7C > T, p. Arg3Ter) and a known splice-site mutation (c.851-33 T > A) were detected in NTRK1 and shown to be associated with CIPA. Conclusion Our findings expand the known mutation spectrum of NTRK1 and provide insights into the aetiology of CIPA.

Penile Replantation: A Retrospective Analysis of Outcomes and Complications.

Purpose Penile replantation is an uncommonly performed procedure, which can alleviate physical and psychosocial sequelae of penile amputation. This study critically appraises the current literature on penile replantation. Methods A comprehensive literature search of the Medline, PubMed, and Google Scholar databases was conducted with multiple search terms related to penile replantation. Data on outcomes, complications, and patient satisfaction were collected. Results A total of 74 articles met inclusion criteria. One hundred and six patients underwent penile replantation, but outcome, complication, and satisfaction data were not standardized across all patients. Penile amputation most often resulted from self-mutilation or trauma. The majority were complete amputations (74.8%). Full sensation was maintained in 68.4% of patients. Most reported adequate urinary function (97.4%) and normal erection (77.5%). Skin necrosis (54.8%) and venous congestion (20.2%) were the most common complications. Urethral stricture (11.0%) and fistula (6.6%) were common urethral complications. Most (91.6%) patients reported overall satisfaction although there was a lack of patient-reported outcomes. Multivariate analysis suggested that complete amputation (ß = 3.15, 95% CI 0.41-5.89, p = 0.024), anastomosis of the superficial dorsal artery (ß = 9.88, 95% CI 0.74-19.02, p = 0.034), and increasing number of nerves coapted (ß = 1.75, 95% CI 0.11-3.38, p = 0.036) were associated with favorable sexual, urinary, and sensation outcomes. Increasing number of vessels anastomosed (ß = -3.74, 95% CI -7.15 to -0.32, p = 0.032) was associated with unfavorable outcomes. Conclusion Although penile replantation is associated with complications, it has a high rate of satisfaction and efficacy. Coaptation of multiple nerves and anastomosis of the superficial dorsal artery should be completed.

Regeneration patterns influence hindlimb automutilation after sciatic nerve repair using stem cells in rats.

INTRODUCTION: Hindlimb autophagy is common after rat sciatic total axotomy and is considered as a sign of neuropathic pain. We applied adult stem cells in a fibrin conduit in a total sciatic axotomy model to improve nerve regeneration, investigating whether a correlation could be detected between stem cells effects on regeneration and limb autophagy. MATERIAL AND METHODS: After sciatic nerve section, a 1-cm sciatic gap was crossed using fibrin conduits. Experimental groups included empty fibrin conduits, fibrin conduits seeded with primary Schwann cells, and fibrin conduits seeded with Schwann cell-like differentiated mesenchymal or adipose-derived stem cells (dMSCs and dASCs). Controls were represented by autografts and by sham rats (tot n=34). At 16 weeks post-implantation, regeneration pattern was analysed on histological sections and related to eventual autophagy. Hindlimbs were evaluated and scored according to autophagy Wall's scale and X-Rays radiological evaluation. RESULTS: All regenerative cell lines significantly improved myelination at the mid conduit level, compared to the empty tubes. However, dMSC could not significantly improve myelination at the distal stump, showing a more chaotic regeneration compared to both other cells groups and controls. Autophagy was correlated to this regeneration patterns, with higher autophagy scores in the empty and dMSC group. CONCLUSION: Hindlimb autophagy can be used as index of neuropathic pain due to nerve lesion or on-going immature regeneration. dMSC group was characterized by a less targeted regeneration comparing to dASC and primary Schwann cells, which confirmed their effectiveness in regeneration and potential in future clinical applications.

Potential relationship of self-injurious behavior to right temporo-parietal lesions.

Self-injurious behavior (SIB) is associated with several neurologic and psychiatric syndromes but rarely with focal lesions. Two patients with lesions of the right temporo-parietal junction presented to psychiatric inpatient services with SIB in the absence of notable neurologic deficits or suicidal ideation. Right temporo-parietal lesions may be associated with disturbances of agency and body ownership, both of which may facilitate SIB. Misoplegia, or hatred of a limb, may be associated with SIB and has been reported without hemiplegia with a right temporo-parietal lesion. Further study is warranted to improve our understanding of the mechanisms underlying SIB.

Pain in Borderline Personality Disorder.

Pain processing in patients with borderline personality disorder (BPD) is abnormal primarily with respect to pain thresholds which are typically elevated or perception of phasic nociceptive stimuli which is reduced. In spite of this common finding, nonsuicidal self-injury (NSSI), often expressed as cutting, is a hallmark sign of the disease and serves to release aversive inner tension. The question thus arises, how does a painful stimulus release inner tension when these patients feel less pain than healthy people? However, intensity discrimination is normal in these patients. Imaging data have provided evidence that inhibitory top-down modulation is increased in BPD patients, and that processing of the affective-emotional pain component is altered. Recent studies have focused on the role of pain, tissue injury and seeing blood in the context of NSSI. Preliminary findings suggest a significant role of pain irrespective of concomitant tissue injury, and of seeing blood expressed as a stronger immediate stress release. Taken together, BPD patients exhibit altered pain processing that can be assigned to altered processing of nociceptive stimuli in prefrontal and limbic brain areas, which may help to mechanistically explain the clinical behavior.

Interpersonal violence, alcohol use, and acquired capability for suicide.

Acquired capability for suicide (ACS), defined as pain tolerance and fearlessness about death, is theorized as necessary to enact suicide. This study examined the associations of interpersonal violence and alcohol use with ACS in 502 college students. General fearlessness/pain tolerance was positively associated with male gender and alcohol use. Fearlessness about death was positively associated with male gender and general physical violence perpetration. However, these risk factors did not explain variance in ACS beyond male gender and history of suicide attempts/nonsuicidal self-injury. These findings add to the understanding of ACS correlates.

Self-mutilation in patients after nerve injury may not be due to deafferentation pain: a case report.

OBJECTIVE: Animals with transected nerves may develop self-mutilating behavior (autotomy) directed at the denervated body part. Autotomy is often thought to be a response to deafferentation pain produced by pathological changes in the dorsal horn, and self-mutilation after dorsal rhizotomy has consequently been used as an outcome measure for the investigation of chronic pain in animal models. A less recognized hypothesis suggests that autotomy is simply an animal's efforts to remove the useless part. We report a case of self-mutilation of the thumb and fingers in a patient with loss of all sensory modalities in the arm after brachial plexus avulsion. CONCLUSION: Asking the patient about the reasons for his self-mutilation provides insights into the cause of autotomy which cannot be established from animal studies. We suggest that autotomy may not be a result of chronic pain, and discuss the human experience and alternative underlying pathological processes.

Autotomy behavior correlates with the DRG and spinal expression of sodium channels in inbred mouse strains.

Patients who have suffered nerve injury show profound inter-individual variability in neuropathic pain even when the precipitating injury is nearly identical. Variability in pain behavior is also observed across inbred strains of mice where it has been attributed to genetic polymorphisms. Identification of cellular correlates of pain variability across strains can advance the understanding of underlying pain mechanisms. Voltage-gated sodium channels (VGSCs) play a major role in the generation and propagation of action potentials in the primary afferents and are therefore of obvious importance for pain phenotype. Here, we examined the mRNA expression levels of the VGSC alpha-subunits Na(v)1.3, Na(v)1.5, Na(v)1.6, and Na(v)1.7, as well as the auxiliary VGSC-related molecule, Contactin. Dorsal root ganglia (DRG) and spinal cords from 5 inbred mouse strains with contrasting pain phenotype (AKR/J, C3H/HeJ, C57BL/6J, C58/J and CBA/J) were analyzed 7 days following sciatic and saphenous nerve transection. In the DRG, Na(v)1.6, Na(v)1.7 and Contactin were abundantly expressed in control animals. Following nerve injury, the residual mRNA levels of Na(v)1.6 (downregulated in two of the strains) correlated tightly to the extent of autotomy behavior. A suggestive correlation was also seen for the post-injury mRNA levels of Contactin (downregulated in all strains) with autotomy. Thus, our results suggest a contribution by DRG Na(v)1.6, and possibly Contactin to neuropathic pain in the neuroma model in mice.

Serial stellate ganglion blocks for intractable postherpetic itching in a pediatric patient: a case report.

BACKGROUND: While intractable itching may be rarely associated with postherpetic neuralgia, it can have catastrophic complications if present. METHOD: We highlight a severe case of postherpetic itching in a 10-year-old male with Fanconi's and aplastic anemia, refractory to conventional treatments and requiring intravenous sedation. RESULTS: Our use of 3 sequential stellate ganglion blocks with 5.5 mL of 0.25% bupivacaine provided significant improvement of the symptoms for 4 months after the last procedure. CONCLUSION: Although further evaluation is needed, we feel that novel use of sympathetic blockade may provide treatment for intractable itching. Highlighted is the possible influence of the sympathetic system in the pathophysiology of postherpetic itch. IMPLICATION: The use of serial stellate ganglion blocks may be a treatment option for patients with intractable itching and postherpertic neuralgia of the neck and arm region. This technique may lead to more permanent solutions such as pulse radiofrequency lesion or chemical neurolysis of sympathetic ganglions for postherpetic itch.

Lesch-Nyhan disease: from mechanism to model and back again.

Lesch-Nyhan disease (LND) is a rare inherited disorder caused by mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by overproduction of uric acid, leading to gouty arthritis and nephrolithiasis. Affected patients also have characteristic neurological and behavioral anomalies. Multiple cell models have been developed to study the molecular and metabolic aspects of LND, and several animal models have been developed to elucidate the basis for the neurobehavioral syndrome. The models have different strengths and weaknesses rendering them suitable for studying different aspects of the disease. The extensive modeling efforts in LND have questioned the concept that an 'ideal' disease model is one that replicates all of its features because the pathogenesis of different elements of the disease involves different mechanisms. Instead, the modeling efforts have suggested a more fruitful approach that involves developing specific models, each tailored for addressing specific experimental questions.

Reflections on the brainstem dysfunction in neurologically disabled children.

This article deals with the neurological basis of brainstem-related symptoms in disabled children. Synaptic interactions of respiratory and swallowing centers, which are briefly reviewed in this study, highlight the significance of the nucleus of solitary tract (NTS) in the stereotyped motor events. Coordination mechanisms between these two central pattern generators are also studied with a focus on the inhibitory action of decrementing expiratory neurons that terminate the inspiratory activity and become activated during swallowing. Dorsal brainstem lesions in hypoxic-ischemic encephalopathy (HIE) affect the area including NTS, and result in symptoms of apneusis, facial nerve paresis, dysphagia, gastroesophageal reflux, and laryngeal stridor. Leigh syndrome patients with similar distributions of medullary lesions show increased sighs, post-sigh apnea, hiccups, and vomiting in addition to the symptoms of HIE, suggesting pathologically augmented vagal reflex pathways. The present article also discusses the pathophysiology of laryngeal dystonia in xeroderma pigmentosum group A, self-mutilation in Lesch-Nyhan syndrome, and sudden unexpected death in Fukuyama congenital muscular dystrophy. Close observation and logical assessment of brainstem dysfunction symptoms should be encouraged in order to achieve better understanding and management of these symptoms in disabled children.

A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic etiology. Cytogenetic abnormalities have been detected in 5-10% of the patients with autism. In this study, we present the clinical, cytogenetic and array-comparative genomic hybridization (array-CGH) evaluation of a 13-year-old male with severe developmental delay, facial dysmorphic features, autism and self mutilation. The patient was found to carry a de novo duplication of chromosome region 8p21 of minimally 6.14 and maximally 6.58 Mb as ascertained by bacterial artificial chromosome (BAC)-based array-CGH. Hitherto, only a few patients with autism with cytogenetically visible duplications involving the chromosome 8p21 region have been described, but the extent of these duplications has not been determined at the molecular level. This represents the smallest rearrangement of chromosomal region 8p21 as yet found in a patient with autism. For 11 of the 36 genes with known functions located within this duplication clear transcription in the brain was found. Of those the STMN4 and DPYSL2 genes are the most likely candidate genes to be involved in neuronal development, and, if altered in gene-dosage, in the autistic phenotype of our patient.

Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat.

The rostral agranular insular cortex (RAIC) receives dopaminergic projections from the mesolimbic system, which has been involved in the modulation of nociceptive processes. In this study we determined the contribution of dopamine D(1) and D(2) receptors in the RAIC regarding nociception processing in a neuropathic pain model, as well as inflammatory articular nociception measured as pain-induced functional impairment in the rat (PIFIR). Microinjection of vehicle or substances into the RAIC was performed after the induction of nociception. The groups were treated with: a dopamine D(1) receptor antagonist (SCH-23390), a dopamine D(1) receptor agonist (SKF-38393), a dopamine D(2) receptor agonist (TNPA) and a dopamine D(2) receptor antagonist (spiperone). Chronic nociception, induced by denervation, was measured by the autotomy score in which onset and incidence were also determined. The SCH-23390 and TNPA groups showed a decrease in the autotomy score and a delay on the onset as compared to control, whereas the PIFIR groups did not show statistical differences. This work shows the differential role of dopamine receptors within the RAIC in which the activation of D(2) or the blockade of D(1) receptors elicit antinociception.

Sex-specific variability and a 'cage effect' independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan.

Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation. The genome scan detected one previously reported quantitative trait locus (QTL) on chromosome 15 (pain1), but no additional QTLs were found. Interestingly, group caging introduced phenotypic noise large enough to completely mask the genetic effect of the chromosome 15 QTL. The reason appears to be that group-caging animals from the low-autotomy strain together with animals from the high-autotomy strain dramatically increases autotomy in the otherwise low-autotomy mice (males or females). The converse, suppression of pain behaviour in the high-autotomy strain when caged with the low-autotomy strain was also observed, but only in females. Even in isolated mice, the genetic effect of the chromosome 15 QTL was significant only in females. To determine why, we evaluated autotomy levels of females in 12 different inbred stains of mice and compared them to previously reported levels for males. Strikingly larger environmental variation was observed in males than in females for this pain phenotype. The high baseline variance in males can explain the difficulty in detecting the genetic effect, which was readily seen in females. Our study emphasizes the importance of sex and environment in the genetic analysis of pain.

Opposite effects of internal globus pallidus stimulation on pallidal neurones activity.

Besides clinical efficacy, the mechanisms of action of deep brain stimulation (DBS) are still debated. To shed light on this complex issue, we have taken the opportunity to record the response of globus pallidus internus (GPi) neurones to 100 Hz stimulations in a case of Lesch-Nyhan syndrome (LNS) where four pallidal electrodes were implanted. Three types of response were observed, 2/19 neurones were unaffected by DBS. About 7/19 neurones were inhibited during DBS stimulation and 10/19 neurones were excited during DBS stimulation. Both effects ceased when DBS was turned off. Inhibited neurones were situated lower that exited ones on the trajectory (1.25 and 4.65 mm above the center of GPi respectively). These observations suggest that locally DBS induces a reversible inhibition of neurone firing rate while at the same time distantly exciting the main afferents to and/or efferents from the GPi. Both actions would result in a strong GPi inhibition that does not preclude increased outflow from the GPi.

Spontaneous pain following spinal nerve injury in mice.

Autotomy behavior is frequently observed in rats and mice in which the nerves of the hindlimb are severed, denervating the paw. This is the neuroma model of neuropathic pain. A large body of evidence suggests that this behavior reflects the presence of spontaneous dysesthesia and pain. In contrast, autotomy typically does not develop in partial nerve injury pain models, leading to the belief that these animals develop hypersensibility to applied stimuli (allodynia and hyperalgesia), but not spontaneous pain. We have modified the widely used Chung (spinal nerve ligation [SNL]) model of neuropathic pain in a way that retains the fundamental neural lesion, but eliminates nociceptive sensory cover of the paw. These animals performed autotomy. Moreover, the heritable across strains predisposition to spontaneous pain behavior in this new proximal denervation model (SNN) was highly correlated with pain phenotype in the neuroma model suggesting that the pain mechanism in the two models is the same. Relative reproducibility of strain predispositions across laboratories was verified. These data indicate that the neural substrate for spontaneous pain is present in the Chung-SNL model, and perhaps in the other partial nerve injury models as well, but that spontaneous pain is not expressed as autotomy in these models because there is protective nociceptive sensory cover.

Multisite integumentary squamous cell carcinoma in an African grey parrot (Psittacus erithacus erithacus).

A 22-year-old male African grey parrot (Psittacus erithacus erithacus) had had episodes of chronic feather picking and self-mutilation for 10 years; it had a 5 cm diameter right axillary wound and a 2 cm left dorsal patagial wound. Initial treatment with azithromycin and wound management was unsuccessful. Biopsies of both masses indicated squamous cell carcinoma. The left patagial tumour was removed completely by electrocautery. Cisplatin was administered weekly into multiple sites on the right axillary tumour and it initially appeared to regress; however, the bird's condition deteriorated after a month of treatment, and it was euthanased. The tumour was confirmed postmortem to be squamous cell carcinoma, which had invaded local tissues. The aetiology of the carcinoma may have been secondary to chronic focal trauma.