Non-pharmacological approach to neuropathic pain: the use of repetitive transcranial magnetic stimulation

Neuromodulation is the branch of neurophysiology related to the therapeutic effects of electrical stimulations of the nervous system. There are currently different practical applications of neuromodulation techniques for the treatment of various neurological disorders, such as deep brain stimulation for Parkinson`s disease and repetitive transcranial magnetic stimulation (rTMS) for major depression. An increasing number of studies have been devoted to the analgesic effects of rTMS in chronic pain patients. RTMS has been used either as a therapeutic tool per se, or as a preoperative test in patients undergoing epidural precentral gyrus stimulation. High-frequency rTMS (a parts per thousand yen5 Hz) is considered to be excitatory, while low-frequency stimulation (a parts per thousand currency sign1 Hz) is considered to exert an inhibitory effect over neuronal populations of the primary motor cortex. However, other parameters of stimulation may play a central role on its clinical effects such as the type of coil, its orientation over the scalp, and the total number of rTMS sessions performed. Experimental data from animals, healthy volunteers, and neuropathic pain patients have suggested that stimulation of the primary motor cortex by rTMS is able to activate brain regions implicated in the processing of the different aspects of chronic pain, and influence brain regions involved in the endogenous opioid system. Over twenty prospective randomized sham-controlled trials have studied the analgesic effects of rTMS on chronic pain. Most of the patients included in these trials had central or peripheral neuropathic pain. Although most studies used a single session of stimulation, recent studies have shown that the analgesic effects of rTMS may outlast the stimulation period for many days when repetitive sessions are performed. This opens the possibility to use rTMS as a therapeutic tool of its own in the armamentarium against neuropathic pain.

Treatment of suicidal people around the world

Background Suicide is a leading cause of death worldwide; however, little information is available about the treatment of suicidal people, or about barriers to treatment. Aims To examine the receipt of mental health treatment and barriers to care among suicidal people around the world. Method Twenty-one nationally representative samples worldwide (n=55 302; age 18 years and over) from the World Health Organization`s World Mental Health Surveys were interviewed regarding past-year suicidal behaviour and past-year healthcare use. Suicidal respondents who had not used services in the past year were asked why they had not sought care. Results Two-fifths of the suicidal respondents had received treatment (from 17% in low-income countries to 56% in high-income countries), mostly from a general medical practitioner (22%), psychiatrist (15%) or non-psychiatrist (15%). Those who had actually attempted suicide were more likely to receive care. Low perceived need was the most important reason for not seeking help (58%), followed by attitudinal barriers such as the wish to handle the problem alone (40%) and structural barriers such as financial concerns (15%). Only 7% of respondents endorsed stigma as a reason for not seeking treatment. Conclusions Most people with suicide ideation, plans and attempts receive no treatment. This is a consistent and pervasive finding, especially in low-income countries. Improving the receipt of treatment worldwide will have to take into account culture-specific factors that may influence the process of help-seeking.

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra-and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Changes in postnatal skeletal muscle development induced by alternative immobilization model in female rat

The objective of this study was to adapt a model of hind limb immobilization to newly weaned female rats and to determine the morphology of shortened soleus and plantaris muscles. Female Wistar rats were divided into three groups: control zero (n = 3) and control and free (n = 8), animals aged 21 and 31 days, respectively, submitted to no intervention, and immobilized (n = 25), animals aged 21 days submitted to immobilization for 10 days and sacrificed at 31 days of age. The device used for immobilization had advantages such as easy connection, good fit, and low cost. The immobilized rats showed a reduction in muscle fiber area and in connective tissue. The adaptation of this immobilization model originally used for adult rats was an excellent alternative for newly weaned rats and was also efficient in inducing significant hind limb disuse.

Representational Difference Analysis (RDA) reveals differential expression of conserved as well as novel genes during caste-specific development of the honey bee (Apis mellifera L.) ovary

In highly eusocial insects, such as the honey bee, Apis mellifera, the reproductive bias has become embedded in morphological caste differences. These are most expressively denoted in ovary size, with adult queens having large ovaries consisting of 150-200 ovarioles each, while workers typically have only 1-20 ovarioles per ovary. This morphological differentiation is a result of hormonal signals triggered by the diet change in the third larval instar, which eventually generate caste-specific gene expression patterns. To reveal these we produced differential gene expression libraries by Representational Difference Analysis (RDA) for queen and worker ovaries in a developmental stage when cell death is a prominent feature in the ovarioles of workers, whereas all ovarioles are maintained and extend in length in queens. In the queen library, 48% of the gene set represented homologs of known Drosophila genes, whereas in the worker ovary, the largest set (59%) were ESTs evidencing novel genes, not even computationally predicted in the honey bee genome. Differential expression was confirmed by quantitative RT-PCR for a selected gene set, denoting major differences for two queen and two worker library genes. These included two unpredicted genes located in chromosome 11 (Group11.35 and Group11.31, respectively) possibly representing long non-coding RNAs. Being candidates as modulators of ovary development, their expression and functional analysis should be a focal point for future studies. (C) 2011 Elsevier Ltd. All rights reserved.

The insulin signaling pathway in honey bee (Apis mellifera) caste development - differential expression of insulin-like peptides and insulin receptors in queen and worker larvae

The insulin/insulin-like signaling (IIS) pathway is an evolutionarily conserved module in the control of body size and correlated organ growth in metazoans. In the highly eusocial bees, the caste phenotypes differ not only in size and several structural features but also in individual fitness and life history. We investigated the developmental expression profiles of genes encoding the two insulin-like peptides (AmILP-1 and AmILP-2) and the two insulin receptors (AmInR-1 and AmInR-2) predicted in the honey bee genome. Quantitative PCR analysis for queen and worker larvae in critical stages of caste development showed that AmILP-2 is the predominantly transcribed ILP in both castes, with higher expression in workers than in queens. Expression of both InR genes sharply declined in fourth instar queen larvae, but showed little modulation in workers. On first sight, these findings are non-intuitive, considering the higher growth rates of queens, but they can be interpreted as possibly antagonistic crosstalk between the IIS module and juvenile hormone. Analyzing AmInR-1 and AmInR-2 expression in ovaries of queen and worker larvae revealed low transcript levels in queens and a sharp drop in AmInR-2 expression in fifth instar worker larvae, indicating relative independence in tissue-specific versus overall IIS pathway activity. (C) 2008 Elsevier Ltd. All rights reserved.

Monoclonal B-cell lymphocytosis in first-degree relatives of patients with sporadic (non-familial) chronic lymphocytic leukaemia

Although biological similarities have been described among monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukaemia (CLL), the relationships between these two conditions are not fully understood, and new epidemiological studies in different populations and different countries continue to be reported. Here, we investigated 167 first-degree relatives from 42 families of patients with non-familial (sporadic) CLL, using four-colour flow cytometry. MBL was found in seven of 167 subjects (4.1%). Monoclonality was detected in all cases either by light-chain restriction or by polymerase chain reaction. Fluourescence in situ hybridization did not show any chromosomal abnormality. The prevalence of MBL according to age was 0 (0/54) in individuals aged less than 40 years, 2.5% (2/81) between 40 and 60 years, and 15.6% (5/32) in individuals over 60 years. The prevalence of MBL cases in individuals over 60 years was similar to that found in familial CLL relatives at the same age group. This suggests that in older first-degree relatives of patients with sporadic CLL, the risk of MBL detection is as high as in older first-degree relatives from CLL families, which could render these individuals belonging to `sporadic CLL families` as susceptible as individuals from `familial CLL` to the development of clinical CLL.

CXCL12 rs1801157 Polymorphism in Patients with Breast Cancer, Hodgkin`s Lymphoma, and Non-Hodgkin`s Lymphoma

Chemokines and their receptors regulate the trafficking of immune cells during their development, inflammation, and tissue repair. The single-nucleotide polymorphism (SNP) rs1801157 (previously known as CXCL12-A/ stromal cell-derived factor-1 (SDF1)-3`A) in CXCL12/SDF1 gene was assessed in breast cancer, Hodgkin`s lymphoma (HL), and non-Hodgkin`s lymphoma (NHL), since the chemokine CXCL12, previously known as SDF1, and its receptor CXCR4 regulate leukocyte trafficking and many essential biological processes, including tumor growth, angiogenesis, and metastasis of different types of tumors. Genotyping was performed by PCR-RFLP (polymerase chain reaction followed by restriction fragment length polymorphism) using a restriction enzyme Hpall cleavage. No significant difference was observed in genotype distribution between breast cancer patients (GG: 57.3%; GA: 39.8%; AA: 2.9%) and healthy female controls (GG: 62.9%; GA: 33%; AA: 4.1%) nor between HL patients (GG: 61.1%; GA:27.8%; AA: 11.1%) and healthy controls (GG: 65.6%; GA: 28.9%; AA: 5.5%), whereas a significant difference was observed in genotype distribution between NHL patients (GG: 51.4%; GA: 47.1%; AA: 1.5%) and healthy controls (GG: 65.6%; GA: 28.9%; AA: 5.5%). Further studies will be necessary to elucidate the cancer chemokine network. However, this study suggests that CXCL12 rs1801157 polymorphism may have important implications in the pathogenesis of NHL. J. Clin. Lab. Anal. 23:387-393, 2009. (C) 2009 Wiley-Liss, Inc.

Role of N-Methyl-D-Aspartate and Non-N-Methyl-D-Aspartate Receptors in the Cardiovascular Effects of L-Glutamate Microinjection Into the Hypothalamic Paraventricular Nucleus of Unanesthetized Rats

We report on the cardiovascular effects of L-glutamate (L-glu) microinjection into the hypothalamic paraventricular nucleus (PVN) as well as the mechanisms involved in their mediation. L-glu microinjection into the PVN caused dose-related pressor and tachycardiac responses in unanesthetized rats. These responses were blocked by intravenous (i.v.) pretreatment with the ganglion blocker pentolinium (PE; 5 mg/kg), suggesting sympathetic mediation. Responses to L-glu were not affected by local microinjection of the selective non-NMDA receptor antagonist NBQX (2 nmol) or by local microinjection of the selective NMDA receptor antagonist LY235959 (LY; 2 nmol). However, the tachycardiac response was changed to a bradycardiac response after treatment with LY235959, suggesting that NMDA receptors are involved in the L-glu heart rate response. Local pretreatment with LY235959 associated with systemic PE or dTyr(CH(2))(5)(Me)AVP (50 mu g/kg) respectively potentiated or blocked the response to L-glu, suggesting that L-glu responses observed after LY235959 are vasopressin mediated. The increased pressor and bradycardiac responses observed after LY + PE was blocked by subsequent i.v. treatment with the V(1)-vasopressin receptor antagonist dTyr(CH(2))(5)(Me)AVP, suggesting vasopressin mediation. The pressor and bradycardiac response to L-glu microinjection into the PVN observed in animals pretreated with LY + PE was progressively inhibited and even blocked by additional pretreatment with increasing doses of NBQX (2, 10, and 20 nmol) microinjected into the PVN, suggesting its mediation by local non-NMDA receptors. In conclusion, results suggest the existence of two glutamatergic pressor pathways in the PVN: one sympathetic pathway that is mediated by NMDA receptors and a vasopressinergic pathway that is mediated by non-NMDA receptors. (C) 2009 Wiley-Liss, Inc.

Influence of treadmill training on motor performance and organization of exploratory behavior in Meriones unguiculatus with unilateral ischemic stroke: Histological correlates in hippocampal CA1 region and the neostriatum

This study examined the effects of motor stimulation via treadmill on the behavior of male gerbils after external carotid ischemic brain lesion. The animals were assigned to five groups; ischemic with no stimulation (SIG), ischemic with stimulation (SIG 12/24/48/72 It after surgery), non-ischemic with no stimulation (CC), non-ischemic with stimulation (CE) and sham, surgery without occlusion with no stimulation (SH). All the animals were tested in the open-field (OF) and rotarod (RR), 4 days after surgery in order to evaluate exploratory behaviors and motor performance. Data were submitted to one-way variance (ANOVA) and Dunnett`s post hoc comparisons. SIG and SIG 12 groups showed a significant decrease in motor response (crossing) when compared to the control group (CC) (F = 20.65, P < 0.05) in the OF. SIG 12 group showed an increase in grooming behavior (F = 23.136, P < 0.05) and all ischemia groups (SIG, SIG 12/24/48/72) spent less time on the RR (F = 10.40, P < 0.05), when compared to the control group (CC). Histological analyses show extensive lesions in the hippocampus and neostriatum for all groups with ischemia (SIG, SIG 12/24/48/72), which are structures involved in the organization of motor behavior. Interestingly, the most pronounced damage was found in animals submitted to motor stimulation 12 h after ischemia which can be correlated to the increased number of grooming behavior showed by them in the OF. These findings suggest that motor stimulation through treadmill training improve motor behavior after ischemia, except when it starts 12h after surgery. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Angiogenic non-Hodgkin T/natural killer (NK)-cell lymphoma: Report of three cases

Angiogenic T/natural killer (NK)-cell lymphoma is a non-Hodgkin lymphoma characterized by necrosis and vascular destruction that is strongly associated with Epstein-Barr virus and AIDS. Early diagnosis is essential to improve the chances of patient survival, but severe local inflammatory infiltrate impairs histologic diagnosis by obscuring neoplastic cells. The most common markers are CD2, CD56, cytoplasmic CD3, and CD43 EBV We describe 3 cases of angiogenic T/NK-cell lymphoma that show the diverse Presentation of the same disease. Patient I was HIV positive and had nasal obstruction, facial edema, and ulceration of the nasal mucosa. Patient 2 had fever, a sore throat, and weight loss. Patient 3 had facial edema, fever, proptosis, and rapid development Of neurologic alterations. Several biopsies were needed for histologic confirmation in these patients, despite positivity for the CD3 and CD56 markers.

Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions

Background Porphyria cutanea tarda (PCT) is a metabolic disease characterized by vesicles and blisters in sun-exposed areas and scleroderma-like lesions in sun-exposed and non-sun-exposed areas. Mast cells participate in the pathogenesis of bullous diseases and diseases that show sclerosis, including PCT. Moreover, transforming growth factor-beta (TGF-beta) is the main cytokine in the development of tissue sclerosis. The correlation of mast cells and TGF-beta with the lesions of PCT has not been examined, however. The possible role of mast cells and TGF-beta (and the relationship between them) in the development of PCT lesions is discussed. Methods To quantify mast cells and cells expressing TGF-beta in skin samples from patients with PCT and controls, immunohistochemical studies were performed in tissue sections allied to morphometric analyses. Results The numbers of mast cells and cells expressing TGF-beta per square millimiter were increased in the PCT group relative to controls, and there was a direct and significant correlation between the mast cell number and cells expressing TGF-beta in PCT. Conclusions The results suggest that the increased number of mast cells and of cells expressing TGF-beta, as well as their direct correlation, may contribute to the pathogenesis of the skin lesions in PCT.

Nomenclature for congenital and paediatric cardiac disease: Historical perspectives and The International Pediatric and Congenital Cardiac Code

Clinicians working in the field of congenital and paediatric cardiology have long felt the need for a common diagnostic and therapeutic nomenclature and coding system with which to classify patients of all ages with congenital and acquired cardiac disease. A cohesive and comprehensive system of nomenclature, suitable for setting a global standard for multicentric analysis of outcomes and stratification of risk, has only recently emerged, namely, The International Paediatric and Congenital Cardiac Code. This review, will give an historical perspective on the development of systems of nomenclature in general, and specifically with respect to the diagnosis and treatment of patients with paediatric and congenital cardiac disease. Finally, current and future efforts to merge such systems into the paperless environment of the electronic health or patient record on a global scale are briefly explored. On October 6, 2000, The International Nomenclature Committee for Pediatric and Congenital Heart Disease was established. In January, 2005, the International Nomenclature Committee was constituted in Canada as The International Society for Nomenclature of Paediatric and Congenital Heart Disease. This International Society now has three working groups. The Nomenclature Working Group developed The International Paediatric and Congenital Cardiac Code and will continue to maintain, expand, update, and preserve this International Code. It will also provide ready access to the International Code for the global paediatric and congenital cardiology and cardiac surgery communities, related disciplines, the healthcare industry, and governmental agencies, both electronically and in published form. The Definitions Working Group will write definitions for the terms in the International Paediatric and Congenital Cardiac Code, building on the previously published definitions from the Nomenclature Working Group. The Archiving Working Group, also known as The Congenital Heart Archiving Research Team, will link images and videos to the International Paediatric and Congenital Cardiac Code. The images and videos will be acquired from cardiac morphologic specimens and imaging modalities such as echocardiography, angiography, computerized axial tomography and magnetic resonance imaging, as well as intraoperative images and videos. Efforts are ongoing to expand the usage of The International Paediatric and Congenital Cardiac Code to other areas of global healthcare. Collaborative efforts are under-way involving the leadership of The International Nomenclature Committee for Pediatric and Congenital Heart Disease and the representatives of the steering group responsible for the creation of the 11th revision of the International Classification of Diseases, administered by the World Health Organisation. Similar collaborative efforts are underway involving the leadership of The International Nomenclature Committee for Pediatric and Congenital Heart Disease and the International Health Terminology Standards Development Organisation, who are the owners of the Systematized Nomenclature of Medicine or ""SNOMED"". The International Paediatric and Congenital Cardiac Code was created by specialists in the field to name and classify paediatric and congenital cardiac disease and its treatment. It is a comprehensive code that can be freely downloaded from the internet (http://www.IPCCC.net) and is already in use worldwide, particularly for international comparisons of outcomes. The goal of this effort is to create strategies for stratification of risk and to improve healthcare for the individual patient. The collaboration with the World Heath Organization, the International Health Terminology Standards Development Organisation, and the healthcare Industry, will lead to further enhancement of the International Code, and to Its more universal use.

Age-related deregulation of Aire and peripheral tissue antigen genes in the thymic stroma of non-obese diabetic (NOD) mice is associated with autoimmune type 1 diabetes mellitus (DM-1)

Gene expression of peripheral tissue antigens (PTAs) in stromal medullary thymic epithelial cells (mTECs) is a key process to the negative selection of autoreactive thymocytes. This phenomenon was termed ""promiscuous gene expression"" (PGE), which is partially controlled by the Aire gene. Nevertheless, reasons for the correlation of Aire and PTAs with the emergence of autoimmune diseases are largely unknown, though it may be a result of a chronological effect. Although the effect of Aire mutations in pathogenic autoimmunity is well know, it could not be a unique cause for autoimmunity. Independently of mutations, temporal deregulation of Aire expression may imbalance Aire-dependent PTAs and/or wide PGE. This deregulation may be an early warning sign for autoimmune diseases as it guarantees autoantigen representation in the thymus. To assess this hypothesis, we studied the expression levels of Aire, Aire-dependent (Ins2) and Aire-independent (Gad67 and Col2a1) PTAs using real-time-PCR of the thymic stromal cells of NOD mice during the development of autoimmune type 1 diabetes mellitus (DM-1). Wide PGE was studied by microarrays in which the PTA genes were identified through parallel CD80(+) mTEC 3.10 cell line expression profiling. The results show that Aire gene was down-regulated in young pre-autoimmune (pre-diabetic) NOD mice. PGE and specific PTA genes were down-regulated in adult autoimmune diabetic animals. These findings represent evidence indicating that chronological deregulation of genes important to negative selection may be associated with the development of an autoimmune disease (DM-1) in mice.

Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway

Common features such as elastic fibre destruction, mucoid accumulation, and smooth muscle cell apoptosis are co-localized in aneurysms of the ascending aorta of various aetiologies. Recent experimental studies reported an activation of TGF-beta in aneurysms related to Marfan (and Loeys-Dietz) syndrome. Here we investigate TGF-beta signalling in normal and pathological human ascending aortic wall in syndromic and non-syndromic aneurysmal disease. Aneurysmal ascending aortic specimens, classified according to aetiology: syndromic MFS (n = 15, including two mutations in TGFBR2), associated with BAV (n = 15) or degenerative forms (n = 19), were examined. We show that the amounts of TGF-beta 1 protein retained within and released by aneurysmal tissue were greater than for control aortic tissue, whatever the aetiology, contrasting with an unchanged TGF-beta 1 mRNA level. The increase in stored TGF-beta 1 was associated with enhanced LTBP-I protein and mRNA levels. These dysiregulations of the extracellular ligand are associated with higher phosphorylated Smad2 and Smad2 mRNA levels in the ascending aortic wall from all types of aneurysm. This activation correlated with the degree of elastic fibre fragmentation. Surprisingly, there was no consistent association between the nuclear location of pSmad2 and extracellular TGF-beta 1 and LTBP-I staining and between their respective mRNA expressions. In parallel, decorin. was focally increased in aneurysmal media, whereas biglycan was globally decreased in aneurysmal aortas. In conclusion, this study highlights independent dysregulations of TGF-beta retention and Smad2 signalling in syndromic and non-syndromic aneurysms of the ascending aorta. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.