Multiple nociceptive pathways in the nervous system have been identified based on structural connectivity studies Willis, , 2007. HApproaches involving neural ensemble recordings combined with optogenetic interventions represent a valid strategy for closing this knowledge gap. However, significant research efforts to simply amass big data without a valid conceptual framework risk being misguided; data without theory are just numbers. We propose a unifying framework for the interpretation of neural data at the cellular and network levels, generating testable hypotheses, and leading to a more comprehensive understanding of pain in the context of network dynamics.Healthcare providers and several branches of government are promoting research initiatives that improve our understanding of the cellular mechanisms of pain. Pain affects a third of the U.S. population with healthcare costs exceeding $600 billions per year  model , a thin layer overlaying sensory thalamus. Taking the epic pain model into consideration, TRN receives strong input from agranular cortical areas. Indeed, pathways for emotion and attention have been shown to converge on TRN  fire in two dynamic and state-dependent modes: tonic and burst discharges of action potentials Sherman, . The resunlikely generator of the pain-induced cortical theta  oscillations in somatosensory cortex using local field potential . Therefore, in addition to the putative epic response at a subcortical level via TRN, traffic patterns between agranular and granular cortices embody cortical feedback and feedforward communication from limbic/paralimbic areas to somatosensory cortex and back in a top-down and bottom-up manner, arguably generating theta oscillations.Here again, applying the epic model of pain can be tested empirically. Deep understanding of the dynamic interactions in the thalamocortical and cortico-cortical networks, which give rise to integrated functional states including pain, is best achieved in the context of the whole organism and its behavior. Suboptimal experimental conditions imposed by pharmacological, electrical stimulation, and lesion approaches in the past have precluded a reliable inference to “causality” between thalamic bursting, cortical state, and pain. Paired, multiunit thalamocortical recordings, as well as paired, laminar cortico-cortical recordings will be necessary to directly test functional connectivity (for example coherence and phase-amplitude coupling) and directional flow of information  between brain networks at a temporal resolution high enough to resolve the neural dynamics in the TRN-thalamocortical network. Ideally, these experiments would be conducted in vivo during awake, freely-behaving states concomitant to intervention techniques with unprecedented selectivity , integration of field potential recordings with resting state imaging data is key to building such biophysically-principled computational models.Our suggested model pertains to pain in general. For acute nociceptive pain, the error signal is rectified upon elimination of the primary cause of pain. In the case of chronic pain, for example neuropathic pain secondary to peripheral nerve injury, the error signal that persists might lead an individual to engage in a multitude of behavioral modifications, some being ineffective or maladaptive. Under such neuropathic conditions, Bayesian inference systematically fails to make accurate sensory predictions due to stochastic and/or excessive nociceptive signals emanating from the injured nerve, thus contributing to symptoms of hypersensitivity such as allodynia and hyperalgesia. We acknowledge, furthermore, that chronic pain induces structural and functional reorganization of brain connectivity patterns and chronic pain epic.Sensory cortical regions are anatomically connected with limbic and paralimbic cortical regions that are responsible for allostatic control, or regulation of the physiological systems of the body  model of pain as a unifying framework for formulating testable hypotheses regarding the relation between thalamic burst and pain, and as a putative cortical feedback mechanism mediating context-dependent pain experiences and coping behaviors.Thalamic neurons fire irregular bursts during neuropathic pain, a common neurologic condition characterized with sensory and affective symptoms that are poorly managed clinically. Conflicting hypotheses regarding the role of thalamic bursts in pain have been proposed. In this opinion letter, we discuss the ECS and LB wrote the paper. CS generated the figure.CS was funded by investigator-initiated awards from Asahi Kasei Pharma and Boston Scientific; LB was funded by NIH, National Institute on Aging R01 AG030311, and National Cancer Institute U01 CA193632.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lastly, semi-quantitative model analysis via microarray data superimposed onto the model with a score flow algorithm has also been performed, which demonstrated significantly higher correct prediction ratios (average of 80%), and the model has been assessed as a predictive clinical tool using published patient microarray data. In summary we present an in silico simulation of the glucocorticoid receptor interaction network, linked to downstream biological processes that can be analysed to uncover relationships between GR and its interactants. Ultimately the model provides a platform for future development both by directing laboratory research and allowing for incorporation of further components, encapsulating more interactions/genes involved in glucocorticoid receptor signalling.Glucocorticoid hormones (GCs) are used to treat a variety of diseases because of their potent anti-inflammatory effect and their ability to induce apoptosis in lymphoid malignancies through the glucocorticoid receptor (GR). Despite ongoing research, high glucocorticoid efficacy and widespread usage in medicine, resistance, disease relapse and toxicity remain factors that need addressing. Understanding the mechanisms of glucocorticoid signalling and how resistance may arise is highly important towards improving therapy. To gain insight into this we undertook a systems biology approach, aiming to generate a Boolean model of the glucocorticoid receptor protein interaction network that encapsulates functional relationships between the GR, its target genes or genes that target GR, and the interactions between the genes that interact with the GR. This model named GEB052 consists of 52 nodes representing genes or proteins, the model input (GC) and model outputs (cell death and inflammation), connected by 241 logical interactions of activation or inhibition. 323 changes in the relationships between model constituents following  Here we present modelling of the glucocorticoid receptor (GR) signalling network. The GR is the effector for a class of drugs known as corticosteroids, which are widely used in medicine for their anti-inflammatory effects and ability to induce apoptosis in leukaemic cells. However, side effects, treatment-related toxicity and glucocorticoid resistance remain and therefore increased understanding of the glucocorticoid receptor mechanism of action may improve therapeutic outcomes. The GEB052 model presented herein has been used to generate predictions for how the network is altered between glucocorticoid-sensitive and glucocorticoid-resistant scenarios, and these predictions have been verified using published gene expression data from established cell lines . The model has also been preliminarily assessed as a predictive clinical tool by correlating model predictions with clinical outcomes of thirteen leukaemia patients. Thus, the GEB052 model demonstrates successful modelling to understand GR function. GEB052 provides accurate predictions and has indicated potential routes through which glucocorticoid resistance may arise. The work presented herein thus demonstrates a proof-of-principle of this modelling approach to furthering GR research, and provides insight into potential mechanisms of corticosteroids resistance. Glucocorticoids (GCs) steroid hormones released from the adrenal cortex as part of the stress response play an important role in a variety of bodily processes such as inflammation, immunity, and numerous metabolic processes –3. TheirGCs exert their effects through the glucocorticoid receptor (GR) which is an intracellular cytoplasmic receptor which, in the absence of a ligand, is part of a complex with chaperones such as heat-shock protein 90 , 11. NumClinically, synthetic GCs such as dexamethasone are used due to their higher potency and stability. Whilst GCs have achieved significant therapeutic outcomes, resistance to treatment and side-effects both remain an issue. Defective GR expression, Bcl-2 overexpression, and other aberrant signalling may contribute to glucocorticoid resistance , 15, 16.Systems biology aims to accurately represent biological phenomena by constructing integrative models of molecular components and their interactions. Some models are quantitatively precise and require measurement of biological kinetic data, though they are often of a smaller scale, aiming to precisely model a particular subset of interactions. This approach has been applied to glucocorticoid research in numerous ways, such as the development of models of GR/c-Jun/Erg (Ets-related gene) crosstalk . The modWe have previously demonstrated that Boolean modelling may be successfully applied to cancer research through generating the PKT206 model of the p53 interactome  which haTo overcome the qualitative nature of the Boolean modelling approach algorithms utilising microarray and/or ChIP-seq data have been developed such as the signal transduction score flow algorithm (STSFA) which analyses Boolean models in a semi-quantitative manner . This alGlucocorticoid receptor model by Emyr Bakker, consisting of 52 nodes) contains 241 interactions. Nodes represent genes/proteins or inputs (glucocorticoid)/outputs (cell death and inflammation). CellNetAnalyzer  success in [Y] trials, chance of success is [Z]”. In these cases [X] equates to the number of correct predictions, [Y] to the total number of predictions and [Z] to the chance of success .To assess whether the correct prediction rates of the model were statistically significant, the WolframAlpha computational knowledge engine , 1  and 2 (large error). A threshold of four  was chosen to determine a node as incorrect. The incorrect node determination for cell-based microarray validation is shown in the To determine if any nodes were systematically incorrect across the comparisons shown in S1 TextThese tables cover information such as the list of interactions within the GEB052 model, GEB052 model validation and STSFA analysis, and the determination of systematically incorrect nodes.(DOCX)Click here for additional data file.


Systemic autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis are more prevalent in females, while cancer shows the opposite pattern. Sex hormones have been repeatedly suggested to play a part in these biases. In this review, we will discuss how androgens and the expression of functional androgen receptor affect immune cells and how this may dampen or alter immune response(s) and affect autoimmune disease incidences and progression.In addition to determining biological sex, sex hormones are known to influence health and disease  Sex hormones exert their effects on many cellular targets, including cells of the immune system. Indeed, sex hormones directly influence immune cell function and development as well as the susceptibility of cells and tissues to damage from aberrant (autoimmune) processes. In this review, we will discuss how androgens and the androgen receptor (AR) affect immune cells and how this may dampen or alter immune response(s) to affect disease incidence and progression.vice versa) and both can be aromatized to estrogens by aromatase , testosterone, androstenedione, and dehydroepiandrosterone (DHEA), are all synthesized from cholesterol in the gonads and adrenal glands . DHT is romatase . Aromata ligands . Moreove ligands , furthervia modulating the transcription of a number of genes by DNA-binding-dependent and -independent mechanisms   , 21. Finn (SHBG) .NR3C5, are known to influence androgen signaling strength. The most widely studied polymorphism affects the number of CAG repeat sequences in exon one of the AR gene. Specifically, AR’s transactivational activity decreases with the presence of longer CAG repeats and vice versa  exhibit neutropenia  in medullary thymic epithelial cells  isolated from rats or women during the ovulatory phase, but not men , Sjögren’s syndrome, multiple sclerosis (MS), and rheumatoid arthritis (RA) . Both seRheumatoid arthritis is characterized by synovial inflammation and swelling, as well as cartilage and bone destruction. Some patients may develop one or more additional systemic sequelae, including cardiovascular disease, pulmonary disorders, lymphoma, lung cancer, psychological disorders, and osteoporosis . Like maWhile estrogens likely contribute to the increased female risk of RA , it has Interestingly, serum androgen levels are not lower prior to the onset of RA in all patients, suggesting that low androgens are not universally predisposing to the development of RA , 133. InThe effect of androgens on RA susceptibility and severity in women is less well understood. Androgens may protect against RA in some women, but other studies suggest that androgens may actually worsen disease severity. As in men, low serum concentrations of androgens, particularly DHEA and/or DHEA-S, are linked with RA in women , 138–140In contrast to the above findings, high androgen concentrations or more potent AR signaling have been reported in some women with more severe RA. For example, one small study reported normal androgen concentrations in premenopausal RA patients, and higher testosterone and DHEA-S in postmenopausal women with RA . More stBecause of the correlation between low serum androgens and RA and the known immunosuppressive properties of androgens, androgens have been utilized to some extent as a treatment for RA. Overall, the administration of androgens to male and female patients had a positive effect for both sexes –148. HowSeveral animal models of RA also show increased susceptibility or more severe disease in females as compared to males –152. ForRegardless of whether serum androgen levels or receptor activity is involved in systemic RA etiology, a separate case has been made for its involvement in disease pathogenesis within affected joints. The synovial fluid of RA patients exhibits elevated levels of free estrogens and reduced concentrations of free androgens, possibly due to increased local aromatization of androgens to estrogens . The conIn summary, with some notable exceptions, the correlation bet-ween low androgen and RA likely exists because RA-associated inflammation dampens serum androgen levels. Improvements in our ability to group RA into less heterogenous disease subgroups may reveal particular subgroups that are more affected by androgen levels than others.via immune modulation, treatment with testosterone improved cognitive performance and slowed brain atrophy  develops 3–4 times more frequently in females than in males and predominantly in individuals of childbearing age, suggesting a role for sex hormones [reviewed in Ref. ]. In add atrophy  and has  atrophy .via blockade of IL-12 (ustekinumab) was not effective (Multiple sclerosis patients display a chronic inflammatory profile characterized by T cell-derived cytokines (IFNγ and IL-17) and circulating antibodies reactive to brain autoantigens –176. Botffective .Studies of EAE  have largely confirmed a protective role for androgens –183. ForAire promoter, driving increased Aire expression by medullary thymic epithelial cells and increased negative selection  and the pathogenic potential of these T cells  are generally considered to be a hallmark of lupus , 191. A ng women , 193.via oxidation than healthy age-matched controls  experienced reduced disease activity, improved cognitive function, enhanced mental well-being, and a reduced need for corticosteroid treatment –228, whiInbred mice that spontaneously develop a lupus-like disease have been extremely helpful toward elucidating the etiology and pathogenesis of lupus. Several spontaneous models of lupus exist [reviewed in Ref. ]. Here, Chemical manipulation of androgens in lupus-prone BWF1 mice also generally supports the hypothesis that androgens are protective in lupus. For example, treatment of BWF1 females with nandrolone decanoate –238 and Many autoimmune diseases that are more prevalent in females, including SLE, are characterized by increased numbers of B cells and circulating autoantibody levels [reviewed in Ref. ]. Some ecolony-stimulating factor 3-receptor (Csf3-r)  . Togethe(Csf3-r) . Interes(Csf3-r)  and polys and RA , 254. Thvice versa). Given that women are more susceptible to many autoimmune diseases, one might expect men to be more susceptible to cancer. Indeed, a number of epidemiologic studies and meta-analyses have recently confirmed that cancer develops more frequently in males than in females (Immune cells must be capable of distinguishing modified-self from self, and yet, must not become unduly activated against unmodified self-antigens. Immune activity outside of these boundaries likely risks the development of cancer or autoimmunity and it follows that immune systems especially good at protecting against cancer may run the risk of triggering autoimmunity (and  females –257. In  females . Many fa females , 258.prior to the diagnosis of cancer are necessary. Not many studies of that kind have been done. In one study, testosterone levels were found to positively correlate with the risk for a subset of epithelial ovarian cancers (As mentioned above, chronic inflammation can lead to suppression of testosterone. Cancer is known to induce a stage of chronic inflammation, and thus in order to study a potential causal relationship between testosterone and cancer development, retrospective cohort analyses investigating levels of testosterone  cancers . Similar cancers . It willvia direct effects on tumor cells remains to be tested. In a separate study of induced thyroid cancer in male mice, gonadectomy led to an upregulation of tumor-suppressor genes (More direct evidence supporting a tumorigenic role for androgen in cancer development comes from animal studies, where susceptibility to cancer in response to chemicals and genetic manipulation often depend on sex hormone levels . For exaor genes . With tuTo conclude, sex-specific biases in autoimmunity and cancer incidence are associated with many differences in immune cell development and function. A significant portion of these differences are the result of exposure to androgens. Androgen-mediated suppression of immune reactivity and inflammation increases the threshold for autoimmunity to develop, but likely lowers the threshold for cancer. Studies further uncovering immune-specific effects of androgens are needed and may lead to the identifi-cation of pathways that could be targeted therapeutically to inhibit the incidence and progression of autoimmunity and cancer.MGB and TNJ contributed equally to this project.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) . Systemic inflammation may well be a major element explaining such findings. Inter-patient and inter-illness variations in neuroimaging findings may arise at least in part from regional genetic, epigenetic and environmental variations in the functions of microglia and astrocytes. Regional differences in neuronal resistance to oxidative and inflammatory insults and in the performance of antioxidant defences in the central nervous system may also play a role. Importantly, replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. Further research involving this form of neuroimaging appears warranted in an attempt to overcome the problem of aetiologically heterogeneous cohorts which probably explain conflicting findings produced by investigative teams active in this field. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool. Many patients with multiple sclerosis (MS), a neuroinflammatory illness, major depressive disorder (MDD), a neuroprogressive condition and chronic fatigue syndrome (CFS) , a phenotype of no fixed aetiology, share a range of underlying abnormalities , 2. ThesDespite the existence of such data, however, there would appear to be no comprehensive review of neuroimaging abnormalities in patients afforded such a diagnosis which includes the most recent evidence obtained via VBM analysis. There have been few attempts to compare the transdiagnostic neuroimaging data obtained for patients with MS and MDD  althoughFunctional dissociation or disconnection between large-scale resting-state neural networks is a characteristic feature of relapsing-remitting MS (RRMS) in the advanced stage of the disease , 33. MorCortical reorganisation in patterns of resting-state network connectivity is evident in patients with a clinically isolated syndrome  and is tSome authors report an increase in the functional connectivity within resting-state networks in patients with RRMS –40 whileSeveral research teams have also reported correlations between abnormal intra-network functional connectivity and clinical parameters, but these relationships are far from straightforward –44. For The same variation in patterns persists for specified dimensions of disability such as impaired motor function where reduced and increased connectivity within the network is associated with impaired motor performance , 48. IncThe picture is if anything more complex in studies investigating the resting-state functional connectivity associated with cognitive dysfunction within the DMN, as impaired and enhanced conductivity between and within sub-regions in the DMN have been repeatedly observed , 52. HowWhen considered as a whole, the data would suggest that in early or mild disease, there is a compensatory positive reorganisation within and between resting-state networks which eventually are overcome by disease progression , 53, 54.N-acetyl aspartate, increased glutamate/glutamine and reduced choline [Conventional structural MRI of MS patients is characterised by the existence of cortical demyelination and focal and diffuse white matter (WM) lesions –58. Rese choline –71. In a choline , 73. It  choline , 75.Grey matter (GM) pathology is evident in the hippocampus, basal ganglia, hypothalamus, cerebellum and spinal cord . GM atroThe reasons for the discrepancy between in vivo and post-mortem studies are not clear but may stem from re-myelination processes which are far more active in GM than WM (reviewed ). HoweveThere is a considerable and accruing body of research demonstrating globally reduced cerebral perfusion and blood volume abnormalities in MS patients obtained via the use of SPECT ; PET 9090 and, mSeveral research teams have reported relationships between abnormal patterns of perfusion and various elements involved in the pathophysiology or pathogenesis of the illness , 97–99. Several studies have revealed dysfunction of functional connectivity within or between large-scale functional resting-state neural networks such as the DMN in patients with MDD using resting-state fMRI . AbnormaIntra-network changes are exemplified by enhanced connectivity within the anterior DMN and abnormal connectivity between the anterior and posterior DMN. Inter-network abnormalities are evidenced by increased connectivity between the anterior DMN and salience network and diminished connectivity between the posterior DMN and the CEN (review ). MDD neDissociation of functional connectivity between the anterior and posterior areas of this region and dissociation between the DMN and other large-scale resting networks are characteristic of patients with MDD , 111. ZhWhile alterations in brain connectivity centring on the DMN continue to be a focus of research, abnormal patterns of connectivity are also seen within and between the affective network and the cognitive control network (CCN) , 114. InSuccessful therapy is associated with changes in connectivity within the DMN and corticolimbic areas, and it is noteworthy that changes in the latter areas correlate with the degree of clinical improvement while changes in the DMN do not . The sucDTI utilising tract-based spatial statistics (TBSS)  has reveInterestingly, Le Win and others reported similar findings using a DTI TBSS-based approach in adolescents with MDD . Lower FYuan and fellow workers reported whole-brain reductions in participants with first-episode geriatric MDD in remission, characterised by low FA values in the right superior frontal gyrus, left middle temporal gyrus, left inferior frontal gyrus, right middle occipital gyrus, right inferior parietal lobule, left lingual gyrus, right putamen and right caudate . Taylor The weight of evidence indicates that compared with healthy controls, those with midlife-onset MDD display decreased FA values in the left anterior limb of the internal capsule, left posterior cingulate cortex, right cingulate cortex, bilateral parahippocampal gyri, hippocampus, pons, right and left frontal lobes, sagittal striatum and cerebellum , 131. ThHuang and others reported lower FA values in the splenium of the corpus callosum, left cingulum, inferior fronto–occipital fasciculi, superior longitudinal fasciculi and uncinate in patients than in controls, and that this measure might serve as a vulnerability marker for the illness . Xiao etWidespread decreases in FA values in the cingulum, superior and inferior longitudinal fascicule and corpus callosum compared with first-episode patients are characteristic of resistant to antidepressant therapy . It is aNot all research teams have reported significant WM abnormalities in MDD patients however , 135. ThSeveral research teams have detected severe or moderate GM volume loss in the amygdala, the thalamus and many cortical brain regions, including the pre- and post-central gyri, orbitofrontal cortex, ACC and temporal cortex and lateral prefrontal cortex –140. RelFrom a treatment perspective, several research teams have reported that patients with treatment-resistant depression display greater reductions in GM volume in the left temporal cortex and right medial frontal cortex compared with age- and sex-matched controls or patients in remission , 146. ReThe pattern of GM structural changes in young first-episode people with MDD is not straightforward, however, with decreases in GM volume in the left lingual gyrus and left putamen and increases in GM volume in the left posterior cingulate cortex and inferior cingulate gyrus, being reported by Yang and others . This abThe earliest data were obtained from studies using PET and SPECT , 157 basOverall, the most common observations are hyperperfusion in the sub-colossal cingulate –166 and There are significant differences in the rCBF abnormalities between patients with refractory versus non-refractory MDD ascertained by ASL , 164. OnSeveral research teams have also reported an improvement or reversal of rCBF abnormalities following successful antidepressant therapy , 170. FoSeveral authors have reported abnormal patterns of functional connectivity in patients afforded a diagnosis of CFS according to international criteria, whose magnitude correlates with levels of fatigue and pain –177. TheWortinger and fellow workers reported a significant decrease in functional connectivity of the salience network to the right posterior insula in adolescent CFS patients compared with age-matched healthy controls. Interestingly, this decrease was negatively associated with the severity of fatigue . In addiThis team also examined the patterns of dynamic and static functional connectivity in CFS compared with unaffected controls during a fatiguing cognitive task and reported major group differences. Specifically, Boissoneault and others reported decreased dynamic connectivity between the hippocampus and right superior parietal lobule and increased static inferior frontal gyrus connectivity to occipital and temporal structures and to the cerebellum . It is aEarly research investigating potential neuroanatomical abnormalities using MRI focused on WM using observer-dependent analysis , 179–181Recent studies based on T1- and T2-weighted MRI using VBM have universally reported significantly increased WM abnormalities in CFS subjects selected according to the “Fukuda” CDC criteria compared with healthy participants –188. PurSeveral research teams utilising VBM have reported reduced global or regional GM volumes in those with CFS , 188–191The results reported by deLange and others appear to be particularly interesting as their studies were specifically designed to examine potential relationships between the severity of symptoms in CFS and cerebral abnormalities and the effect of cognitive-behavioural therapy (CBT) on those cerebral abnormalities respectively , 191. InMost of the SPECT studies investigating potential CBF abnormalities in CFS have reported areas of significant cerebral hypoperfusion, at either a global , 192 or Ischise et al. compared rCBF in 60 CFS participants and 14 healthy controls and reported significant reductions in cortical/cerebellar rCBF ratios in the frontal, temporal, parietal and occipital lobes, providing objective evidence of widespread functional impairment of the brain in the vast majority of their CFS subjects . Schwart99mTc-HMPAO SPECT differences between CFS and MDD patients was carried out by Costa and others [99mTc-HMPAO SPECT imaging patterns of rCBF in 33 CFS subjects (55 ± 10 years), 26 age-matched MDD participants and 19 healthy participants in an attempt to investigate the potential pathophysiology of CFS [The largest study examining potential d others . It incld others . These ad others . Goldstey of CFS . Importay of CFS .More recent research using xenon-computed tomography, ASL and high-resolution SPECT reported consistently impaired CBF at a global and regional level at rest and during exercise –200. YosThe potential capacity of SPECT to differentiate CFS from MDD may be highly significant as CFS is a purely descriptive diagnosis reliant on phenotype only, and there is accumulating evidence that the diagnosis identifies a clinically and aetiologically heterogeneous syndrome rather than a discrete biological entity even when such a diagnosis is made via the application of international guidelines , 202. UnThere is widespread agreement that the relationship between the presence of systemic inflammation and various dimensions of neuropathology is established via the conveyance of inflammatory signals to the brain through a range of humoral and neural routes culminating in the activation of microglia and astrocytes , 207. OnAnother source of neuropathology is more indirect however and stems from the loss or corruption of the regulatory functions exerted by these glial cells via a sophisticated communication system with neurones and oligodendrocytes founded on the secretion of exosomes containing mRNAs, miRNAs, caspases and P2X7 (reviewed in ). This iMicroglia also display distinct regional differences in density and transcriptional identity particularly in bioenergetic and immunoregulatory pathways , 217. ThPredictably, astrocytes also display extensive variability in biochemical, biophysical and immunoregulatory properties in distinct brain regions . TAntioxidant defence systems also demonstrate pronounced regional differences in composition and efficacy. For example, thioredoxin and thioredoxin reductase levels vary in different brain regions . This isDifferent discrete neuronal populations existing in different brain regions display differential susceptibility to neurodegenerative stressors which is a phenomenon often described as selective neuronal vulnerability (SNV). Well-documented examples include neurones in the entorhinal cortex, frontal cortex, hippocampal CA1 region and amygdala, which are the most susceptible to neurodegenerative death in populations of neurones most sensitive to the neurodegeneration associated with Alzheimer’s disease , 232. ThBrain volume and structure are strongly influenced by genetic factors –242 and We begin by briefly summarising the key neuroimaging findings.In MS, there is evidence of impaired neural connectivity and functional dissociation on resting-state fMRI, which correlates with the severity of disability. Cortical demyelination and reduced cerebral perfusion also occur. Early GM atrophy appears to be predictive of the subsequent level of disability and of the prognosis.MDD is associated with dysfunction of functional connectivity and both microstructural and macroscopic WM abnormalities, including disrupted tracts. There is evidence of GM volume loss in several regions.CFS is associated with cerebral hypoperfusion, while large VBM studies have shown evidence of GM and WM changes.The evidence given in this paper points to the likelihood that systemic inflammation may be a major underlying cause of structural and functional neuroimaging abnormalities reported in seemingly diverse disorders including MS, MDD and CFS. Furthermore, reported inter-patient and inter-illness differences may be a function of regional genetic, epigenetic and environmental variations in microglial and astrocytic functioning.While SPECT appears to be able to differentiate CFS from MDD, its use of ionising radiation makes it unlikely to be a neuroimaging modality of choice in the future for this purpose. Rather, efforts are likely to be undertaken to develop corresponding functional magnetic resonance-based techniques instead. Not only are magnetic resonance techniques free of the use of ionising radiation, they also afford a higher resolution than does SPECT (even high-resolution SPECT). In this vein, a further development is likely to be the use of machine learning classification methodologies, which may, for example, be able in the near future to differentiate different disorders and, within a given disorder, be able to classify patients with a given diagnosis. Finally, there is also a strong case for further combining neuroimaging techniques with investigative modalities from the fields of biochemistry, neurophysiology, environmental medicine, immunology and epigenetics.


The Editorial on the Research TopicUsing Stress-Based Animal Models to Understand the Mechanisms Underlying Psychiatric and Somatic DisordersChronic or repeated stress, particularly psychosocial stress, is an acknowledged risk factor for numerous affective and somatic disorders in modern societies. Thus, there is substantial evidence showing that chronic stress can increase the likelihood of major depressive disorder and anxiety disorders, as well as cardiovascular diseases, irritable bowel syndrome and pain syndromes, to name but a few, in vulnerable individuals. Although a number of pharmacological agents are available to treat such stress-related disorders, many patients do not respond to them, and those who do often report a number of side effects.Consequently, a major emphasis in modern basic research is to uncover the underlying etiology of these disorders and to develop novel efficacious treatment strategies. Animal models can be utilized to unravel the biological mechanisms underlying specific disorders and test the efficacy of novel drugs. While animal models cannot mimic psychiatric and somatic disorders in their entirety, assessing the impact of certain risk factors for the disorders will facilitate the understanding of their etiology and treatment options. Consistent with this knowledge, and with clinical evidence purporting chronic stress to be a risk factor for such diseases, recent attempts have focused on the development of adequate stress paradigms. It is believed that psychosocial stress paradigms are more relevant to the human situation than non-social stress paradigms, because the vast majority of stressors reported by patients suffering from psychiatric or somatic disorders are social in nature. Therefore, there is a growing consensus that social stress paradigms are better placed to reveal the behavioral, neuroendocrine, or immunological mechanisms underlying chronic stress-induced pathology. However, in order to maximize our understanding of the mechanisms underlying stress-related disorders, various different models are necessary, including models employing physical  or pharmacological  stressors. Moreover, there is accumulating evidence suggesting that stress-induced gut dysbiosis and systemic low-grade inflammation play a causal role in the development of stress-associated somatic and affective disorders. Therefore, chronic/repeated stress models that result in reduced gut microbial diversity and/or promote chronic immune activation are of special relevance and importance.In this research topic, we have collated novel research articles (four) and comprehensive review articles (five) from various leaders in the field of stress-based research. The overarching goal of the topic is to reveal how chronic/repeated stress models can help us to better understand the etiology of psychiatric and somatic disorders.Monteiro et al. developed an 8-week-long CUS protocol that results in classical stress-related outcomes, such as increased adrenal weight and increased anxiety- and depressive-like behavior. Their results suggest that this 8-week protocol can be used to assess the underlying mechanisms of stress-related alterations in C57BL/6 mice.The first article describes a novel chronic unpredictable stress (CUS) protocol, which was developed for C57BL/6 mice. Given the unreliability of commonly utilized 4-week-long CUS protocols in C57BL/6, Kinlein et al. demonstrate that non-invasive corticosterone administration via the drinking water for 28 days (25 μg/ml) results in a dysregulated response to a subsequent acute stressor. While corticosterone-treated mice did not show a plasma corticosterone response to swim exposure, their central c-fos response to this acute stressor was actually increased in numerous brain regions. Taken together, these findings suggest that this model can be used to determine how altered HPA axis function contributes to central dysregulation to an acute stressor.Chronic stressor exposure can also be mimicked by treating rodents chronically with corticosterone. Here, Greenwood et al. assess the effect of repeated (22 days) contextual fear conditioning on behavior and the sleep/wake cycle to a subsequent acute foot shock. Their findings demonstrate that the increased anxiety-related behavior and disrupted sleep/wake behavior evoked by acute stress is enhanced by prior fear conditioning. Taken together, this study suggests that repeated stress increases the vulnerability to novel subsequent stressors.Another system disrupted by chronic/repeated stressor exposure is the sleep/wake cycle. In their study, Rowson et al. expose male and female HIV-1 transgenic rats to chronic stress in adolescence (or non-stressed controls) and reveal that the presence of the transgene affects behavior and microglial structure, particularly in females. However, the addition of stressor exposure did not further affect these alterations, suggesting that there is little interaction between stress and HIV-1 viral proteins.The extent to which chronic stress interacts with HIV-1 viral proteins to impact behavior and neuroinflammatory processes is largely unknown, but of growing research interest. Addressing this question, Eisenmann et al. suggest that acute stress decreases the sensitivity to myocardial ischemia–reperfusion injury, while chronic stress even increases myocardial sensitivity to such an injury.In the second section of the research topic, complementing the original research articles, are five review articles covering a range of topics related to stress-based research. The first review article describes the use of basic rat models to gain a better understanding of the effect of chronic stress on myocardial sensitivity to ischemic injury. Musazzi et al. summarize our current understanding of the biphasic adaptations of the glutamatergic system in the prefrontal cortex during stressor exposure. The implications of these adaptations for our understanding of the etiology, and possible treatment, of stress-related disorders are then discussed.Stress has been well documented to affect synaptic plasticity and cause dramatic alteration of the glutamatergic system. In their review article, Langgartner et al. discuss the knowledge that such models have provided in relation to psychiatric and somatic disorders. They focus particularly on one such model, the chronic subordinate colony housing (CSC) paradigm, which causes numerous stress consequences, including increased anxiety-related behavior, spontaneous colitis, and HPA axis changes.There has been a growing reliance on chronic psychosocial stress models in basic research, due to the belief that such models more accurately reflect the clinical situation. Gur et al. discuss the evidence revealing that although the gut microbiota is relatively resistant to change, at particular time points, such as early life, stress can affect the microbiota and lead to detrimental outcomes for parturition and infant neurodevelopment. Moloney et al. review current animal models of stress-induced visceral pain, which aim to reflect irritable bowel syndrome in patients. Their wide-ranging review describes the influence of a number of factors, such as stress, gender, gut microbiota and epigenetic changes, in the etiology and potential treatment of visceral pain.Finally, given the growing interest in the role of the brain–gut axis on affective behavior and somatic disorders, there are two reviews focusing on this topic. Taken together, the articles collated in this research topic provide a broad overview of the role that stress-based animal models have in deepening our understanding of stress-induced disorders. Although not comprehensive, the articles cover models relevant for anxiety disorder, major depressive disorder, alcohol abuse, cardiovascular diseases, ulcerative colitis, and irritable bowel syndrome. Importantly, given the large comorbidity between such disorders, placing these articles together in one research topic ensures an overview about how multiple systems interact during chronic stressor exposure. Such multimodal research is becoming increasingly necessary to enhance our understanding of psychiatric and somatic disorders.Both the authors contributed to the writing of the editorial and agreed with the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Metastases in the paranasal sinuses are rare; renal cell carcinoma is the most common cancer that metastasizes to this region. We present the case of a patient with a 4-month history of a rapidly growing mass of the nasal pyramid following a nasal trauma, associated with spontaneous epistaxis and multiple episodes of hematuria. Cranial CT scan and MRI showed an ethmoid mass extending to the choanal region, the right orbit, and the right frontal sinus with an initial intracranial extension. Patient underwent surgery with a trans-sinusal frontal approach using a bicoronal incision combined with an anterior midfacial degloving; histological exam was compatible with a metastasis of clear cell renal cell carcinoma. Following histological findings, a total body CT scan showed a solitary 6 cm mass in the upper posterior pole of the left kidney identified as the primary tumor. Although rare, metastatic renal cell carcinoma should always be suspected in patients with nasal or paranasal masses, especially if associated with symptoms suggestive of a systemic involvement such as hematuria. A correct early-stage diagnosis of metastatic RCC can considerably improve survival rate in these patients; preoperative differential diagnosis with contrast-enhanced imaging is fundamental for the correct treatment and follow-up strategy. Renal cell carcinoma (RCC) is the most common kidney cancer, with approximately 35,000 new cases in the US each year ; RCC maiWe present the case of a patient with a single, rapidly growing mass in the upper portion of the nasal pyramid, with late, postnasal surgery histological diagnosis of renal cell carcinoma that allowed primary tumor identification.A 72-year-old man was referred to our institution with a 4-month history of a voluminous mass in the upper portion of the nasal pyramid following a nasal trauma. He had been treated a few weeks earlier at a different ENT service for a massive spontaneous epistaxis. The patient also reported a long history of hematuria, previously attributed to renal tuberculosis occurring over 40 years before. At admission, a cranial CT scan showed a large soft tissue ethmoid mass extending to the right and left choanal region, the right orbit, the right frontal sinus, and an initial intracranial extension with partial erosion of the crista galli. MRI confirmed the evidence found at computed tomography . Fine neThe patient underwent surgery with a trans-sinusal frontal approach using a bicoronal incision combined with an anterior midfacial degloving to excise the mass; however, the right orbital and especially the initial intracranial extension did not allow a complete removal of the neoplasm. Considerable bleeding occurred during surgery. The histological exam revealed a clear cell renal cell carcinoma . Based oNasal cavity and paranasal sinus cancers are usually primary tumors. Metastases to the paranasal sinuses are rarely found; among them, renal cell carcinoma is the most common cancer to metastasize to this region (49%) followed, respectively, by bronchus, urogenital ridge, breast, and gastrointestinal tract , 20. RCCRCC tumor cells can reach the sinonasal region via two routes: the first includes inferior vena cava, lungs, heart, and the maxillary artery; the second involves the communication of the avalvular vertebral venous plexus and the intracranial venous plexus . MaxillaMetastatic RCC to the sinonasal district has been reported as the presenting sign of this disease in a few cases , 34, whiThe key point in RCC presenting with a sinonasal metastasis is differential diagnosis with primary tumors such as adenocarcinomas, angiofibromas, hemangiopericytomas, melanomas, hemangiomas, metastatic tumors from the breast and lungs, and, more rarely, systemic diseases such as Wegener's and midline granulomas . In factIn this case, CT scan allowed the identification of a neoformed paranasal sinus mass; however, only histological exam identified the mass as a metastasis of RCC and led to the execution of total body CT scan to identify primary tumor. Although difficult, differential preoperative diagnosis is fundamental for the correct treatment and follow-up strategy; contrast-enhanced imaging plays a central role since a preoperative biopsy of the nasal mass may be difficult in these patients due to massive recurring bleeding and, in some cases, may result in only necrotic tissue inconclusive on histopathology . The ENTPrognosis of metastatic RCC is poor; however, a correct early-stage diagnosis of metastatic disease can considerably improve survival rate: literature reports that excision of solitary metastatic lesion of renal cell carcinoma following nephrectomy results in a 41% survival at 2 years and 13% survival at 5 years . The solAlthough metastatic RCC is often resistant to chemotherapy and radiotherapy, numerous agents targeting VEGF and non-VEGFR pathways should be taken into account for the treatment of advanced RCC. Multitargeted VEGF tyrosine kinase inhibitors (TKIs) include sorafenib , sunitinIn conclusion, metastatic renal cell carcinoma should always be suspected in patients with nasal or paranasal masses, especially if associated with symptoms suggestive of a systemic involvement such as hematuria; early-stage diagnosis of metastatic disease can considerably limit perioperative complications and improve survival rate.


Alpha- and Betaproteobacteria. While latitude does not seem to strongly influence AAP abundance, clear patterns of community structure and composition along geographic regions were observed as indicated by a strong macro-geographical signal in the taxonomical composition of AAPs. Overall, our results suggest that the distribution patterns of freshwater AAPs are likely driven by a combination of small-scale environmental conditions (specific of each lake and region) and large-scale geographic factors .Aerobic anoxygenic phototrophs (AAPs) have been shown to exist in numerous marine and brackish environments where they are hypothesized to play important ecological roles. Despite their potential significance, the study of freshwater AAPs is in its infancy and limited to local investigations. Here, we explore the occurrence, diversity and distribution of AAPs in lakes covering a wide latitudinal gradient: Mongolian and German lakes located in temperate regions of Eurasia, tropical Great East African lakes, and polar permanently ice-covered Antarctic lakes. Our results show a widespread distribution of AAPs in lakes with contrasting environmental conditions and confirm that this group is composed of different members of the  Their discovery last decade in the ocean challenged our view of the aquatic C cycle in which heterotrophic bacteria were considered strict consumers of organic matter produced by photosynthetic phytoplankton  use organic carbon (C) for their metabolism and growth but can derive a portion of their energy requirements by harvesting light using bacteriochlorophyll Alpha- and Betaproteobacteria . Links between AAP abundance, diversity and an array of environmental variables were also explored to better understand the spatial dynamics of AAP communities.In this study, we investigated AAP abundance and phylogenetic diversity in freshwater ecosystems in a set of lakes from three continents, covering temperate (Mongolian and German lakes in Eurasia), tropical (Great East African lakes) and polar  regions. We assessed AAP diversity by cloning and sequencing of the Lakes located in four different geographic areas were sampled in this study: 1) Mongolian Lakes Gun Selenge, Terkhiin Tsagaan, Gun Arkhangai, Boon Tsagaan and Ugii Nuur; (2) African Lakes Victoria, Kivu, Edward, and Albert; (3) McMurdo Dry Valleys Antarctic Lakes Bonney, Fryxell, Hoare, Miers and Vanda; and (4) Lake Stechlin located in the Mecklenburg Lake district  were measured on a CFX96 thermocycler  using Maxima SYBR Green qPCR Master Mix  and the PCR conditions previously described for pufM  and Ensembl databases (www.ensembl.org). Values shown here are average abundances at the different depths analyzed.Abundance of AAP and total bacteria were assessed by quantitative polymerase chain reaction (qPCR) of the pufM clone library construction, we investigated the presence of the pufM gene at different depths with Denaturing Gradient Gel Electrophoresis (DGGE) as described by Salka et al. (pufM gene was amplified by using forward primer pufL (5′-CTKTTCGACTTCTGGGTSGG-3′) and reverse primer pufM (5′-CCATSGTCCAGCGCCAGAA-3′) as described in Salka et al. . Chimera formations were identified by UCHIME . For community analyses, a dissimilarity matrix (Bray–Curtis) was constructed based on the relative abundance (square root transformed) of each phylotype. Patterns of community structure were visualized using hierarchical cluster and non-metrical multidimensional (nMDS) analyses. Mantel tests were conducted to find correlations between the phylotype matrix and a matrix of environmental variables . The null hypothesis (Ho) of “no relationship between matrices” was tested applying Spearman rank's correlation coefficient and 999 permutations. Additionally, using the ENVFIT function, we tested for significant relationships between these environmental variables and the nMDS ordination of samples. Finally, permutational tests (PERMANOVA) were employed to examine the community differences among lake trophic status, and geographic and latitudinal regions. Community statistical analyses were run in R  were used to assess the links between AAP abundance and physicochemical variables using the JMP software . Variables were log-transformed when necessary. The results were threshold at ns Pike, . RichnesThe geographic and limnological characteristics of the lakes studied are summarized in Table a pigment and thus, only AAP cells expressing the pigment at the moment of sampling are enumerated which may lead to their underestimation. Measures based on qPCR suffer from other biases related for example to primer specificity . In fact, the highest temperatures (average 26°C) correspond to the great African lakes where low abundances of AAPs were found.The relative abundance of AAPs was on average higher in temperate lakes than in tropical and Antarctic lakes. Values within each region varied considerably  concentration, DOC:Chla ratio, water transparency, and lake altitude have also been shown to influence AAP abundance in certain freshwater lakes . Lake Vanda was the most dissimilar lake compared to the rest of Antarctic lakes. Interestingly, Lake Vanda has unusually warm waters for such cold environments possibly due to a seawater origin . Nevertheless, we cannot discard that other regional factors based on the local conditions influence the AAP assemblages. For example, lakes in the two northern regions have similar age and have probably been exposed to similar major climatic events, namely the last glacial period of the Quaternary, ending ~11,700 years ago with the start of the Holocene.According to the distance-decay hypothesis, community similarity declines with increasing geographic distance if species tend to be locally adapted or if they are dispersal limited . Linear fitting of environmental factors to the nMDS ordination revealed a certain effect of several measured variables, but none was statistically significant . Altogether, these results indicate that latitude and potentially climatic factors are strong determinants of AAP community composition, but the patterns observed reflect a certain adaptation to specific environmental features.Additionally, a certain degree of influence of local conditions on the pattern of community structure was found . While differences in species richness along latitudinal gradients are clear in macro-organisms with higher proportions of species in the tropics , but with some exceptions in which either one dominated . In addition, OTU #146 clustering with Limnohabitans was also fairly abundant in Lake Victoria.At the phylotype level, our results suggest a strong macro-geographical signal in taxonomical composition, being clearly less variable across lakes within the same region than across regions Figure . In factRhodobacter clade, they are highly dissimilar, likely representing new organisms. Contrarily, the most abundant phylotypes in Lakes Fryxell and Miers were OTU#106 and #112, respectively, both related to Crater Lake strain HTCC528 (AY584589), while Rhodoferax-related OTU#14 dominated Lake Hoare, all three belonging to the Betaproteobacteria. With the exception of Lake Gun Selenge in which the betaproteobacterial OTU#162 was the most abundant clone, Mongolian lakes were dominated by members of the Alphaproteobacteria, particularly OTU#140 and #182, within the Rhodobacter cluster but fairly distant, and OTU#102 (Jannaschia-like). As previously described by Salka et al.  or to a large cluster of betaproteobacterial sequences that represent an unidentified group (OTU#91).In Antarctica, Lakes Bonney and Vanda were largely dominated by the alphaproteobacterial OTU#55, #56, and #124 closely related among them. Although these clones cluster within the a et al. , German Alpha- and Betaproteobacteria regardless of the geographic region, while Gammaproteobacteria AAPs do not occur in fresh waters, supporting the hypothesis of taxonomic partitioning along salinity gradients  and large-scale geographic factors .The detection of AAPs in all lakes surveyed confirms the widespread distribution of this functional group in contrasting freshwater ecosystems located across wide geographic and latitudinal gradients, including perennially ice-covered Antarctic lakes. In terms of abundance, no clear patterns are found across latitudes. Likewise, species richness and diversity do not strongly correlate with latitudinal gradients contrary to what has been observed for other organisms and biomes. Composition of AAPs is highly variable across lakes and regions but generally composed of members of the IF and HG conceived this work. HG, HS, JP, and AC participated in the sampling campaigns and provided samples. IF performed all laboratory analyzes and JG helped with phylogenetic sequence reconstruction. IF analyzed the data and wrote the paper. All authors made comments and suggestions to the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The purpose of this article is to present a rare case of localized, solitary amyloid tumor of tongue base and emphasize some of the characteristic features of challenging clinical and histopathologic diagnosis. In this paper, we focused on the clinical and pathological specifications of this rare tumor, so any unnecessary examinations or measures may be spared. Negative staining of amyloid material with AAC and osseous metaplasia noted in the histopathologic examination may not be thought as definite criteria for localized amyloidosis, but a supporter of localized, solitary amyloid tumor diagnosis. Amyloid can affect any site in thehead and neck including the orbit, sinuses, oral cavity, salivary glands,pharynx, and larynx. Amyloid involvement of tongue is almost always secondaryto systemic amyloidosis and localized involvement is extremely rare , 2.The etiology, treatment, andoutcome of systemic amyloidosis are totally different from localizedamyloidosis. The mean survival of patients with systemic amyloidosis is between5 to 15 months, whereas patients with localized amyloidosis have excellentprognosis [To rule out a systemic amyloidosisfor these patients is extremely critical because this can markedly change theexpected morbidity and mortality . AbdominThe purpose of this article is topresent a rare case of localized, solitary amyloid tumor of tongue base andemphasize some of the characteristic features of challenging histopathologicdiagnosis.A 61-year-old male patientpresented with pyrosis of tongue and a nodular mass in tongue base. Head andneck examination revealed a 1 × 1 cm well-circumscribed, rubbery, nodular massat the right side of the tongue base. His review of systems was negative forsymptoms including fever and weight loss.A computed tomography was performedand a possible granulomatous or inflammatory mass with calcification wasreported . An inciRough and irregular mass, 2 cm in diameter, was dissected from surrounding normal tissue withminimal tissue loss and enbloc excision could be achieved via transcervical suprahyoid approach.Postoperative microscopic examination of the specimenrevealed a well-circumscribed submucosal lesion characterized withstructureless eosinophilic material deposition. Overlying mucosa was inflamed and focally eroded. The amorphous, more orless homogenous eosinophilic materialresembled amyloid histologically and on Congo red staining, exhibited the classical apple-greenbirefringence under polarizedlight. Deposits of amyloid were also found in and around the walls of smallblood vessels. Immunohistochemical examination of the matrix with monoclonalantibody AA-Congo (AAC) revealed a non-AA-type amyloid deposition . At theDiagnostic workup includingcomplete blood count, liver and renal function tests, urine analysis,esophagography, chest X-ray, electrocardiography, echocardiography, bone-marrowbiopsy, ESR, RF, ANA, and abdominal fat biopsy was carried out.All examinations for exclusion ofsystemic amyloidosis, including bone-marrow and abdominal fat biopsies, werefound to be negative for Congo red staining and amyloid deposition. Bone-marrowaspiration biopsy was found to be free of any type of infiltrations. Thus, thepatient was determined to be free of systemic amyloidosis and diagnosed aslocalized, solitary amyloid tumor of the tongue base.Annual examinations were performed inthe four-year follow-up period.The differential diagnosis of the mass in tongue base includesneoplastic processes and also lingual thyroid. Because the mass was settledunder normal appearing mucosa, a preoperative incisional biopsy was performedin order to rule out thyroid tissue and malignancy. We could not achieve adefinitive pathology with preoperative biopsy so we planned total excision ofthe mass.When amyloidosis is the histopathologic diagnosis in the patientspresenting with a localized mass in head and neck region, the main diagnosticdilemma of the surgeon becomes the extension of the disease. Many diagnosticexaminations were proposed to rule out a systemic disease. Histopathologicexaminations of these lesions may help clinicians about the necessity of thediagnostic examinations. Amyloid tumor of tongue base is a rare condition andmay not be predicted preoperatively, therefore there is little information onthe clinical and histopathologic features of the disease. In this paper, wefocused on the clinical and pathological specifications of this rare tumor, soany unnecessary examinations or measures may be spared and patient may beinformed clearly about the disease.Also, in the literature there is no consensus on terminology of thedisease. We did not prefer to use the term “localized amyloidosis of tonguebase” for this disease because diffuse involvement of tongue with systemicamyloidosis may be mistaken with well-circumscribed amyloid tumor. The terms“localized primary amyloid tumor” and “solitary amyloid tumor” were both usedfor localized amyloid deposits without systemic amyloidosis or multiple myelomain the literature, and better distinguish from the systemic form and betterdefines the disease. So we decided to use the term “solitary amyloid tumor” forthe diagnosis after ruling out systemic involvement of the disease because itbriefly underlines the nature of the disease.The definitive treatment oflocalized amyloidosis was cited to be surgery. Surgery alone may be 100%curative [Although, negative staining withAAC and osseous metaplasia which is noted in histopathological examinationsupports non-AA-type amyloidosis, we performed these examinations to supportour diagnosis. Negative staining of amyloid material with AAC is mostly seen inprimary type of amyloidosis. Also, osseous metaplasia noted in the histopathologicexamination may not be thought as definite criteria for localized amyloidosis, but a supporter oflocalized, solitary amyloid tumor diagnosis. There is data about osseousmetaplasia in the literature regarding the solitary amyloid tumor of other tissues, and to A submucosal, surgically well-defined,well-circumscribed, and rubbery mass in tongue base with calcifications onradiologic studies may not be surgically differentiated from other tumors oftongue. When histopathology reveals amyloid deposits on light microscopy, theseclinical findings may come out as important features in order to differentiatelocal disease from involvement of tongue by a systemic disease.With this little informationregarding the clinical and histopathologic features of localized, solitaryamyloid tumor of tongue base, we may not discuss the necessity of theexaminations in order to rule out systemic disease including abdominal fat andbone-marrow biopsy. Therefore, the publication of more cases or series of thedisease may yield better characterization of the histopathologic, radiologic,and clinical features of solitary amyloid tumor of tongue base.


There is an interest for intervention studies aiming at the prevention of disability in community-dwelling physically frail older persons, though an overview on their content, methodological quality and effectiveness is lacking.A search for clinical trials involved databases PubMed, CINAHL and Cochrane Central Register of Controlled Trials and manually hand searching. Trials that included community-dwelling frail older persons based on physical frailty indicators and used disability measures for outcome evaluation were included. The selection of papers and data-extraction was performed by two independent reviewers. Out of 4602 titles, 10 papers remained that met the inclusion criteria. Of these, 9 were of sufficient methodological quality and concerned 2 nutritional interventions and 8 physical exercise interventions.No evidence was found for the effect of nutritional interventions on disability measures. The physical exercise interventions involved 2 single-component programs focusing on lower extremity strength and 6 multi-component programs addressing a variety of physical parameters. Out of 8 physical exercise interventions, three reported positive outcomes for disability. There was no evidence for the effect of single lower extremity strength training on disability. Differences between the multi-component interventions in e.g. individualization, duration, intensity and setting hamper the interpretation of the elements that consistently produced successful outcomes.There is an indication that relatively long-lasting and high-intensive multicomponent exercise programs have a positive effect on ADL and IADL disability for community-living moderate physically frail older persons. Future research into disability prevention in physical frail older persons could be directed to more individualized and comprehensive programs. Frail elderly people are at much higher risk for falls, infections, disabilities, hospitalization, institutionalization, and death, compared with their age-matched non-frail counterparts -3. In scA widely accepted definition and clear criteria for frailty are lacking ,5,13. MaOn May 16 2007 databases PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and CINAHL were searched for randomized- and controlled clinical trials by using "frail*", "vulnerable", "at risk", "high risk", "low functioning", and the MESH terms "chronic disease" and "disabled persons" in combination with the MESH term "aged". Search terms for outcomes focused on disability measures and included terms like "disabil*", "functional decline", "functional capabilit*", "functional performance", "independen*" and MESH terms "activities of daily living", "quality of life" and "well being". To restrict the search to interventions that targeted community-dwelling elderly terms like "home*", "in-home*", "communit*", "independent living" and MESH term "primary care" were added. Additionally studies were searched by hand-searching reference lists from relevant papers. The search was restricted to articles in English, Dutch and German. There was no restriction for type of intervention or year of publication.Clinical trials where community-dwelling frail elderly were the target group were included. Studies had to include frail elderly based on at least one of the physical frailty indicators as described by Ferrucci et al. . Table 1A first selection of relevant studies was made on title-level using a conservative approach, meaning that in case of doubt an article would always be screened on abstract-level. The second (abstract-level) and third selection phase (full-text level) were independently undertaken by two reviewers (RD and EvR) scoring 'relevant', 'doubt' or 'irrelevant' on forms. In case of inconsistencies, the reviewers discussed the scoring. Consensus on 'irrelevant' led to the exclusion of an article. On one occasion the reviewers asked for the involvement of a third party (LdW) in order to reach consensus. The same reviewers also performed independently the quality assessment of included studies as well as the data extraction. Inconsistencies in scoring between reviewers was discussed until consensus was reached. As the included trials all turned out to be randomized controlled trials the methodological quality was assessed using an adaptation of the Cochrane Back Review Group list of criteria Table  19]. Th. Th19]. Four thousand six hundred and two titles were identified in the literature search. After screening the titles, 127 studies were considered relevant for further screening on abstract-level. Of these, another 69 studies were excluded, because of not meeting the inclusion criteria  and focused on the physical condition of the participants, except for one  that indThe inclusion criteria used varied from rising from a chair, to descending stairs, knee extensor strength, oxygen-uptake, physical inactivity, involuntary weight loss, low BMI, dietary assessment, gait test, balance test and mobility problems , howeveOut of the 10 randomized controlled trials that evaluated interventions for physically frail community-living elderly on disability, 9 were considered to be of sufficient methodological quality. No consistent findings were found in these 9 trials regarding their effect on disability.There is no evidence that nutritional interventions for frail elderly, despite an observed effect on total energy intake and weight gain , result The differences between the interventions hamper the interpretation of elements that consistently produced successful outcomes. Although malnutrition and physical frailty markers are considered strong indicators for functional decline in the elderly ,32, the A systematic review was conducted to assess the content, the methodological quality and the effectiveness of intervention studies for the prevention of (ADL/IADL) disability in community-dwelling physically frail older persons. There is no evidence that nutritional interventions for frail older persons, despite an observed effect on total energy intake and weight gain, result in positive effects on disability-level. No evidence appeared that single lower extremity strength-training, despite the effect on strength and walking function, has an effect on disability for physically frail older persons. There is some indication that long-lasting high-intensive exercise programs for moderate physically frail older persons can have an effect on disability outcomes.The authors declare that they have no competing interests.RD, EvR, LdW and WvdH developed the original idea for the review. RD performed the search strategy and the selection, extracted the data and wrote the manuscript. EvR was involved in the selection process and data extraction. EvR, LdW, WvdH and GIJMK provided valuable comments during the process of writing this manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Table 4: General characteristics and outcomes of included trials. The data provided informs about features of interventions, measurements and outcomes of trials included in the systematic reviewClick here for file


The mammalian Natriuretic Peptide (NP) system consists of neuro-hormones, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c-type natriuretic peptide (CNP), and the N-Terminal fragment of BNP (NT-pro-BNP). In response to some cardiovascular derangement the heart (acting as an endocrine organ), brain and other structures secretes natriuretic peptides in an attempt to restore normal circulatory conditions. Their actions are modulated through membrane-bound guanylyl cyclased (GC) receptors. They induce diuresis, natriuresis and vasodilation in the presence of congestive heart failure. These neuro-hormones also play a role in the suppression of neointimal formation after vascular injury. In addition, they act as antifibrotic and antihypertrophic agents preventing cardiac remodeling after myocardial infarction. Further, NP have diagnostic and prognostic role in heart failure, vasoconstriction, left ventricular late remodeling after MI and others. At present, some drugs such as Nesiritide, NEP inhibitors and vasopeptidase inhibitors were synthetized from NP, to antagonize these cardiovascular derengements. In future, it will be possibile to elaborate some drugs similar to petidase inhibitors and some CNP-like drugs able to reduce many symptoms of cardiovascular derangements without significant side effects. Natriuretic Peptide (NP) System is composed of neurohormones synthesized by the heart, brain and other organsAtrial Natriuretic Peptide (ANP); Brain Natriuretic Peptide (BNP); C-type Natriuretic Peptide (CNP)N Terminal fragment of pro BNP (NT-pro-BNP) must be also considered. This last derives from the proteolysis of proform BNP.At present, the mammalian natriuretic peptide system consists of some substances: ANP is the first discovered member of this family. The major site of synthesis in normal heart is the atrium, and secretion is stimulated by stretch. In normal adult heart, ventricular tissue produces only minor amounts of ANP, but major amounts are found in ventricles of fetuses and in patients with LV hypertrophy. ANP is a 28-amino acid peptide stored and released by atrial myocytes in response to atrial distension and stretch. In addition, it also increases angiotensin II and/or endothelin rise-concentrations as a consequence of sympathetic stimulation.Elevated levels of ANP generally are found in hypervolemic states inducing a condition of congestive heart failure. It is present in patients with heart failure and chronic atrial fibrillation (AF). In this connection, ANP levels were higher among those with AF of longer duration than in decompensated patients with AF of shorter lengthBNP was primarily discovered in porcine brain, but the highest concentration of peptide is found in the heart. It is a 32 amino-acid peptide, synthesized within the ventricles in response to myocyte stretch and/or pressure overload8. It is released both as an active hormone and an inactive N-terminal fragment (NT pro-BNP). Recently, Elnomany and Abdelhameed found that BNP levels are elevated in patients with symptomatic LV dysfunction. The reduction of Mitral Annulus Posterior Excursion (MAPSE), as the index of left ventricular dysfunction, appears strongly correlated with plasma BNP levels. This correlation provides a simple, accurate and reproducible tool for early diagnosis of LV dysfunctionIn addition, BNP levels are higher in patients with dyspnea (shortness of breath) due to heart failure than in patients with dyspnea induced by other causes. Consequently, BNP measurement in the emergency room helps in to discriminate two types of dyspnea. Besides, BNP appears to be a useful marker of cardiovascular risk, even in persons without clinical evidence of cardiovascular disease. Finally, BNP levels were employed to predict the risk of heart failure atrial fibrillation and stroke or transient ischemic attack. Conclusively, the hemodynamic effects of BNP are largely similar to those of ANP.C-type Natriuretic Peptide was originally isolated from porcine brain extracts but, the major site of synthesis are the vessel walls. The peptide plays a role in the suppression of neo-intima formation after injuryNumerous compounds limiting ventricular remodeling after MI heve been reported. These include angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, aldosterone antagonists, and matrix metalloproteinase inhibitors. Although almost all these agents have been given orally contrary to CNP, this last has the advantage concerning short period of treatment and fewer side effects.N-terminal fragment of Brain Natriuretic Peptide (NT pro-BNP) derives from the proteolysis of pro-BNP (composed of 108 amino-acids). It consists of 76 amino-acids and recently caused great interest for its possible role in monitoring cardiac insufficiencyThe NP serum levels are important not only as indicators of numerous cardiovascular derangements, but also as markers of their severity. ANP are found elevated in patients suffering from MI and having congestive heart failureThis diagnostic value was recently confirmed by Coutance et al. Although elevated BNP levels have a high sensitivity to detect patients at risk of death, the specificity of this neuro-hormone is lowThe beneficial effects of NP on cardiovascular disease stimulated the development of new compounds able to prolong and enhance these positive effects. Of these:Nesiritide is a recombinant form of human BNP, approved for use in the acute treatment of congestive heart failure caused by systolic dysfunctionThe agent is indicated for intravenous treatment and has advantageous, pluripotent properties in ADHF including hemodynamic, neurohormonal, lusitropic, and reverse remodeling effects. In addition, it was satisfactorily compared with other vasodilating agents and did not promotes arrhythmogenesisSubsequently, a number of other drugs deriving from CNP have been prepared30More recently, a new class of drugs similar to NEP inhibitors have been shown to be efficacious in animal models with heart failure. Treatment with NEP-inhibitor, Candoxantril, increases urinary sodium and significantly elevates filtration fraction with no significant effect on glomerular filtration rate, renal plasma flow or lithium clearance. A reduction in aldosterone concentration is also evident in these patients34There are, however, complex interactions between ACE and NEP inhibition. Both ACE and NEP metabolize the kinin peptides bradykinin and kallidin, whereas NEP converts angiotensin I to angiotensin and metabolizes Angiotensin II and endothelin. Addition of NEP inhibition to ACE inhibition potentiates the ACE-inhibitor-induced increase in kinin levels. But, the combined ACE/NEP inhibition increases the risk of angioedema and may counteract any benefit of ACE inhibitionConclusively, NP is an endogenous system able to induce most common circulatory derangements, such as water retention, vasoconstriction in response to CHF. In addition, the system causes endothelial dysfunction and left ventricular late remodeling. To avoid these negative effects, new derived drugs are recently prepared to reduce, eliminate or delay the symptoms of cardiac and vascular impairments. They act by performing some cardiovascular and renal actions such as: natriuresis; increase of glomerular filtration; systemic vasodilation; inhibition of renin release; reduction of left ventricular remodeling; reduction of venous and “wedge” pressure.These drugs must be able to attain, extend, and stabilize neuro-hormonal, hemodynamic and clinical improvements of symptoms of some cardiovascular disease, such as chronic heart failure, myocardial infarction or systemic hypertension. In future, these drugs will become more and more important, because they act by addressing common cardiovascular symptoms through endogenous principles, which allows resolution of symptoms or retard progression of symptoms without adverse side effects.


Intracapsular fractures of the proximal femur account for a major share of fractures in the elderly. The primary goal of treatment is to return the patient to his or her pre-fracture functional status. There are multiple internal fixation options  and hemi and total hip arthroplasty. Open reduction and internal fixation has been shown to have a high rate of revision surgery due to nonunion and avascular necrosis. Hip replacement arthroplasty  is a viable treatment option.Eighty-four elderly patients (age >70 years) with a femoral neck fracture were treated over a five-year period (January 2001 to December 2006). Eighty of the 84 patients underwent some form of hip replacement after appropriate medical and anesthetic fitness.We had good results in all the patients in terms of return to pre-fracture level of activity, independent ambulation and satisfaction with the procedure. Patients over the age of 80 years who underwent bipolar hemiarthroplasty all progressed well without any complication. Patients in their seventies underwent some form of total hip replacement and barring one case of deep infection, two cases of deep vein thrombosis and three cases of dislocation (which were managed conservatively), there were no real complications.Hip replacement  is a successful procedure for the elderly population over 70 years with femoral neck fractures. Return to pre-morbid level of activity and independent functions occur very swiftly, avoiding the hazards of prolonged incumbency. We have proposed a treatment algorithm following the results of treatment of this fracture in our series. We have also reviewed the different contemporary treatment options used  fixation, hemi and total hip replacement) used for treatment of an elderly patient with of femoral neck fracture. Intracapsular fractures of the proximal femur form a major share of fractures in the elderly.Management of femoral neck fractures in elderly patients has been controversial. Femoral neck fractures have been considered ‘unsolvable fractures’ in the older era of orthopedicsImportant factors to consider in choosing any treatment modality are intrinsic, viz. patient age, general medical condition, type of fracture; and extrinsic, viz. availability of facilities and socio-economic status.Though non-operative treatment of these fractures has been documented,11We present the results of treatment of this fracture in our series of 84 elderly patients over a five-year period. We have also reviewed the literature for different contemporary treatment options used  in an elderly patient with femoral neck fracture. Based on the results of our study, we developed a treatment algorithm.We have reviewed 84 elderly patients  with a femoral neck fracture treated by a single surgeon over a five-year period (January 2001 to December 2006).There were 49 male and 35 female patients of average age 78 years . Associated co-morbidities included combinations of diabetes mellitus, hypertension, chest disorders, cardiac disorders, renal diseases, hepatic diseases, neurological and psychiatric illnesses and one patient had had deep venous thrombosis in the past. Fourteen per cent (12 patients) had more than five coexisting morbidities and 65% (54 patients) had less than three co-morbid factors .The patients had presented to us either immediately after a trivial fall or after being treated conservatively at home or outside over a period averaging two weeks . Four patients were either bedridden or wheelchair-bound or had severe co-morbidities and were treated conservatively with bed-rest and physiotherapy as tolerated. The remaining 80 patients underwent surgery . All patWe opted for total hip arthroplasty procedure in the majority of our patient population (where life expectancy was greater than five years), all those with pre-existing acetabular pathology (inflammatory or arthritic). All patients were offered the options of cemented, hybrid and cementless fixation, as well as alternative implant tribological characteristics . Final decision rested on factors ranging from patient choice of range of motion, capabilities expected post-surgery, economics, bone density and implant availability. In general, patients with better bone stock and lesser number of co-morbid factors were offered cemented or hybrid hips; whereas those with poor bone stock and greater number of co-morbid factors were treated with cementless hips.Cemented implants accounted for nearly 78% of all operated cases. The implants used included the cemented total hip  in 54% 43 patients) , the cem patientsPostoperative protocol for patients with cemented implants  involved full weight-bearing as soon as possible (as per patient ability to stand supported) and active hip and knee exercises. Patients with hybrid hip replacements were initially mobilized to partial weight-bearing for three weeks and then graduated to full weight-bearing over the next three weeks. Patients with cementless implants  were mobilized to non-weight-bearing for three weeks, partial weight-bearing for the following nine weeks and then allowed full weight-bearing without support. Active hip abduction exercises were initiated at six weeks.Patients were reviewed at two weeks , six weeks, three months, six months, 12 months, 24 months and 60 months and assessed using clinical and radiological criteria. Clinical criteria used were absence of pain and limp, as well as the ability to perform activities of daily living independently and the Harris Hip scores (performed to quantify results only). All patients were studied radiologically for signs of loosening, subsidence (cemented implants), lysis and osteointegration (cementless implants).We had good results in the patients that we treated, in terms of return to pre-fracture level of activity, independent ambulation and satisfaction with the procedure. We used the anterolateral approach in all patients and the blood loss averaged 184 ml . Harris Hip scores of our 80 operated patients (documentation purposes only) averaged 81  at final follow-up.The outline of our treatment algorithm had been initially prepared following conclusions derived from literature review and after analyzing the results of our study, has been modified to the protocol described in our paper.Hemiarthroplasty was reserved for patients of age more than 80 who were independently mobile, had severe co-morbidities and needed excessive movements. We performed cemented bipolar hemi-arthroplasties in 19 patients and cementless bipolar hip replacement in five. These included those with previous deep vein thrombosis (DVT) or high risk of Pulmonary Emobolism, evidence of recent or past infection in the hip. This did not in any way delay the mobilization protocol. No patient underwent cementless Austin-Moore or Thompson prosthesis implantation. All patients proceeded well without any complication.The complications that we encountered included one case of deep infection necessitating one episode of debridement and six weeks of parenteral antibiotics, two cases of DVT (managed with heparinization and delayed rehabilitation) but no fatal PE, three dislocations , two instances of thigh pain , five patients developed superficial bedsores  and seven patients developed acute confusional states  .Although the follow-up period is short  and our study is non-randomized (limiting the efficacy of our results), non-controlled and retrospective, the results were consistent with contemporary literature.8Hip fractures in the elderly patient group result in implications in medicine, rehabilitation, psychiatry and healthcare economics. Conservative treatment is fraught with all the complications of prolonged recumbency viz. chest infections, formation of pressure sores and disuse osteoporosis. Non-operative management may be preferable for non-ambulatory, institutionalized patients with marked dementia who experience minimal discomfort within the first few days after the injury.1et al.,et al.,Amongst the surgically treated group, the methods preferred are either internal fixation or various forms of arthroplasty . Most recent randomized studies have demonstrated high re-operation rates 34-43%) following reduction and fixation of displaced intracapsular hip fractures.815-43% follRandomized trials of patients with limited mobility or impaired cognitive function have suggested that a unipolar cementless hemiarthroplasty (like the Austin-Moore or Thompson prosthesis) is the treatment of choice.1318It is clear that a patient with antecedent symptomatic osteoarthritis or inflammatory arthritis of his/her hip, who subsequently suffers a displaced subcapital hip fracture, would benefit most from a total hip replacement compared to a hemiarthroplasty.194The potential advantage of using total hip replacement relates to its highly predictable results, with survivorship of greater than 90% at 10 years and its unparalleled results in terms of pain relief and overall function. In addition, the use of total hip replacement avoids the potential need for revision secondary to acetabular pain from ongoing acetabular erosion.1381214121417et al.What remains unclear is whether certain hip fracture patients, with no preexisting hip pathology, would benefit from total rather than hemiarthroplasty. Rogmark et al.et al.et al.et al.22An argument against primary arthroplasty has been the possibility of increased postoperative mortality. Holmberg et al.,According to a prospective randomized comparative study by Keating grant and Masson Similarly, other randomized studies121617Our study, though non-randomized, non-controlled and retrospective, demonstrates acceptable results consistent with contemporary studies.81114


Environmental Health Perspectives, In the November issue of Perfluoroalkanesulfonamides, which may be metabolized to PFOS, have been used in grease- and water-repellant packaging for foods, particularly pizza, french fries, and other fried foods. The Canadian Total Diet Study  detectedThe pregnancies studied by PFOA and PFOS repel fat and are distributed in body water, particularly plasma. Women with a reduced plasma or body water volumes would distribute the same body burden of perfluoroalkane acids in a smaller space, producing higher perfluoroalkane acid concentrations. Fat-free body mass and total body water volumes are important predictors of birth weight , giving A reasonable next step in addressing the question of whether perfluoroalkane acids (at current human blood concentrations) play a role in fetal growth will be studies in which maternal nutrition and body composition, as opposed to body weight, are considered as possible confounders.


We recently developed a multiresolution PDE-based deformablesurface whose deformation behavior is governed by partialdifferential equations (PDEs) such as the weighted minimal surfaceflow. Comparing with the level-set approach, our new model hasbetter control of the mesh quality and model resolution, and ismuch simpler to implement since all the computations are local.The new deformable model is very useful for a variety of medicalimaging applications including boundary reconstruction, surfacevisualization, data segmentation, and topology discovery. In thispaper, we demonstrate both the accuracy and robustness of ourmodel on areas such as medical image segmentation through a numberof experiments on both real (MRI/CT) and synthetic volumetricdatasets.


We report a 58-year-old woman with cutaneous adenoid cystic carcinoma arising on the chest treated with Mohs micrographic surgery. The patient remained tumor-free at 24-month follow-up. To date, only six other cases of cutaneous adenoid cystic carcinoma were reportedly managed by Mohs surgery. Cutaneous adenoid cystic carcinoma has low potential for distant metastasis but is notorious for its aggressive infiltrative growth pattern, frequent perineural invasion, and high risk of local recurrence after excision. We propose that Mohs surgery is an ideal method to achieve margin-free removal of cutaneous adenoid cystic carcinoma. A brief literature review is provided. Adenoid cystic carcinoma (ACC) is commonly known as a malignant neoplasm of salivary glands in the head and neck region . Rarely,A 58-year-old, otherwise healthy, Caucasian female was referred to the Department of Dermatology at the University of Wisconsin for treatment of a biopsy proven adenoid cystic carcinoma on the right mid-chest. She had a lesion of “basal cell carcinoma” surgically excised on her right mid-chest 14 years previously. The actual slides of the previous excision were not retrievable, while the pathology report did state that the lesion was “a basal cell carcinoma which in some areas presents gland-like formations, adenoid cystic characteristics and focal areas of keratinization, but it predominantly is an adenoid basal cell carcinoma.” The patient had done well until one year prior to the referral when she noted two tender, flesh-colored nodules adjacent to the scar. A punch skin biopsy confirmed the diagnosis of adenoid cystic carcinoma concerning for its infiltrative growth pattern and perineural invasion. A thorough preoperation physical examination revealed a healthy-appearing Caucasian female with an approximately 15 × 15 mm, poorly defined, tender, erythematous patch with focal crust and a hypopigmented scar notable on the right mid-sternum region . There wThe patient underwent Mohs surgery for excision of the tumor. The specimens were processed using fresh frozen tissue stained with hematoxylin and eosin. It revealed an infiltrative dermal tumor composed of basaloid cells arranged in cords, nodules, and cribriform islands embedded in a fibrous stroma, with a lack of continuity with the surface epidermis. Prominent glandular and ductal differentiation and cystic spaces containing mucinous materials, and eosinophilic globules of amorphous material were noted . The chaTo further rule out an extracutaneous primary site of the tumor and search for evidence of metastasis, additional work-up was completed including a breast examination, mammogram, computed tomographic (CT) scans of the head, neck, chest, and abdomen, and head and neck examination by an otolaryngologist. All were within normal limits. The patient is now 24 months postoperative, and there is no sign of local recurrence or distant metastasis. The authors acknowledge that for our patient, the Mohs excision of the tumor preceded the work-up for possible extracutaneous sources. The work-up was slightly delayed due to prior-authorization processes involved with her insurance company. We wish to emphasize that ideally it is advisable to complete the entire work-up prior to excision, in order to exclude any extracutaneous source and thus confirm the diagnosis of primary cutaneous ACC.ACC is most commonly seen as a neoplasm of the major and minor salivary glands. It can also arise from a variety of primary sites, including the external auditory canal, lacrimal gland, respiratory tract, uterus, cervix, vulva, breast, thymus, prostate, esophagus, and skin , 4. WhenCutaneous ACC was first reported by Boggio in 1975 , the meaMicroscopic findings of cutaneous ACC are characterized by basaloid cells in the mid to deep dermis, arranged in cords and islands forming tubular structures and cribriform patterns, usually with a lack of connection to the overlying epidermis or adnexal structures , 7. TherWhether cutaneous ACC is a tumor of eccrine or apocrine origin has not been determined. There is some observational evidence suggesting that this tumor might be apocrine in origin. ACC often arises from ceruminous glands of the external ear canal, which are modified apocrine glands. Histologically, cutaneous ACC must be differentiated from adenoid basal cell carcinoma (BCC). Adenoid BCC also may demonstrate a cribriform pattern with areas of cystic degeneration and abundant mucin. However, it can be differentiated from cutaneous ACC by its continuity with the epidermis or adjacent hair follicle, the presence of peripheral palisading and retraction artifact, and often the lack of perineural invasion. Immunohistochemical studies may assist in further differentiating adenoid BCC from ACC. For instance, in contrast to adenoid BCC, cutaneous ACC often stains positively for S-100, epithelial membrane antigen (EMA) and is variably positive with carcinoembryonic antigen (CEA) , 3, 8. OAnother close mimicker of cutaneous ACC is mucinous carcinoma of the skin which typically shows islands of basaloid eccrine cells embedded in lakes or pools of mucin separated by fibrous septa –12. The Histological differential diagnosis of ACC should also include primary cutaneous cribriform apocrine carcinoma, which is a rare, low-grade cutaneous apocrine carcinoma. Microscopically primary cutaneous cribriform apocrine carcinoma is a nonencapsulated dermal tumor with an extensive cribriform pattern formed by multiple interconnected basophilic epithelial cells that are arranged in solid nests or tubular structures, and many small round spaces in between , 16. As The standard treatment for cutaneous ACC is wide local excision with tumor-free margins established by permanent sections , 7. AdjuOnly 7 cases –24, inclIt is worth clarifying the term “discontinuous perineural extension.” While tumors normally spread in a continuous manner, they may spread asymmetrically along the nerve. Also, tissue manipulation for horizontal sections during Mohs surgery may distort a nerve and result in “skip-areas” . TherefoSome authors have questioned whether routine hematoxylin and eosin staining of fresh frozen sections from Mohs surgery provides optimal visualization of tumor margins in the treatment of cutaneous ACC. Lang et al. preferred to use permanent sections instead . Given tBased on the nature of cutaneous ACC and the success rate of Mohs surgery in other cutaneous malignancies that exhibit perineural invasion, we propose that Mohs surgery is superior to wide local excision to achieve a more complete excision of this tumor and to reduce the rate of local recurrence. In the seven cases treated by Mohs surgery, there has been no local recurrence with a follow-up range of 10–28 months. However, a limited case number and insufficient follow-up period does not allow us to draw a definitive conclusion. We hope to see more cases managed by Mohs surgery, so that one might be able to compare whether there is indeed a lower recurrence rate in cases treated with Mohs surgery as opposed to wide local excision. Additionally, since recurrence of cutaneous ACC can occur as late as 35 years postexcision [