The spontaneous K-complex during stage 2 sleep: is it the 'forerunner' of delta waves?

The hypothesis that K-complexes (KCs) contribute to the process of synchronization leading to Slow-Wave Sleep (SWS) was evaluated by measuring their dynamic evolution across sleep cycles and before transitions to rapid eye movement (REM) or to SWS. KC density and inter-KC intervals respectively decreased and increased across the sleep cycles, revealing linear trends. Comparisons among transitions from stage 2 to SWS or to REM sleep showed a prevalence of KCs before the shift to SWS as compared to REM. Changes in KC density before the shift to SWS were fitted by a linear regression, at variance with the transition to REM sleep. Intra-night variations of KCs, paralleling the well-known decrease of slow waves across sleep cycles, and intracycle variations before shifting to SWS, both converge to indicate that KCs can be considered as the forerunner of delta waves.     

The 'danger' sensors that STOP the immune response: the A2 adenosine receptors?

Immune cells not only destroy pathogens but might also cause collateral injuries to normal tissues. The surprisingly low incidence of post-inflammatory complications is explained here by a 'danger-sensing' physiological mechanism that ensures the tissue-protecting negative feedback inhibition of overactive immune cells. We focus here on immunoregulatory influences of 'non-immune' signaling molecules in physiological and pathophysiological tissue microenvironments. We propose that hypoxia-associated accumulation of extracellular adenosine might be an important immunoregulatory signal. A2 receptors for extracellular adenosine might act as both primary sensors of excessive collateral tissue damage during an immune response and triggers of the emergency downregulation of overactive immune cells. Regulation by extracellular adenosine would protect normal organs from injury and/or re-direct immune responses.     

The biographical component of schizophrenia: a two-faced definition of relationship?

The schizophrenic's disturbed relationship with reality is generally ascribed to a mental illness of endogenous origin. Following the author's paper on a fixation disorder (1) provable in these patients, she expounds that their disturbed relationship with reality does not primarily concern their consciousness of objective reality but of their own self. As a result of contradictory definitions of relationship within his group (2,3) the schizophrenic is unable to integrate the awareness of his potentialities with the awareness of his social role. He cannot protect himself against a joker role imposed on him since his fixation disorder acts like a one-way valve impeding him from taking an active part in the definition of relationship. A hypothesis is presented as to how the schizophrenic's described fixation disorder may cause this one-way functioning of the definition of relationship.     

The response of the host microcirculation to bacterial sepsis: does the pathogen matter?

Sepsis results from the interaction between a host and an invading pathogen. The microcirculatory dysfunction is now considered central in the development of the often deadly multiple organ dysfunction syndrome in septic shock patients. The microcirculatory flow shutdown and flow shunting leading to oxygen demand and supply mismatch at the cellular level and the local activation of inflammatory pathways resulting from the leukocyte–endothelium interactions are both features of the sepsis-induced microcirculatory dysfunction. Although the host response through the inflammatory and immunologic response appears to be critical, there are also evidences that Gram-positive and Gram-negative bacteria can exert different effects at the microcirculatory level. In this review we discuss available data on the potential bacterial-specific microcirculatory alterations observed during sepsis.     

The somatic component of schizophrenia: a dissociation of the goals of visual attention and bifoveal fixation?

The presence of disorders of eye movements is today regarded as 'the strongest candidate for a genetically transmitted biological trait marker of schizophrenic disorders' (1). The present study is based on the experience, rather than the behaviour, of one patient in a search for a method of objectifying his visual problems. This method was found to be a simple test, which demonstrates a disturbance of fixation: while one eye accommodated on the figure without vergence, the other, vergent, eye fused with the image of the related background. The disorder had been misdiagnosed as 'exophoria' in conventional ophthalmological examinations, because prevailing ophthalmological theory accepts only one mode of vision; according to the most recent researches, however, it is necessary to distinguish two complementary modes of vision--one for panorama and one for detail--which differ in their coordination of vergence and accommodation. This new bimodal theory of vision--presented here for the first time--made it possible to understand the cause of the disorder as a substitution of sighting for fixation, due either to a disinhibition of panorama vision during fixation vision, or to an interchange of ipsilateral temporal and contralateral nasal projections from the retina, both associated with a fixation disparity. After correction of the patient's fixation disparity according to an unusual method, the dissociation of the visual goals was remedied and the mental disturbances of the patient vanished.     

Mast cells: A key component in the pathogenesis of Neuromyelitis Optica Spectrum Disorder?

Neuromyelitis Optica Spectrum Disorder (NMOSD) is characterized as an autoimmune, inflammatory and demyelinating disease of the Central Nervous System (CNS). Its pathogenesis is due to the presence of anti-aquaporin 4 immunoglobulin G1 antibodies (anti-AQP4IgG), with presence of lymphocytes T Helper 1 and 17 (TH1 and TH17), in addition to previous neuroinflammation.The Mast cell (MC) is a granular cell present in all vascularized tissues, close to vessels, nerves, and meninges. In CNS, MCs are in the area postrema, choroid plexus, thalamus and hypothalamus. MC has ability to transmigrate between the nervous tissue and the lymphoid organs, interacting with the cells of both systems. These cells reach the CNS during development through vessel migration. Most MCs reside on the abluminal side of the vessels, where it can communicate with neurons, glial cells, endothelial cells and the extracellular matrix.Considering the role of MCs in neurodegenerative diseases has been extensively discussed, we hypothesized MCs participate in the pathogenesis of NMOSD. This cell represents an innate and adaptive immune response regulator, capable of faster responses than microglial cells. The study of MCs in NMOSD can help to elucidate the pathogenesis of this disease and guide new research for the treatment of patients in the future. We believe this cell is an important component in the cascade of NMOSD neuroinflammation.     

Emotion Effects on the N170: A Question of Reference?

We investigated whether face-specific processes as indicated by the N170 in event-related brain potentials (ERPs) are modulated by emotional significance in facial expressions. Results yielded that emotional modulations over temporo-occipital electrodes typically used to measure the N170 were less pronounced when ERPs were referred to mastoids than when average reference was applied. This offers a potential explanation as to why the literature has so far yielded conflicting evidence regarding effects of emotional facial expressions on the N170. However, spatial distributions of the N170 and emotion effects across the scalp were distinguishable for the same time point, suggesting different neural sources for the N170 and emotion processing. We conclude that the N170 component itself is unaffected by emotional facial expressions, with overlapping activity from the emotion-sensitive early posterior negativity accounting for amplitude modulations over typical N170 electrodes. Our findings are consistent with traditional models of face processing assuming face and emotion encoding to be parallel and independent processes.     

Serum lipoproteins: Trojan horses of the immune response?

T cells recognizing lipid antigens presented by CD1 molecules have an important role in the immune response. Several lipid antigens for CD1-restricted T cells have been identified, as have some rules of CD1 loading and CD1-restricted presentation. Little is known, however, about the delivery of lipid antigens from either extracellular compartments or CD1-negative cells to CD1-expressing antigen-presenting cells (APCs). A recent study provides evidence for a role for apolipoprotein E in binding lipid antigens and delivering them to APCs.     

Combination of monoclonal antibodies and DPP-IV inhibitors in the treatment of type 1 diabetes: A plausible treatment modality?

Regulatory T cells (Tregs) are crucial for the maintenance of immunological tolerance. Type 1 diabetes (T1D) occurs when the immune-regulatory mechanism fails. In fact, T1D is reversed by islet transplantation but is associated with hostile effects of persistent immune suppression. T1D is believed to be dependent on the activation of type-1 helper T (Th1) cells. Immune tolerance is liable for the activation of the Th1 cells. The important role of Th1 cells in pathology of T1D entails the depletion of CD4⁺ T cells, which initiated the use of monoclonal antibodies (mAbs) against CD4⁺ T cells to interfere with induction of T1D. Prevention of autoimmunity is not only a step forward for the treatment of T1D, but could also restore the β-cell mass. Glucagon-like peptide (GLP)-1 stimulates β-cell proliferation and also has anti-apoptotic effects on them. However, the potential use of GLP-1 as a possible method to restore pancreatic β-cells is limited due to rapid degradation by dipeptidyl peptidase (DPP)-IV. We hypothesize that treatment with combination of CD4 mAbs and DPP-IV inhibitors could prevent/reverse T1D. CD4 mAbs have the ability to induce immune tolerance, thereby arresting further progression of T1D; DPP-IV inhibitors have the capability to regenerate the β-cell mass. Consequently, the combination of CD4 mAbs and DPP-IV inhibitor could avoid or at least minimize the constraints of intensive subcutaneous insulin therapy. We presume that if this hypothesis proves correct, it may become one of the plausible therapeutic options for T1D.     

Is insulin resistance an essential component of PCOS?: The influence of confounding factors

Insulin resistance is often considered a regular component of polycystic ovary syndrome (PCOS). Many interventional studies assume a state of insulin resistance in all patients. However, the evidence is based on small samples that are often insufficient to adjust for significant confounding factors. Moreover, several studies have not confirmed differences in insulin sensitivity between women with PCOS and healthy controls, especially in non-obese patients. This debate article provides an overview of the data published regarding the presence of abnormal or normal insulin sensitivity in PCOS. In conclusion, available data offer evidence that a substantial subgroup of women with PCOS have insulin sensitivity comparable with healthy controls if matched carefully for potential confounding factors.     

Anticholinergic therapy for overactive bladder: A nicotinic modality?

Until recently the treatment of Overactive Bladder (OAB) has primarily been aimed at mitigating hypercholinergic activity in the bladder via antagonism of muscarinic acetylcholine receptors. However, antimuscarinic therapies have limited efficacy and significant side effects. It is now known that nicotinic acetylcholine receptor (nAChR) subtypes are expressed in the urothelium and on afferent nerve fibers in the bladder, and it is believed that these receptors serve to communicate urgency and facilitate voiding function. This presents the opportunity for an alternative to the antimuscarinic approach, one which involves inhibition of nAChRs in the bladder that are chronically overstimulated by acetylcholine. Specifically, we hypothesize that an orally administered nAChR-selective inhibitor with extensive renal elimination will result in higher local concentrations in the bladder and lower systemic exposure than current therapies, representing a novel targeted approach to the treatment of OAB with a more favorable side effect profile.     

Unravelling the nature of non-specific effects of vaccines—A challenge for innate immunologists

Epidemiological observations have shown that vaccines can influence morbidity and mortality more than can be ascribed to target-disease immunity. A growing number of immunological studies have helped identify possible biological mechanisms to explain these so-called nonspecific effects (NSE) of vaccines, including heterologous T-cell reactivity and innate immune memory or ‘trained innate immunity’, which involves epigenetic reprogramming of innate immune cells. Here, we review the epidemiological evidence for NSE as well as human, animal and in vitro immunological data that could explain these NSE, and discuss priorities for future epidemiologic and immunologic studies to further unravel the biology and optimize the benefits of current and new vaccines.     

Exercise and the immune system: a model of the stress response?

Exercise influences natural immunity, T- and B-cell functions, and cytokine responses, through circulatory (hemodynamic) changes and by endocrine hormones secreted in response to physical stress. The magnitude of the effects on the immune system reflects the intensity, duration and chronicity of the exercise. In this review, Laurie Hoffman-Goetz and Bente KlarlundPedersen suggest that exercise-immune interactions can be viewed as a subset of stress immunology.     

T-cell suppression of human antibody responses: specific or non-specific?

Although ‘disorders of immunoregulation’ are thought to be characteristic of a variety of human diseases, Robin Callard argues here that this conclusion is too often readily drawn from investigations which measured non-specific rather than antigen-induced, antigen-speck suppression.     

Implant fracture of the Regenerex® modular metal tibial component: A report of three cases

BackgroundImplant fractures are a very rare complication in primary total knee replacement (TKR) surgery and with modern implant designs and improved metals these events have nearly been eliminated. In this case series we report three cases of tibial metal baseplate fractures in uncemented Regenerex® TKR.MethodsCases originated from a prospective case series of 80 patients operated between 2013 and 2016. Five patients were pilot cases and 75 were participants in a prospective randomized double-blinded clinical trial that evaluated different adjuvant bone anti-resorptive medical therapies. All patients were treated with an uncemented press-fit Regenerex® Porous Titanium Construct tibial tray and matching cemented (Refobacin Bone Cement R) patella and femoral components (hybrid implant).ResultsWe report three cases of medial side metal baseplate fractures of a modular finned tibial stem. All three baseplate fractures were in male patients. Confirmed failure of the implant occurred after 10, 12 and 23 months, in situ, with a mean follow-up of 15 months (range 10-23).ConclusionsBased on the current case series we cannot make any causal inferences. Failures may represent a multifactorial process with a cascade of events with implant failure as the result. However, like in most other case reports of metal failures in the literature, the implant fractures in this report were located on the medial side of the tibial component in male patients.     

The subdural space of the spine: A lymphatic sink? Myodil's last message

Following the radiological study of a large number of myelograms, starting over 50 years ago when the only clinical contrast medium available to show the contents of the spinal canal was an iodized oil, the author has collected a number of examples where the oil was inadvertently injected into the subdural area, rather than the intended subarachnoid space. By taking follow‐up films at various intervals following the inadvertent injection, it has been possible to study the extent to which the subdural space could become visualized from a lumbar injection, the contrast medium sometimes passing to the top of the cervical region and the lower part of the sacrum. Also, the contrast passed outward along the peri‐neural lymphatic sheaths or spaces of the issuing spinal nerves, where it might remain for months, and under the influence of gravity it could extend for a considerable way. It also passed into abdominal and thoracic lymph vessels and nodes. Considering the morphology, predictability, and ease with which the demonstrated subdural space fills, the author concludes that the subdural region is a true and functionally significant “space,” and an important conduit or functional part of the body's lymphatic system. He also considers that it has implications for the spread or dissemination of various organisms, substances or pathological conditions, as well as being part of the normal conduit for reabsorption of CSF with implications for hydrocephalus, and with potential for misplacement of spinal anaesthetic agents. Clin. Anat. 23:829–839, 2010. © 2010 Wiley‐Liss, Inc.     

The immunology of primary biliary cirrhosis: the end of the beginning?

The chronic liver disease primary biliary cirrhosis (PBC) is characterised by autoreactive B‐cell and T‐cell responses directed against mitochondrial antigens. In recent years these responses have been extensively characterised and the principal PBC associated autoantigen identified as pyruvate dehydrogenase complex (PDC). The identification of anti‐PDC responses (present in over 95% of PDC patients) has given rise to important questions pertinent to our understanding of the pathogenesis of PBC. What specific role to anti‐PDC responses play in target cell damage? How and why does immune tolerance break down to as highly conserved and ubiquitously expressed self‐antigen as PDC? Why does breakdown in tolerance to an antigen present in all nucleated cells result in damage restricted to the intra‐hepatic bile ducts? In attempting to answer these key questions we have, in this review, proposed a unifying hypothesis for the pathogenesis of PBC.