Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

Comparison of Bispectral Index (BIS) and Patient State Index (PSI) as objective measures of sedation and analgesia in critically ill/injured patients

Critically ill and injured patients require pain relief and sedation to reduce the body's stress response and to facilitate painful diagnostic and therapeutic procedures. Presently, the level of sedation and analgesia is guided by the use of clinical scores which can be unreliable. There is therefore, a need for an objective measure of sedation and analgesia. The Bispectral Index (BIS) and Patient State Index (PSI) were recently introduced into clinical practice as objective measures of the depth of analgesia and sedation. ^ Aim. To compare the different measures of sedation and analgesia (BIS and PSI) to the standard and commonly used modified Ramsay Score (MRS) and determine if the monitors can be used interchangeably. ^ Methods. MRS, BIS and PSI values were obtained in 50 postoperative cardiac surgery patients requiring analgesia and sedation from June to December 2004. The MRS, BIS and PSI values were assessed hourly for up to 6-h by a single observer. ^ The relationship between BIS and PSI values were explored using scatter plots and correlation between MRS, BIS and PSI was determined using Spearman's correlation coefficient. Intra-class correlation (ICC) was used to determine the inter-rater reliability of MRS, BIS and PSI. Kappa statistics was used to further evaluate the agreement between BIS and PSI at light, moderate and deep levels of sedation. ^ Results. There was a positive correlation between BIS and PSI values (Rho = 0.731, p<0.001). Intra-class correlation between BIS and PSI was 0.58, MRS and BIS 0.43 and MRS and PSI 0.27. Using Kappa statistics, agreement between MRS and BIS was 0.35 (95% CI: 0.27–0.43) and for MRS and PSI was 0.21 (95% CI: 0.15–0.28). The kappa statistic for BIS and PSI was 0.45 (95% CI: 0.37–0.52). Receiver operating characteristics (ROC) curves constructed to detect undersedation indicated an area under the curve (AUC) of 0.91 (95% CI = 0.87 to 0.94) for the BIS and 0.84 (95% CI = 0.79 to 0.88) for the PSI. For detection of oversedation, AUC for the BIS was 0.89 (95% CI = 0.84 to 0.92) and 0.80 (95% CI = 0.75 to 0.85) for the PSI. ^ Conclusions. There is a statistically significant positive correlation between the BIS and PSI but poor correlation and poor test agreement between the MRS and BIS as well as MRS and PSI. Both the BIS and PSI demonstrated a high level of prediction for undersedation and oversedation; however, the BIS and PSI can not be considered interchangeable monitors of sedation. ^

In vivo longitudinal studies of spinal cord injury and vascular endothelial growth factor treatment

Approximately 12,000 new cases of spinal cord injury (SCI) are added each year to the estimated 259,000 Americans living with SCI. The majority of these patients return to society, their lives forever changed by permanent loss of sensory and motor function. While there are no FDA approved drugs for the treatment of SCI or a universally accepted standard therapy, the current though controversial treatment includes the delivery of high dosages of the corticosteroid methyliprednisolone sodium succinate, surgical interventions to stabilize the spinal column, and physical rehabilitation. It is therefore critically important to fully understand the pathology of injury and determine novel courses and rationally-based therapies for SCI. ^ Vascular endothelial growth factor (VEGF) is an attractive target for treating central nervous system (CNS) injury and disease because it has been shown to influence angiogenesis and neuroprotection. Preliminary studies have indicated that increased vasculature may be associated with functional recovery; therefore exogenous delivery of a pro-angiogenic growth factor such as VEGF may improve neurobehavioral outcome. In addition, VEGF may provide protection from secondary injury and result in increased survival and axonal sprouting. ^ In these studies, SCI rats received acute intraspinal injections of VEGF, the antibody to VEGF, or vehicle control. The effect of these various agents was investigated using longitudinalmulti-modal magnetic resonance imaging (MRI), neuro- and sensory behavioral assays, and end point immunohistochemistry. We found that rats that received VEGF after SCI had increased tissue sparing and improved white matter integrity at the earlier time points as shown by advanced magnetic resonance imaging (MRI) techniques. However, these favorable effects of VEGF were not maintained, suggesting that additional treatments with VEGF at multiple time points may be more beneficial, Histological examinations revealed that VEGF treatment may result in increased oligodendrogenesis and therefore may eventually lead to remyelination and improved functional outcome. ^ On the neurobehavioral studies, treatments with VEGF and Anti-VEGF did not significantly affect performance on tests of open-field locomotion, grid walk, inclined plane, or rearing. However, VEGF treatment resulted in significantly increased incidence of chronic neuropathic pain. This phenomenon could possibly be attributed to the fact that VEGF treatment may promote axonal sprouting and also results in tissue sparing, thereby providing a substrate for the growth of new axons. New connections made by these sprouting axons may involve components of pathways involved in the transmission of pain and therefore result in increased pain in those animals. ^

Quality of life, symptom experience, and use of complementary and alternative medicine among women with ovarian cancer

The objectives of this dissertation were to determine the quality of life in women with ovarian cancer and the association of their physical and emotional well-being with the number of symptoms, duration of symptoms, and the scores of common symptoms of ovarian cancer; to study the prevalence of complementary and alternative medicine techniques for symptom relief and its association with the number of symptoms, age, education, insurance, comorbidity, and satisfaction with medical care they received, and their pre-diagnostic experience of symptoms.^ This study was based on a secondary data analysis of a study of early detection of ovarian cancer. A sample of 139 women with ovarian cancer was recruited and was administered a questionnaire comprised of questions on their quality of life, their symptoms and what they did about the symptoms, whether they used any complementary and alternative medicine techniques, and other medical conditions they had. Out of this sample, 53 patients underwent in-depth interviews relating to their symptoms before the diagnosis and their experiences with the health care system leading to the ovarian cancer diagnosis. ^ In article #1, ovarian cancer patients were observed to have significantly poorer quality of life on all subscales and summary scores except pain, compared to that of the general population of US women. Physical well-being scores were negatively associated with the number of symptoms before diagnosis and a significant negative association of comorbidity index was observed with physical well-being. Higher education and increase in time since diagnosis was found to have better physical scores. Emotional well-being scores showed marginally significant associations with number of symptoms and bloating. ^ In article #2, a thematic content analysis of the ovarian cancer patients’ interviews revealed that on recognition of their symptoms women first assumed their symptoms to be a normal transient occurrence due to a pre-existing disease condition, or due to some other disease. A series of misattributions of their symptoms on their and their doctors’ part impacted their health care seeking.In article #3, a significantly greater likelihood of CAM use with an increase in the number of symptoms was observed.^ Based on the foregoing results, it is important to educate women on possible signs of ovarian cancer and also to educate doctors about the results of current research regarding ovarian cancer diagnosis. This will help to avoid a delay in getting a diagnosis and improve women’s quality of life. It emphasizes the diagnosis of ovarian cancer in earlier stages by more sensitive screening techniques. This study emphasizes the importance of consideration of comorbidity in any quality of life research. Additionally, educating women in the safe use of CAM techniques carries immense significance because the efficacy and safety of many of the currently advertized CAM products has not been scientifically validated. Further research is needed to confirm the findings of this study. ^

Complications of misoprostol and other abortion induction methods in the developing world: A systematic review

OBJECTIVE: To systematically review published literature to examine the complications associated with the use of misoprostol and compare these complications to those associated with other forms of abortion induction. ^ DATA SOURCES: Studies were identified through searches of medical literature databases including Medline (Ovid), PubMed (NLM), LILACS, sciELO, and AIM (AFRO), and review of references of relevant articles. ^ STUDY SELECTION AND METHODS: A descriptive systematic review that included studies reported in English and published before December 2012. Eligibility criteria included: misoprostol (with or without other methods) and any other method of abortion in a developing country, as well as quantitative data on the complication of each method. The following is information extracted from each study: author/year, country/city, study design/study sample, age range, setting of data collection, sample size, the method of abortion induction, the number of cases for each method, and the percentage of complications with each method. RESULTS: A total of 4 studies were identified (all in Latin America) describing post-abortion complications of misoprostol and other methods in countries where abortion is generally considered unsafe and/or illegal. The four studies reported on a range of complications including: bleeding, infection, incomplete abortion, intense pelvic pain, uterine perforation, headache, diarrhea, nausea, mechanical lesions, and systemic collapse. The most prevalent complications of misoprostol-induced abortion reported were: bleeding (7-82%), incomplete abortion (33-70%), and infection (0.8-67%). The prevalence of these complications reported from other abortion methods include: bleeding (16-25%), incomplete abortion (15-82%), and infection (13-50%). ^ CONCLUSION: The literature identified by this systematic review is inadequate for determining the complications of misoprostol used in unsafe settings. Abortion is considered an illicit behavior in these countries, therefore making it difficult to investigate the details needed to conduct a study on abortion complications. Given the differences between the reviewed studies as well as a variety of study limitations, it is not possible to draw firm conclusions about the rates of specific-abortion related complications.^

Strength and stiffness of repaired tendons

Rotator cuff tears of the shoulder are a common cause of pain and disability. Although surgery is frequently beneficial, re-tearing of the tendons is likely to re-occur. In many cases even if the reparation is successful it will still generate discomfort, problems with mobility, as well as a sharp pain. This project is funded in the cooperation with the Hospital Clinico San Carlos de Madrid. The purpose of this work is to analyze the effect of the surgical repair and the application of different therapies, including mesenchymal stem cell therapy on the biomechanical properties (strength and stiffness) of the repaired tendon. An animal model of rotator cuff tendon reparations has been developed on laboratory rats.To obtain the mechanical response of the healthy and repaired tendons, it was necessary to develop an experimental set up to reproduce the in-vivo working conditions of the tendons (37 ºC, immersed in physiological serum), and especially the load transfer. The biomechanical properties (maximum load and stiffness) have been measured in healthy and repaired tendons. A total of 70 rats are used in this particular study. It has been found that the repaired tendon is stronger than the original on. However, the repaired tendons demonstrate less flexibility than the healthy (original) ones prior to the damage

In vivo zippering of inner and outer mitochondrial membranes by a stable translocation intermediate

It was previously assumed that the import of cytoplasmically synthesized precursor proteins into mitochondria occurs through a single structure spanning both outer and inner membranes at contact sites. Based on recent findings, however, the two membranes appear to contain independent translocation elements that reversibly cooperate during protein import. This feature makes it difficult to generate a means of isolating a fully integrated and functional translocation complex. To study these independent translocases in vitro and in vivo, we have constructed a chimeric protein consisting of an N-terminal authentic mitochondrial precursor (delta1-pyrroline-5-carboxylate dehydrogenase) linked, through glutathione S-transferase, to IgG binding domains derived from staphylococcal protein A. This construct becomes trapped en route to the matrix, spanning both outer and inner membranes in such a way that the entire signal-less delta1-pyrroline-5-carboxylate dehydrogenase moiety reaches the matrix, while only the folded protein A domain remains outside. During in vivo import of this precursor, outer and inner membranes of yeast mitochondria become progressively “zippered” together, forming long stretches of close contact. Using this novel intermediate, the outer and inner mitochondrial membrane channels, which normally interact only transiently, can be tightly joined (both in vitro and in vivo), forming a stable association. This suggests a method for isolating the functional translocation complex as a single entity.

Why do children have chronic abdominal pain, and what happens to them when they grow up? Population based cohort study

Objective: To test the hypotheses that children with abdominal pain have anxious parents and come from families with high rates of physical illness and that they grow up to suffer from high rates of medically unexplained symptoms and psychiatric disorders.

Causalgia, pathological pain, and adrenergic receptors

Control of expression of molecular receptors for chemical messengers and modulation of these receptors’ activity are now established as ways to alter cellular reaction. This paper extends these mechanisms to the arena of pathological pain by presenting the hypothesis that increased expression of α-adrenergic receptors in primary afferent neurons is part of the etiology of pain in classical causalgia. It is argued that partial denervation by lesion of peripheral nerve or by tissue destruction induces a change in peripheral nociceptors, making them excitable by sympathetic activity and adrenergic substances. This excitation is mediated by α-adrenergic receptors and has a time course reminiscent of experimental denervation supersensitivity. The change in neuronal phenotype is demonstrable after lesions of mixed nerves or of the sympathetic postganglionic supply. Similar partial denervations also produce a substantial increase in the number of dorsal root ganglion neurons evidencing the presence of α-adrenergic receptors. The hypothesis proposes the increased presence of α-adrenergic receptors in primary afferent neurons to result from an altered gene expression triggered by cytokines/growth factors produced by disconnection of peripheral nerve fibers from their cell bodies. These additional adrenergic receptors are suggested to make nociceptors and other primary afferent neurons excitable by local or circulating norepinephrine and epinephrine. For central pathways, the adrenergic excitation would be equivalent to that produced by noxious events and would consequently evoke pain. In support, evidence is cited for a form of denervation supersensitivity in causalgia and for increased expression of human α-adrenergic receptors after loss of sympathetic activity.

The effects of practice on the functional anatomy of task performance

The effects of practice on the functional anatomy observed in two different tasks, a verbal and a motor task, are reviewed in this paper. In the first, people practiced a verbal production task, generating an appropriate verb in response to a visually presented noun. Both practiced and unpracticed conditions utilized common regions such as visual and motor cortex. However, there was a set of regions that was affected by practice. Practice produced a shift in activity from left frontal, anterior cingulate, and right cerebellar hemisphere to activity in Sylvian-insular cortex. Similar changes were also observed in the second task, a task in a very different domain, namely the tracing of a maze. Some areas were significantly more activated during initial unskilled performance (right premotor and parietal cortex and left cerebellar hemisphere); a different region (medial frontal cortex, “supplementary motor area”) showed greater activity during skilled performance conditions. Activations were also found in regions that most likely control movement execution irrespective of skill level (e.g., primary motor cortex was related to velocity of movement). One way of interpreting these results is in a “scaffolding-storage” framework. For unskilled, effortful performance, a scaffolding set of regions is used to cope with novel task demands. Following practice, a different set of regions is used, possibly representing storage of particular associations or capabilities that allow for skilled performance. The specific regions used for scaffolding and storage appear to be task dependent.

The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex

Numerous human and animal studies indirectly implicate neurons in the anterior cingulate cortex (ACC) in the encoding of the affective consequences of nociceptor stimulation. No causal evidence, however, has been put forth linking the ACC specifically to this function. Using a rodent pain assay that combines the hind-paw formalin model with the place-conditioning paradigm, we measured a learned behavior that directly reflects the affective component of pain in the rat (formalin-induced conditioned place avoidance) concomitantly with “acute” formalin-induced nociceptive behaviors (paw lifting, licking, and flinching) that reflect the intensity and localization of the nociceptive stimulus. Destruction of neurons originating from the rostral, but not caudal, ACC reduced formalin-induced conditioned place avoidance without reducing acute pain-related behaviors. These results provide evidence indicating that neurons in the ACC are necessary for the “aversiveness” of nociceptor stimulation.

Optic neuritis in pediatric population: A review in current tendencies of diagnosis and management

Optic neuritis is an inflammation of the optic nerve and may be related to different systemic conditions. The clinical presentation of this pathology usually includes sudden loss of visual acuity (VA) which may be unilateral or bilateral, visual field restriction, pain with eye movements, dyschromatopsia, a relative afferent pupillary defect and optic disk swelling. Optic neuritis in children has specific clinical features and a better prognosis than in adulthood. Although usually appears an underlying viral disease, the main concern for practitioners is the relationship of optic neuritis with multiple sclerosis. In addition to the classical techniques as magnetic resonance imaging (MRI), current tendencies of diagnosis for eye practitioners include new imaging devices as optical coherence tomography (OCT), useful to show a thinning of the retinal fibers layer (RFL) after the inflammatory episode. Regarding the management of these patients, short-term intravenous steroid dosages seem to be the best option to treat acute attacks characterized by a very poor bilateral VA.

The anatomy of Russian information warfare. The Crimean operation, a case study. OSW Point of View Number 42, May 2014

The Crimean operation has served as an occasion for Russia to demonstrate to the entire world the capabilities and the potential of information warfare. Its goal is to use difficult to detect methods to subordinate the elites and societies in other countries by making use of various kinds of secret and overt channels (secret services, diplomacy and the media), psychological impact, and ideological and political sabotage. Russian politicians and journalists have argued that information battles are necessary for “the Russian/Eurasian civilisation” to counteract “informational aggression from the Atlantic civilisation led by the USA”. This argument from the arsenal of applied geopolitics has been used for years. This text is an attempt to provide an interpretation of information warfare with the background of Russian geopolitical theory and practice.

The mystery of pain : a book for the sorrowful /

Mode of access: Internet.

The anatomy of freedom.

Mode of access: Internet.