Cerebral small vessel disease  leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians. The clinical picture of cerebral small vessel disease (CSVD) is complex since the disease develops insidiously and its etiology is only partly understood. Limited correlations between neurological symptoms, imaging diagnostic and pathological findings impede an early enough diagnostic and therefore therapy. It’s obvious, however, that an illness of rather small blood vessels leads to subtle development of dementia and / or episodes of stroke-like symptoms if neurological sensitive areas are affected by so called strategic infarcts. Lacunes, diffuse white matter lesions  and microbleeds are the pathognomonic pathological correlates detectable with modern imaging diagnostic.Lacunes, found in 6% to 11% of autopsied brains, are defined as scars or remnants of small infarcts with a diameter ranging from 3 to 20 mm predominantly found in the basal ganglia, thalamus, pons, subcortical and cerebellar white matter areas[More than 40 years ago Fisher described the “segmental arterial wall disorganization” of small penetrating cerebral arteries defined by vessel enlargement due to wall remodeling with “loss of meshwork”, “hemorraghic extravasation” and deposits of fibrinoid material as one uFrom the current point of view the chronic small vessel wall alterations found in CSVD comprise three subtypes including lipohyalinosis, arteriolosclerosis and cerebral amyloid angiopathy (CAA). EspeciaMoreover, common acute lesions found in CSVD are cerebral microbleeds and primary intracerebral hemorrhages, discussed as consequence of small vessel wall fragility converging with acute hemodynamic changes possibly caused by fluctuations of the blood pressure,8. MicroOcclusions of degenerative altered small vessels, typically found in cerebral macroangiopathy associated with thrombotic or embolic stroke, might be a reasonable explanation for lacunar infarcts, but those occlusions are a rather rare event in brain autopsy of patients with CSVD. Thus, WWe have recently collected data in the model of spontaneously hypertensive stroke-prone rats (SHRSP) that strikingly support the importance of an early BBB dysfunction for the development of CSVD, which will be discussed in this review.Only few animal models have been recognized to be suitable for describing CSVD,10. AlthSHRSP were obtained by selective breeding from spontaneously hypertensive rats (SHR) for the development of spontaneous infarcts-13 and e3, larger non-territorial infarcts anyhow commonly distributed in specific territories of the large cerebral arteries, rarely covering multiple vascular territories or seen in the border zones of the large cerebral arteries as well as territorial infarcts in some cases affecting the whole hemisphere[SHRSP develop small lacunar-like lesions with a volume ranging from 2 to 57 mmmisphere,19,20. Tmisphere. Howevermisphere.Ischemic lesions are predominately found in cortical areas  and In contrast, the exact localization and extent of WML have been rarely investigated in SHRSP and therefore the respective existing data is quite incomplete. Myelin stainings show a rarefication of white matter substance accompanied by a general volume expansion in SHRSP with BBB leakage. For theBy genetic factors SHRSP develop a vascular risk profile, which comprises arterial hypertension, insulin resistance and hyperinsulinemia, mixed hyperlipidemia and elevated levels of free fatty acids. This geStarting a longitudinal study with around 130 SHRSP  we were able to define some kind of pathological cascade which is described in the following: The small vasculature of rather juvenile SHRSP is not distinguishable from age matched Wistar controls. However starting from an age of 12 weeks, in SHRSP we occasionally found in capillaries of the basal ganglia, the hippocampus and cortical areas intraluminal accumulations of erythrocytes  within their walls and within the adjacent perivascular parenchyma indicating associated BBB damage at already young ages  FigureI would tDisturbances of autoregulation of small vessel tonus represent another possible reason that at least promotes the formation of stases. This is reflected in constrictions and dilatations of the vessel wall we occasionally found in arteriolar segments with stases  SHR (SHRSR), an animal model with polygenetic and multifactorial inheritance of chronic arterial hypertension, including renal factors, prostaglandin-adrenergic interactions and abnormalities of the pituitary gland, developConcluding, SHRSP exhibit a complex cascade of CSVD and until now it is unclear, whether SHR develop a comparable natural course of microvascular dysfunction accompanied by histopathological phenomena exceeding their described BBB leakage.Thus, coming back to the headline of this review we can state that the SHRSP develops overt infarcts that mainly originate from breakdown of the BBB and not from occluded vessels. Thrombotic occlusions of small penetrating vessels occur only at the end of a pathological cascade originated by endothelial damage. This may have important clinical consequences. Patients with stroke-like symptoms caused by thrombotic or embolic occlusions of large vessels generally benefit from an anti-thrombotic treatment. But the effect of such a treatment could be even detrimental if stroke patients suffer from multiple small vessel lesions originally caused by BBB leakage.Moreover, one has to ask what is the main difference between SHRSP and controls? Do control rats develop the pathology of CSVD cascade only later on or in other words: Are the vascular risk factors in SHRSP some kind of accelerator for a pathology caused in controls simply by aging? We also found an increasing number of stases in older control rats correlating with vascular changes in the kidney comparable to the findings in SHRSP. Control rats exhibit limited mini- and microbleeds and so far no one exemplar developed overt ischemic lesions. Thus, it is obvious that the vascular system also in control rats undergoes an age-dependent impairment. But probably only a very little fraction of them will develop the typical pathological cascade of CSVD we have found in SHRSP.The genetically most related population to SHRSP is the SHRSR. The risk profile also includes chronic arterial hypertension with disturbances of renal factors. HoweverThus, besides aging and vascular risk factors we suppose that CSVD pathology needs a certain combination of genetic risk factors and is in its development positively or negatively influenced by lifestyle. In this regard it is very important to mention that the incidence and development of overt infarcts in SHRSP can be heavily promoted by a high salt diet. Moreover, an application of a salt-loaded diet induces an abrupt malign increase of the arterial blood pressure, associated with forced vessel wall ruptures leading to an extended breakdown of the BBB with associated cerebral edema and large primary intracerebral hemorrhages,19,20,38Concluding, the conglomerate of vascular and genetic risk factors in SHRSP obviously favors an initially small and insidious age-dependent developing of endothelial injuries leading to an increasing BBB leakage. The vascular system seems to react with a restricted coagulation which causes stases of erythrocytes as a rather byproduct.It is a challenge for modern imaging diagnostics to detect these early vascular changes to selectively recognize patients with an elevated vascular risk profile. One approach could be the development of new, especially renal biomarkers in blood and urine. Therefore, in SHRSP we have just started to investigate urine concentrations of the kidney-injury-molecule-1 (KIM-1), marking a renal tubular damage. We are Meanwhile our probably best weapon against small cerebral vascular diseases is the promotion of healthy campaigns persuading people to prevent the age driven progress of CSVD under the slogan:More physical activity, less salt, no smoking!Aβ: Amyloid-β; BBB, Blood brain barrier; CAA: Cerebral amyloid angiopathy; CE-μMRA: Contrast-enhanced magnetic resonance microangiography; CSVD: Cerebral small vessel disease; HE: Hematoxylin Eosin; IgG: Immunoglobulin G; KIM-1: Kidney-injury-molecule-1; MCA: Middle cerebral artery; MRI: Magnetic resonance imaging; MRA: Magnetic resonance angiography; SHR: Spontaneously hypertensive rats; SHRSP: Spontaneously hypertensive stroke-prone rats; SHRSR: Spontaneously hypertensive stroke-resistant rats; SPECT: Single photon emission compute tomography; STL: Solanum tuberosum lectin; vWF: Von-Willebrand factor; WML: White matter lesions.The authors declare that they have no competing interests.SS, CB, CC and HB wrote the manuscript. All authors read and approved the final manuscript.


Hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. While there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. Our algorithm can assist clinicians in maintaining blood glucose ([Gbl]) within a desired target range while avoiding hypoglycemia.Our model predictive control (MPC) algorithm uses insulin and glucose as control inputs and a linearized model of glucose-insulin-fatty acid interactions. To allow the controller model to learn from data, a moving horizon estimation (MHE) technique tailored the tissue sensitivity to insulin to individual responses. Patient data  were from the HIDENIC database at the University of Pittsburgh Medical Center. [Gbl] measurements, typically hourly, were interpolated to impute a measurement every 5 minutes. The model captured patient [Gbl] via nonlinear least squares by adjusting insulin sensitivity (SI) and endogenous glucose production (EGP0). The resulting virtual patient (VP) is used to evaluate the performance of the MPC-MHE algorithm.MPC controller performance on one VP is shown in Figure The MPC-MHE algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of 10 VPs. Furthermore, the MHE scheme updates patient parameters in real time in response to changing patient dynamics.


Female genital tuberculosis (TB) remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquiredimmunodeficiency syndrome (AIDS). Genital TB is commonly asymptomatic, andit is diagnosed during infertility investigations. Despite of recent advances in imaging tools, such as computerized tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpingography is still the standard screeningtest for evaluation of tubal infertility and a valuable tool for diagnosis of femalegenital tuberculosis. Tuberculosis gives rise to various appearances on hysterosalpingography (HSG) from non-specific changes to specific findings. The present pictorialreview illustrates and describes specific and non-specific radiographic features of femalegenital tuberculosis in two parts. Part I presents specific findings of tuberculosis relatedto tubes such as "beaded tube", "golf club tube", "pipestem tube", "cobble stone tube"and "leopard skin tube". Part II describes adverse effects of tuberculosis on structure ofendometrium and radiological specific findings such as "dwarfed" uterus with lymphaticintravasation and occluded tubes, "T-shaped" tuberculosis uterus, "pseudounicornuate"uterus and "Collar-stud abscess", which have not been encountered in the majority ofnon-tuberculosis cases. Female genital tuberculosis (FGTB) is one formof extrapulmonary manifestations of tuberculosis,while it includes 5% of all female pelvic infectionsand 10% of pulmonary tuberculosis cases . Itis mThe reported prevalence of genital tuberculosishas shown a descending trend in developed countries,but recently, its rate has started to increaseagain due to co-infection with human immunodeficiencyvirus (HIV) and the development of drug-resistantstrains of Mycobacterium tuberculosis -6.Primary infection of the female genital organs isvery rare , and is Diagnosis of genital TB may be difficult becausemajority of cases are asymptomatic; in addition,facilities for mycobacterium culture and histopathologyare limited in high-prevalence countries-11. In tThis pictorial review describes specific and nonspecificradiographic features of tubes caused bytuberculosis as seen on HSG.Mycobacterium tuberculosis is responsible fordisease in approximately 90-95% of cases and producesgranulomatous salpingitis and endometritisleading irregular menstrual bleeding and infertility.In 5-10% of patients, the infection results from Mycobacteriumbovis, especially when the source ofinfection is acquired from the gastrointestinal cases, 18.Genital tuberculosis usually spread to genitalsite from three routes, including hematogenous,lymphatic or adjacent viscera , while iPrimary infection of genital TB is rare, and mayresult from direct introduction of TB bacilli atsexual intercourse with a male partner with genitourinaryTB. Ascending spread of infection fromthe vagina, cervix and the vulva has been reported.Tha fallopian tubes are the initial focus of femalegenital tuberculosis, and usually involved bilaterallynot symmetrically . The patThe transitional region between the isthmusand ampulla is the most frequent site of tubalobstruction. Sometimes, hydrosalpinx or pyosalpinxwith thick fibrotic wall is formed at thedistally blocked fallopian tube.The ovaries areoften seen in normal appearance and the diagnosisis established only on histopathologicalstudies .In some cases, ovarian tubercle, adhesion, capsularthickening and ovarian or pelvic abscess areformed .Most of the cases involved in genital TB have been detected in reproductive age; a range of 20-45 year-old . GenitalTuberculous lesions of the cervix present withpostcoital bleeding, abnormal discharge and,on examination, have appearances similar tocancer of the cervix . InvolveHysterosalpingographic presentation of tubalTB vary from non-specific changes such as hydrosalpinxto specific pattern such as "beadedtube", "golf club tube", "pipestem tube", "cobblestone tube" and the "leopard skin tube". Of courThe presence calcified lymph nodes in thepelvis or in the course of fallopian tubes mayenable the diagnosis of the TB. Plain films ofthe pelvis may show such calcifications whichmust be differentiated from other causes of calcificationssuch as calcified pelvic nodes, calcifieduterine myomas, urinary calculi, pelvicphleboliths and calcification in an ovarian dermoid. The calCaseous ulceration of tubal mucosa createsan irregular, ragged or divertucular appearanceon the contour of the tubal lumen on HSG. Divierticularcavities surrounding of the ampullarportion may give it a "tufted" like appearance. Isthmic diverticula may resemblesalphingitis isthmica nodosa, "TB-SIN" likeappearances can be differentiated from classicSIN . In "TB-SIN diverticular outpouchingare larger, asymmetric, with a morebizarre pattern (in size and number) and arenot usually restricted to the isthmic portionof the tube as compared with those of SIN ,16. TheTubal occlusion in tuberculosis is consideredthe most common finding seen on HSG and occursmost commonly at the junction between theisthmus and ampulla. in the region of isthmus andampulla. Although cornual occlusion followingampullar obstruction is the most common site oftubal occlusion caused with any factor, it is not socommon in tuberculosis.Multiple constrictions along the course of fallopiantube may form due to scarring and present as"beaded" appearance . While tOcclusion of the isthmus or fimbrial end of thetube filled with serous or clear fluid produce aretort-shaped dilation of the tube (large-sausageshaped)which initially is a pyosalpinx that changeto hydrosalpinx. Hydrosalpinx is usually moderateor slight with a "golf club like appearance" to theampulla  16)..16).Twisting of the hydrosalpinx may result in afloral pattern- "the floral hydrosalpinx" .ThickenIntraluminal scarring can give rise to a cobblestonepattern which is an effective radiographic sign of intraluminaladhesions in hydrosalpinges and associatedwith concern of infertility  34). A . A 34). In chronic tuberculosis, following repeatedepisodes of acute exacerbation, a dense peritubalconnective tissue scarring occurs in andaround the tubes, leading to peritubal adhesions.The tubes become vertically or horizontallyfixed, interfering with access of fallopiantubes to the ovary at ovulation and transport ofthe ovum.In this non-specific finding, the contrastspill from a vertically fixed tube appears to bebounded laterally by adhesions, which givesrise to straight spill appearance . ThefalDense adhesions may resemble lead to visualizationof septations and bizarre "criss-crossspill" pattern. Sometimes, peritoneal granulomasformation produces small rounded fillingdefects seen additionally to these septations.Everted fimbria with a patent orifice impartingcharacteristic "tobacco pouch" appearance.HSG is considered as an important diagnostic tool inthe investigation of internal architecture of female genitaltract and helpful procedure in diagnosis of femalegenital tuberculosis. Tubal and uterine lesion scarringremained of genital TB, are presented as specific andnon-specific radiographic features which should bediffered from other pathological conditions. Since theincidence of genital tuberculosis has been increasedduring the past two decades, the clinicians increasinglyfaced with cases of genital TB and its consequencessuch as infertility, so reviewing of these features areconsidered in differential diagnosis of the causes of infertilityand timing intervention and treatment.


Recent findings from electrophysiology and multimodal neuroimaging have elucidated the relationship between patterns of cortical oscillations evident in EEG/MEG and the functional brain networks evident in the BOLD signal. Much of the existing literature emphasized how high-frequency cortical oscillations are thought to coordinate neural activity locally, while low-frequency oscillations play a role in coordinating activity between more distant brain regions. However, the assignment of different frequencies to different spatial scales is an oversimplification. A more informative approach is to explore the arrangements by which these low- and high-frequency oscillations work in concert, coordinating neural activity into whole-brain functional networks. When relating such networks to the BOLD signal, we must consider how the patterns of cortical oscillations change at the same speed as cognitive states, which often last less than a second. Consequently, the slower BOLD signal may often reflect the summed neural activity of several transient network configurations. This temporal mismatch can be circumvented if we use spatial maps to assess correspondence between oscillatory networks and BOLD networks. It is understood that whereas functional MRI (fMRI) can effectively describe the spatial activation patterns of whole-brain networks, it is limited to measuring the delayed hemodynamic response observed in the blood oxygen level dependent (BOLD) signal. This delay limits its ability to describe rapid changes in neural activity underlying the sequential processing stages inherent to any cognitive task. We can obtain much higher temporal resolution from electroencephalography (EEG), magnetoencephalography (MEG), or electrocorticography (ECoG) data. However, due to limitations on the number and location of feasible electrode placements and to difficulties in measuring signals from sub-cortical regions, these methods do not provide complete whole-brain neural activity measures with a spatial precision equivalent to that of fMRI. The above temporal and spatial limitations can be addressed through studies combining fMRI data with simultaneously recorded EEG data, or with co-registered MEG or ECoG data recorded in separate sessions. To best interpret the results of such multimodal studies, one must understand the relationship between the BOLD signal, neuronal activity at a local level, oscillations in neuronal assemblies, and the large-scale rapid oscillatory networks measurable with EEG, MEG, and ECoG. Here, we describe how cortical oscillations organize post-synaptic potentials and neuronal firing, functionally connecting activity in disparate regions to form the widespread cortical networks observed in the BOLD signal.At the local level, several studies have used invasive techniques to simultaneously record action potentials (APs), BOLD signal strength, and cortical oscillations. It should be noted that the BOLD signal might be expected to correspond less closely to APs measured via single-cell and multi-unit recordings than to local field potentials (LFPs), which reflect post-synaptic potentials summed across large numbers of neurons, because a single fMRI voxel typically contains more than a million neurons  and slow (30–50 Hz) gamma ranges  may organize activity at a local level by integrating some signals while segregating others, and simultaneously coordinate multiple organized local patterns across much greater distances. These multi-frequency patterns provide an optimal explanation for the mechanisms of cognitive processing because they dynamically change at the same pace as cognition.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.


Rapamycin binds with FK- binding protein 12 to inhibit the mechanistic  Target of Rapamycin (mTOR) protein [Rapamycin  is a macrocyclic antibiotic produced by the bacteria in vitro is less pronounced than the Warburg effect in cancer, identifying the cellular metabolism behind fibrosis suggests at potential therapies directed at fibroplasia. Our investigations into fibroblast metabolism and rapamycin's inhibitory effect suggests at a critical link between cellular metabolism and unregulated fibroblast proliferation that could elucidate rational druggable targets to mitigate LTS and fibrosis in general.Fibrosis is the terminal pathological outcome of myriad chronic inflammatory diseases. The process is defined by the excessive accumulation of fibrous connective tissue components of the extracellular matrix  in inflamed tissue . The excmTOR's regulatory role makes the protein a critical node between metabolism and cell proliferation. Environmental factors such as stress and energy influence mTOR, which in turn regulates protein, lipid, and nucleotide biosynthesis, mitochondrial proliferation and function, cell growth and development amongst other cell functions. In fibroblasts mTOR regulates cell kinetics and collagen and other extracellular matrix molecule production. Inhibition of mTOR has been explored in cancer, cardiovascular disease, autoimmunity, and metabolic disorders. In immune cells including T-lymphocytes and macrophages, mTOR subunit inhibition results in reduced metabolism which in turn impacts immune cell activation and function . Based oAlternatively myofibroblasts have been the focus of extensive research in fibrosis, given their role in secreting ECM and collagen along with their fundamental contribution to wound contracture. Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to myofibroblasts. EMT is increasingly recognized as a contributing factor to tissue fibrosis following epithelial injury and a fundamental process involved in carcinogenesis and metastasis. Inhibition of mTOR signaling through rapamycin has been shown to attenuate the process of EMT. This offers additional mechanistic rationale for mTOR inhibition as a therapeutic strategy in human fibrosis.Strong preclinical and human evidence also offers support for the use of rapalogs beyond its effects modulating the end-effectors of fibrinogenesis (fibroblasts & myofibroblasts). In preclinical models, immunocompromised mice exhibit decreased fibrosis during wound repair . T-cell Rapamycin is a Food and Drug Administration (FDA)-approved drug that promotes long term tolerance in organ transplant patients, and is incorporated within coronary stents to reduce restenosis and accelerated arteriopathy. Rapamycin and rapalogs mechanism of action is to bind to FKBP12 to inhibit a subunit protein of mTOR, mTORC1 , 7. FiguOutstanding questions to be addressed include the specific signaling pathway by which rapamycin inhibits fibroplasia, and if more specific targeting of these cellular mechanisms would be effective in treating the disease in the trachea as well as other organs. Future studies will also address therapeutic delivery with sustained topical application ideal to address organ specific fibrosis and avoid side effects associated with systemic administration. Specific to LTS, a rapamycin-eluting stent could assist in suppressing the inflammatory response, fibroblast proliferation, and collagen synthesis seen in LTS while providing structural support of the tracheal wall.


Healthy animals perform better than those that are diseased; therefore there are significant benefits from preventing disease on farm by investigating new vaccine delivery systems. Recently, viral vectors have risen to prominence as candidates for generating immune responses. Of these viral candidates, lentiviruses are attractive as they have the ability to transduce non-dividing antigen presenting cells. For example, lentiviral vectors have been shown to produce an antigen-mediated immune response in mice, providing long term, sterile protection against Malaria.Transformed human embryonic kidney 293T) cells were transfected with four plasmids which encode the various vector components for the production of lentiviral vectors. Vectors produced so far contain an eGFP reporter cassette to facilitate measurement of infectivity by flow cytometry. Self-inactivating (SIN) vectors have been produced to decrease the probability of the generation of replication-competent virus[93T cellsin vitro. Integration deficient vectors appear to have to correct phenotype as eGFP-positive cells decreased over time in dividing cells.Stable expression of antigens is important to a successful vaccine, therefore the stability of ovine lentiviral transduction was evaluated over a 4 week period with eGFP-positive cells measured periodically. 50% of cells remained eGFP-positive after 4 weeks in rapidly dividing cells suggesting a sustained, stable transduction. Ovine lentivirus vectors have the ability to infect a wide range of cell types from different species with similar efficiency to the well characterised murine leukaemia virus (MLV) vector. Self-inactivating vectors with non-active LTRs retain the ability to express transgenes in vitro. Future studies will investigate ovine lentiviral vectors mechanisms of immune response in vitro and study their efficiency to deliver appropriate immunity in vivo.We have created a novel, self-inactivating, integration deficient ovine lentiviral vector which retains the ability to express transgenes


Pulmonary vein stenosis (PVS) is a known complication after catheter ablation of arrhythmias. Surprisingly, little information is available on its manifestations in the lung. We describe the case of a 39-year-old woman who presented from an outside hospital with worsening shortness of breath after catheter ablation of pulmonary veins for atrial fibrillation. After an initial diagnosis of pneumonia and its nonimprovement with antibiotics, a surgical lung biopsy was done and interpreted as nonspecific interstitial pneumonia (NSIP) with vascular changes consistent with pulmonary arterial hypertension. Later, she was admitted to our institution where a transthoracic echocardiogram (TTE) and subsequent computed tomography (CT) angiogram of the heart showed severe stenosis of all four pulmonary veins. The previous lung biopsy was rereviewed and reinterpreted as severe parenchymal congestion mimicking NSIP. Our case demonstrates that PVS is an underrecognized complication of catheter ablation, and increased awareness among both clinicians and pathologists is necessary to avoid misdiagnosis.  A 39-year-old woman with no history of smoking presented with a nine-month history of progressive dyspnea on exertion and dry cough. One month before the onset of symptoms, she underwent a successful cardiac ablation of pulmonary veins for refractory atrial fibrillation. Computed tomography (CT) of the chest was done eight weeks prior to presentation and revealed bilateral scattered ground-glass opacities, diffuse septal thickening, and patchy consolidations in left lung Figures . After fAt admission, she was comfortable at rest, saturating at 92% with clear lungs on auscultation. Repeat imaging showed continued presence of diffuse septal thickening and ground-glass opacities Figures . BecauseSubsequently, her steroids were tapered, and, after we discussed the case with cardiologists at our institution, the patient underwent balloon angioplasty with pulmonary vein stenting . Six weeThe incidence of PVS after catheter ablation for atrial fibrillation ranges from 1% to 3% . Lung paIn conclusion, postablative patients with any pulmonary symptoms should have a high suspicion for PVS. It not only mimics other disease entities clinically and radiographically, but also can mimic other etiologies histologically, as seen with our case. Such delay and misdiagnoses subject patients to erroneous treatment and can cause irreversible secondary pulmonary parenchymal and vasculature changes with poorer outcomes .


Although motivational disturbances are common in schizophrenia, their neurophysiological and psychological basis is poorly understood. This electroencephalography (EEG) study examined the well-established motivational direction model of asymmetric frontal brain activity in schizophrenia. According to this model, relative left frontal activity in the resting EEG reflects enhanced approach motivation tendencies, whereas relative right frontal activity reflects enhanced withdrawal motivation tendencies. Twenty-five schizophrenia outpatients and 25 healthy controls completed resting EEG assessments of frontal asymmetry in the alpha frequency band (8–12 Hz), as well as a self-report measure of behavioral activation and inhibition system (BIS/BAS) sensitivity. Patients showed an atypical pattern of differences from controls. On the EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores did not significantly correlate with BIS/BAS scores or with clinical symptom ratings among patients. The overall pattern suggests a motivational disturbance in schizophrenia characterized by elements of both diminished approach and elevated withdrawal tendencies. Motivational impairment has been linked to schizophrenia since Kraepelin’s inversely related to regional activity. Left frontal activity  is believed to reflect approach motivation, whereas right frontal activity  is associated with withdrawal motivation. These asymmetrical frontal EEG findings are supported by lesion studies, though hemodynamic studies have been less consistent Considerable evidence supports the motivational direction model of asymmetric frontal brain activity Frontal asymmetries assessed in the resting EEG are believed to relate to stable dispositional motivational tendencies. Consistent with this notion, several studies demonstrate associations between degree of lateralization of activation and scores on conceptually related self-report motivational trait measures. For example, in studies using the BIS/BAS scales Frontal asymmetry and motivational tendencies have been examined explicitly in schizophrenia in only two prior studies. One found that recent-onset patients showed more right frontal lateralization  than healthy controls during a two-minute recording with eyes closed The current study assessed both resting frontal EEG asymmetries and self-reported approach/withdrawal tendencies in schizophrenia. The prior literature, though very limited, led to the prediction that patients would show relatively more right frontal lateralization and higher BIS scores than matched healthy controls. We also explored whether frontal asymmetries relate to individual differences on the BIS/BAS and to symptom levels among patients.Twenty-five outpatients with schizophrenia and 25 healthy control subjects participated in this research. Schizophrenia patients were recruited from outpatient treatment clinics at the Veterans Affairs (VA) Greater Los Angeles Healthcare System and through presentations in the community. Patients met criteria for schizophrenia based on the Structured Clinical Interview for DSM-IV Axis I Disorders SCID . None ofHealthy controls were recruited through flyers posted in local newspapers, websites, and posted advertisements. An initial screening interview excluded potential control participants with identifiable neurological disorder or head injury, had schizophrenia or other psychotic disorder in a first-degree relative, or were not sufficiently fluent in English. Potential controls were screened with the SCID and excluded for history of schizophrenia or other psychotic disorder, bipolar disorder, recurrent depression, lifetime history of substance dependence, or any substance abuse in the last 6 months. Potential controls were also administered portions of the Structured Clinical Interview for DSM-IV Axis II Disorders SCID-II  and exclAll SCID interviewers were trained through the Treatment Unit of the Department of Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center (MIRECC) to a minimum kappa of 0.75 for key psychotic and mood items For all patients, psychiatric symptoms during the previous month were rated using the expanded 24-item UCLA version of the Brief Psychiatric Rating Scale BPRS  by a traAll participants completed the BIS/BAS The research design and methods reflect standard procedures for studies of frontal EEG asymmetry Off-line analysis was performed using Brain Vision Analyzer software . All EEG data were re-referenced to the average of the mastoids t-tests and for categorical variables with chi-square tests; descriptive data for clinical symptom ratings in the patient group are also presented. For the main data analyses, group differences in alpha asymmetry scores and self-reported BIS/BAS scores were evaluated with independent samples t-tests. Finally, we evaluated whether asymmetry scores were associated with BIS/BAS scores and symptoms (patients only) using Pearson correlation coefficients within each group.For demographic data, group differences for continuous variables were evaluated with Demographic information for both groups and clinical data for the schizophrenia group are presented in The schizophrenia group had a typical age of onset and was chronically ill. They showed mild to moderate levels of clinical symptoms at the time of testing that are comparable to prior studies of stabilized outpatients Descriptive statistics and results of between-group comparisons are summarized in Although patients had numerically lower mean scores on the secondary index (F8–F7) than controls, the groups did not significantly differ. Finally, for the analysis of the P4–P3 electrodes, there was no significant group difference in parietal asymmetry scores.As shown in Among patients the F4–F3 asymmetry index was not significantly correlated with BIS, BAS, or any of the three BAS subscales . Similarly, for controls, the F3–F4 asymmetry index was not significantly correlated with BIS, BAS, or BAS subscale scores . There were no significant correlations between asymmetry and total symptoms or symptom subscale scores on the BPRS . Results for the correlation analyses were essentially identical using Spearman correlation coefficients.In this first study to evaluate approach and withdrawal motivation in schizophrenia using both self-report and EEG measures, patients showed an atypical pattern of differences from controls. On the resting EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation in the schizophrenia group. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores however, were not significantly correlated with self-reported motivational traits in either group. The overall pattern of group differences converges to suggest a motivational disturbance in schizophrenia characterized by elements of both diminished approach tendencies and elevated withdrawal tendencies.The current between-group motivational differences confirm and extend the few prior studies using either EEG or self-report measure alone. Regarding EEG, the two groups showed opposite asymmetry patterns at mid-frontal sites, the most commonly examined sites in the frontal asymmetry literature The patients’ elevated self-reported scores on the BIS scale, but normal scores on the BAS scales, also converge with the few prior relevant studies in schizophrenia Overall, the current findings suggest that when it comes to understanding motivational factors that hold people with schizophrenia back from pursuing personally relevant goals, it is important to consider multiple processes. Diminished initiation and persistence in goal-directed activities may stem from a lack of desire to pursue potentially rewarding outcomes and/or a strong drive to avoid potentially unpleasant emotions and cognitions associated with efforts to pursue desired outcomes.Results from the current study are not fully consistent with prior studies, in that frontal asymmetry scores did not significantly correlate with symptom levels or with BIS/BAS scores. Regarding symptoms, Jetha et al. We also did not find significant correlations between frontal asymmetry and scores on the BIS/BAS scales in either patients or controls. Such correlations have been reported in some studies in clinical and healthy samples, though a number of studies have failed to find significant correlations, particularly for the BIS scale The current finding of increased withdrawal motivational tendencies in schizophrenia should be interpreted in the context of some limitations. First, this cross-sectional study of chronically ill patients cannot address the question of whether this pattern precedes the onset of schizophrenia or is the consequences of living with a severe mental illness. Although prior research demonstrating the same asymmetry pattern is present in recent-onset patients and that asymmetry scores show good longitudinal stability in schizophrenia is consistent with the notion that elevated right frontal lateralization reflects an enduring trait that is present from at least the early post-onset period Although the approach and withdrawal motivational framework has been extensively studied in internalizing and externalizing disorders, the current findings suggest it may be informative for understanding motivational disturbances in the psychosis dimension of psychopathology as well. The framework has treatment implications for schizophrenia patients with elevated withdrawal motivation. For example, CBT, emotion regulation, and mindfulness interventions that target symptoms such as anxiety and hyper-arousal may be useful for these individuals, and frontal asymmetries have been found to provide an informative biomarker in the context of these types of treatment studies Data S1(SAV)Click here for additional data file.


Hypertrophic cardiomyopathy (HCM) with midventricular hypertrophy is an uncommon phenotypic variant of the disease. Midventricular hypertrophy predisposes to intracavitary obstruction and downstream hemodynamic sequelae.We present a case of HCM with midventricular hypertrophy and obstruction diagnosed after a CT scan of the abdomen incidentally revealed a filling defect in the left ventricular apex. Transthoracic echocardiography demonstrated mid left ventricular hypertrophy and obstruction, as well as an aneurysmal apex containing a large thrombus. Cardiovascular MRI showed a spade-shaped left ventricle with midcavitary obliteration, an infarcted apex and regions of myocardial fibrosis. Due to the risk of embolization and a relative contraindication to anticoagulation, the patient underwent surgery including thrombectomy, septal myectomy and aneurysmal ligation.Hypertrophic cardiomyopathy with midventricular hypertrophy leads to cavity obstruction, increased apical wall tension, ischemia and ultimately fibrosis. Over time, patchy apical fibrosis can develop into a confluent scar resembling a transmural myocardial infarction in the left anterior descending coronary artery distribution. Aneurysmal remodeling of the left ventricular apex potentiates thrombus formation and risk of cardioembolism. For these reasons, hypertrophic cardiomyopathy with midventricular obstruction portends a particularly poor prognosis and should be recognized early in the disease process. Hypertrophic cardiomyopathy is defined as a myocardial disease characterized by unexplained left ventricular hypertrophy in association with non-dilated ventricular chambers . The dis2) status-post gastric bypass surgery over ten years prior to presentation was admitted for evaluation of an upper gastrointestinal bleed. Postoperatively following gastric bypass surgery, the patient became hemodynamically unstable and developed acute kidney injury. Although her renal function improved, the underlying etiology of her postoperative complications remained unknown. An abnormal electrocardiogram noted several years later suggested a prior myocardial infarction, retrospectively hypothesized incurred perioperatively. The abnormal electrocardiogram prompted invasive coronary angiography which showed no evidence of obstructive coronary artery disease. During the current admission for upper gastrointestinal bleeding, an abdominal CT scan with intravenous contrast serendipitously revealed a filling defect in the left ventricular apex. Transthoracic echocardiography confirmed the presence of a large, heterogeneous apical mass and additionally showed midventricular hypertrophy measuring 20 mm in the interventricular septum, resulting in systolic apposition of the midventricular segments  with midcavity hypertrophy , a measured ejection fraction of 65% and an aneurysmal apex , oxygen supply-demand mismatch, ischemia and ultimately infarction and fibrosis. Patients with HCM also have abnormally thickened intramural arteries with decreased luminal size . CoupledThe increasingly utilized CMR technique of native T1 mapping characterizes myocardium based on quantitative T1 relaxation times, altered by the presence of fibrosis, without the need for intravenous gadolinium contrast agent. Increased T1 relaxation times in hypertrophic cardiomyopathy correlate with abnormalities in left ventricular systolic function even in the absence of late gadolinium enhancement . In the Patients with HCM and midventricular obstruction may exhibit a characteristic echocardiographic Doppler pattern of blood flow in the left ventricle . Due to This morphological variant of HCM deserves clinical recognition. In a Japanese study  of 490 cMaron et al.  have queHypertrophic cardiomyopathy with midventricular hypertrophy and obstruction is a relatively uncommon variant of HCM that may lead to an infarcted apex and aneurysm formation. Mid ventricular obstruction with apical aneurysm formation predisposes to thrombus formation and portends a poor prognosis. Repercussions of aneurysm formation included ventricular arrhythmias, thromboembolism, predisposition to end stage disease and death. Physicians should be aware of this variant and consider these patients to be at higher risk when making management decisions.


Iron oxide nanoparticles (IONPs) are frequently used for biomedical applications including magnetic resonance imaging, drug delivery or tumor treatment by hyperthermia. Since IONPs can reach the brain from periphery or are directly applied into the brain, the investigation of potential adverse effects of IONPs on properties and functions of the different types of brain cells is an important task. In order to directly compare different types of brain cells concerning the uptake and toxicity of IONPs, we synthesized fluorescent IONPs and characterized these BODIPY-labeled particles regarding their physicochemical properties. In the medium used for the cell studies, these particles had a hydrodynamic diameter of around 158 ± 28 nm and a negative surface charge with a zeta-potential of -10 ± 2 mV. Exposure of primary cultures of rat astrocytes, neurons and microglial cells revealed that among these cell types, microglial cells accumulated IONPs most rapidly. However, microglial cells were also most vulnerable towards acute IONP-induced stress while astrocytes and neurons were not acutely damaged by IONPs. In microglial cells, but not in astrocytes or neurons, IONPs were found to be localized in lysosomes and large amounts of reactive oxygen species (ROS) were observed after IONP-exposure. The IONP-induced toxicity in microglial cells was prevented by neutralizing lysosomes or by chelation of intracellular ferrous iron ions, suggesting that the toxic potential of IONPs in microglia involves rapid particle uptake, liberation of ferrous iron from the internalized IONPs in the acidic lysosomal compartment and iron-catalyzed ROS formation. These data suggest that also in brain IONPs may harm microglial cells and compromise microglial functions.


Abnormal accumulation of cytosolic aggregates or inclusion bodies is a hallmark of several neurodegenerative diseases. Many common or specific molecular components such as ubiquitin, α-synuclein, TDP-43, or tau in neuronal cytosolic inclusion bodies have been identified as being associated with cellular pathogenic mechanisms of disease. Recently, stress granule (SG) marker proteins such as PABP and G3BP were found in cytosolic inclusion bodies of patients with frontotemporal lobar dementia (FTLD), alzheimer's disease (AD), or amyotrophic lateral sclerosis (ALS), suggesting that inappropriate SG dynamics contribute to pathogenic mechanisms . MoreoveFUS mutations [atg7 siRNA increased the number of SGs, whereas activation of autophagy reduced SG accumulation. Further analysis showed that mutant FUS-positive SGs were regulated by autophagy regulation in post-mitotic neurons. Most importantly, autophagy activation reduced mutant FUS-positive SG accumulation as well as mutant FUS-mediated neurite fragmentation and cell death in response to oxidative stress in disease-associated cultured neurons, suggesting a role for persistent SGs in neurodegeneration as well as involvement of autophagy in ALS-linked SG regulation. However, this finding needs to be confirmed in transgenic animal models and patients with specific iPSC-derived neurons associated with persistent SGs and SG aggregates [To address these questions, our study investigated the role of autophagy, which controls the quality of proteins or organelles, in the regulation of ALS-linked SGs and neurodegeneration in disease-associated cultured neurons . Fused iutations . Interesgregates .Our study provides important insights into the roles of autophagy and disease-associated SGs in neurodegeneration. SGs are generally considered as a defense mechanism in neurons under stress conditions. However, persistent SGs in neurons might actually inhibit protein translation by sequestering mRNA and RNA-binding proteins, which are normally involved in transcriptional regulation in the nucleus or transport of mRNAs into dendrites/axons. Therefore, persistent SGs can lead to accumulation of toxic components/loss of essential components even after stress. According to our unpublished data, mutant FUS sequesters mRNAs that are involved in neuronal integrity into persistent SGs, which induces neurite fragmentation/shrinkage caused by oxidative stress in cortical neurons.atg5−/− MEFs causes SG formation/accumulation without any stress, suggesting that cellular homeostasis of SGs is tightly associated with autophagy. During normal aging or disease progression in the brain, dysregulated or insufficient autophagy combined with environmental factors such as acute or chronic stresses may accelerate SG formation and development of persistent SGs into larger cytosolic inclusions, leading to increased stress vulnerability in neurons as well as neurodegeneration.Moreover, our studies have shown that autophagy deficiency in However, the following questions remain to be answered in the context of autophagic regulation of SGs in physiology and pathology: How do cells regulate and harmonize formation/disassembly/autophagic degradation of SGs in response to different stresses in physiology and pathology? Which signals induce autophagic clearance of physiological or pathological SGs as opposed to disassembly of SGs or fusion with P-bodies? How are transient or persistent SGs recognized by autophagy machineries? What is the specific role of autophagy in regulation of SGs in relation to neuronal RNA granules such as P-bodies or transporting RNA granules in polarized neurons? More detailed studies are needed to elucidate autophagic regulation of SGs. Therefore, future efforts will provide novel opportunities for therapeutic intervention by targeting regulation of SGs via manipulation of the autophagic pathway in several neurodegenerative diseases associated with SGs such as ALS .


Odorant Receptor genes). To identify whether shifts in pheromone composition among related lineages of orchid bees are associated with divergence in chemosensory genes of the olfactory periphery, we searched for patterns of divergent selection across the antennal transcriptomes of two recently diverged sibling species Euglossa dilemma and E. viridissima.Insects rely more on chemical signals  than on any other sensory modality to find, identify, and choose mates. In most insects, pheromone production is typically regulated through biosynthetic pathways, whereas pheromone sensory detection is controlled by the olfactory system. Orchid bees are exceptional in that their semiochemicals are not produced metabolically, but instead male bees collect odoriferous compounds (perfumes) from the environment and store them in specialized hind-leg pockets to subsequently expose during courtship display. Thus, the olfactory sensory system of orchid bees simultaneously controls male perfume traits (sender components) and female preferences (receiver components). This functional linkage increases the opportunities for parallel evolution of male traits and female preferences, particularly in response to genetic changes of chemosensory detection .We identified 3185 orthologous genes including 94 chemosensory loci from five different gene families . Our results revealed that orthologs with signatures of divergent selection between Our results suggest that rapid changes in the chemosensory gene family occurred among closely related species of orchid bees. These findings are consistent with the hypothesis that strong divergent selection acting on chemosensory receptor genes plays an important role in the evolution and diversification of insect pheromone systems.The online version of this article (doi:10.1186/s12862-015-0451-9) contains supplementary material, which is available to authorized users. Olfaction allows animals to perceive volatile chemicals from the environment and is therefore essential for the detection and discrimination of food resources, predators, and conspecifics in a diverse array of taxa , 2. In iOstrinia nubilalis, has shown that divergence in pheromone recognition might be best explained by nucleotide substitutions in pheromone receptor genes .


Historically, the catheter peak-to-peak pressure gradient (PPG) has been used as the diagnostic gold standard to evaluate the degree of pulmonary outflow tract obstruction in congenital heart disease (CHD) and was employed to decide when to intervene. Today, estimated maximal Doppler gradients are generally decisive. Cardiovascular phase contrast magnetic resonance (PCMR) measurements are frequently performed during routine follow-up. However, it remains unclear how to deal with PCMR flow velocities that can also serve for the estimation of pressure gradients.In 75 patients with pulmonary outflow tract obstruction maximal and mean PCMR gradients were compared to maximal and mean Doppler gradients. Additionally, in a subgroup of 31 patients maximal and mean PCMR and Doppler pressure gradients were compared to catheter PPG.Maximal and mean PCMR gradients underestimated pulmonary outflow tract obstruction as compared to Doppler . However, in comparison to catheter PPG, maximal PCMR gradients and mean Doppler gradients revealed best agreement . Mean PCMR gradients underestimated, while maximal Doppler gradients systematically overestimated catheter PPG .Estimated maximal PCMR pressure gradients and mean Doppler gradients from routine CHD follow-up agree well with invasively assessed PPG. There is evidence to either apply maximal PCMR gradients or mean Doppler gradients  to evaluate the severity of pulmonary outflow tract obstruction during follow-up of CHD.N/A.


Gradually increasing prosthetic ankle stiffness influenced the shape of the prosthetic ankle plantarflexion moment, more closely mirroring the intact ankle moment. Increasing ankle stiffness also corresponded to increased prosthetic ankle power generation  and increased braking ground reaction forces of the amputated leg. These findings further our understanding of how to deliver assistance with powered knee-ankle prostheses and the compensations that occur when specific aspects of assistance are added/removed.Powered knee-ankle prostheses are capable of providing net-positive mechanical energy to amputees. Yet, there are limitless ways to deliver this energy throughout the gait cycle. It remains largely unknown how different combinations of active knee and ankle assistance affect the walking mechanics of transfemoral amputees. This study assessed the relative contributions of stance phase knee swing initiation, increasing ankle stiffness and powered plantarflexion as three unilateral transfemoral amputees walked overground at their self-selected walking speed. Five combinations of knee and ankle conditions were evaluated regarding the kinematics and kinetics of the amputated and intact legs using repeated measures analyses of variance. We found eliminating active knee swing initiation or powered plantarflexion was linked to increased compensations of the ipsilateral hip joint during the subsequent swing phase. The elimination of knee swing initiation or powered plantarflexion also led to reduced braking ground reaction forces of the amputated  The number of individuals with lower-limb amputations living in the U.S. is projected to grow dramatically , and comand ankle joints affect the walking mechanics of amputees. This is especially true when examining outcomes in transfemoral amputees and during overground walking. Interesting prior studies have sought to emulate autonomous prosthetic systems with externally-powered devices and treadmill-based test beds to answer some of these questions regarding the plantarflexive assistance occurring during the mid- to late stance phase of walking  are comg . While and ankle assistance influence the walking mechanics of transfemoral amputees. With the rapid advances in powered prosthetic hardware and the encouraging prior studies that demonstrate the potential benefits of these devices [Little is known about how combinations of knee  devices , 27, theThree male subjects with unilateral amputations at or above the knee . Repeated trials were conducted until five clean force plate contacts were captured for both amputated and intact legs. Ground reaction force (GRF) and kinematic data  were collected using an eight-camera motion capture system . For each subject, reflective markers were placed on the posterior sacrum and bilaterally on the posterior superior iliac spine (PSIS), anterior superior iliac spine (ASIS), greater trochanter, lateral and medial femoral epicondyle, lateral and medial malleolus, posterior heel, dorsal foot, and fifth metatarsal head. Clusters of three markers affixed to thermoplastic shells were wrapped bilaterally to the thigh and shank.τ, at the knee and ankle joints as a function of three impedance parameters: joint stiffness, k, equilibrium angle, θe, and damping coefficient, b, according to i corresponded to the knee or ankle joint, θ was the joint angle and Subjects wore a powered knee and ankle prosthesis featuring on-board mechanical sensors, including sensors to measure knee and ankle position and velocity, as well as axial load applied through the shank . Sensor xtension . TransitTo provide knee swing initiation, the prosthesis knee equilibrium angle was increased from 0° to 60–75° flexion (ranged across subjects) during terminal stance as a linear function of decreasing prosthesis vertical load ; the stiSpatiotemporal, kinematic and kinetic data were analyzed using Visual3D  and Matlab . Kinematics were segmented from heel contact to heel contact; kinetic data were segmented from heel contact to toe-off (stance phase) and toe-off to heel contact (swing phase), and normalized to body mass (kg). All data were low-pass filtered and averaged across strides. Average peak values were calculated for joint kinematics. Average positive and negative values were calculated for GRF and joint kinetics during stance, and also calculated for joint kinetics during swing. To provide objective comparisons of these metrics across all conditions, across-subject statistics were performed . For each quantity, two analyses of variance with repeated measures (ANOVAs) were evaluated (α = 0.05). One two-way ANOVA tested the effects of powered plantarflexion and increasing ankle stiffness. The second tested the effect of swing initiation. Post-hoc tests using a Bonferroni correction factor were used to identify differences between conditions.Increasing ankle stiffness had a significant effect on stance time of the intact leg (p = 0.02), with a trend toward reduced stance time. There were no differences in step length, step time, swing time, overall cycle time, walking speed, stride length, or stride width for either amputated or intact legs .amputated leg was affected by increasing ankle stiffness (p = 0.023) and powered plantarflexion  of the Powered plantarflexion had a significant effect on the peak stance phase knee flexion angle of the intact leg (p = 0.002), with a trend toward less knee flexion with powered plantarflexion. Knee swing initiation increased peak knee flexion of the amputated leg in swing , and powered plantarflexion and increasing ankle stiffness had a significant interaction effect on average positive hip power , knee flexion moment (p = 0.043), and ankle plantarflexion moment , were decreased and others increased. We found in the absence of knee swing initiation, these transfemoral amputees compensated by reducing the braking  ground reaction force of the intact leg . This fien shown . In thisintact leg also occurred with a lack of powered plantarflexion in the presence of knee swing initiation  the knee extension moment in early stance, irrespective of ankle stiffness . While many studies have been focused on reducing the metabolic cost of amputee walking by providing assistance at the ankle joint exclusively, this investigation reveals that the synchronization of ankle and knee power in late stance and monitoring how these changes influence kinetics of proximal joints and joints of the intact leg may be especially important to resolve the increased metabolic cost of amputee walking. Finally, based on the biomechanical outcomes evaluated in this study, when fitting elderly patients or other patients at risk of exhibiting gait instability or sustaining fall-related injuries with active knee-ankle prostheses, control strategies that deliver both active knee and ankle assistance may prove to be detrimental. Powered plantarflexion and knee swing initiation were shown to increase braking ground reaction forces relative to conditions that did not provide these functions, which would likely influence stability in the sagittal plane. Thus, hybrid solutions which selectively deliver active knee or ankle assistance could be beneficial. These implications are subjective, and we also understand that individual patient needs could be coupled and be presented simultaneously. Thus, as mechanically-active devices become more commonplace, studies which comprehensively identify how specific aspects of active knee and ankle control influence the biomechanics of locomotion are likely to become increasingly important.


Mucormycosis is an invasive mycotic disease caused by fungi in the zygomycetes class. Although ubiquitous in the environment, zygomycetes are rarely known to cause invasive disease in immunocompromised hosts with a high mortality even under aggressive antifungal and surgical therapy. Clinically, mucormycosis frequently affects the sinus occasionally showing pulmonary or cerebral involvement. However skeletal manifestation with Rhizopus microsporus (RM) osteomyelitis leading to emergency surgical proximal femoral resection with fatal outcome has not been described yet.We report the case of a 73-year-old male suffering from myelodysplastic syndrome with precedent bone marrow transplantation. Six months after transplantation he consulted our internal medicine department in a septic condition with a four week history of painful swelling of the right hip. Radiography, computed tomography and magnetic resonance imaging revealed multiple bone infarcts in both femurs. In the right femoral head, neck and trochanteric region a recent infarct showed massive secondary osteomyelitis, breaking through the medial cortex. Emergency surgical proximal femoral resection was performed due to extensive bone and soft tissue destruction. Microbiological and basic local alignment search tool (BLAST) analysis revealed RM. Amphotericin B and posaconazole treatment with septic revision surgery was performed. However the disease ran a rapid course and was fatal two months after hospital admission.This alarming result with extensive RM osteomyelitis in the proximal femur of an immunocompromised patient may hopefully warn medical staff to perform early imaging and aggressive surgical supported multimodal treatment in similar cases.The online version of this article (doi:10.1186/1471-2334-14-488) contains supplementary material, which is available to authorized users. Zygomycetes are environmental nonseptate molds widely distributed in soil, plants, and decaying material , 2. The Previously reported risk factors for mucormycosis are prolonged neutropenia, immunosuppression, iron overload and prolonged hyperglycemia or manifest diabetes. Patients treated with allogeneic hematopoietic stem cell transplantation  often suffer from a combination of these risk factors . The proHere we describe the unique case of fatal invasive osteomyelitis in an allo-HSCT recipient caused by RM. Extensive diagnostic evaluation revealed multiple old bone infarcts complicated with invasive fungal disease. Although systemic antifungal treatment and repetitive radical surgery was started immediately cure could not be provided.We report on a 73-year-old male with recently diagnosed myelodysplastic syndrome RAEB I showing complex karyotype. A routine-checkup revealed a tricytopenia in the blood count as well as a mild splenomegaly, further examinations including bone marrow biopsy confirmed the diagnosis. Facing the high-risk constellation of this disease  and theEleven months later allogeneic matched unrelated donor stem cell transplantation after conditioning chemotherapy with fludarabine, treosulfane as well as antithymocyte globuline and prophylactic immunosuppressive medication containing of cyclosporine and mycophenolatmofetile was performed successfully. No relevant complications occurred during the first weeks of follow-up besides moderate acute graft versus host disease of the skin which was immediately responsive to steroid treatment. Bone marrow examinations one month after transplantation showed complete cytogenetic remission of the disease as well as complete donor chimerism. With no further signs of graft versus host disease and a good clinical condition of the patient the immunosuppressive treatment could be constantly tapered during the following months. Continuous prophylactic antiinfectious medication with acyclovir, co-trimoxazole and posaconazole was administered.Six months after transplantation without remaining medication the patient was presented to our internal emergency department with a critical septic condition showing fever (body temperature above 40°C) and dyspnea, and was immediately transferred to the intensive care unit (ICU). Intubation and mechanical ventilation had to be initiated due to respiratory failure. Computed tomography (CT) scan revealed bilateral infiltrations referring to atypical pneumonia and regional osteopaenia with mild focal bone lysis at the level of the lumbar spine. Lumbar spondylodiscitis was ruled out by magnetic resonance tomography imaging (MRI).No relevant bacterial, viral or fungal cause could be identified by bronchoalveolar lavage and multiple blood culture collections during the stay on the ICU. Cardiac echocardiography was performed and culture-negative endocarditis could be ruled out. The patient constantly improved under combinatory empiric antibiotic, antiviral and antifungal (azole) medication, extubation could be performed 7 days after intubation. While the respiratory situation completely stabilized, the clinical condition of the patient constantly deteriorated in the following days. For the first time the patient reported right hip pain.In consequence ultrasound, CT and MRI of the right hip and thigh were performed in order to identify and localize a potential inflammatory focus. The imaging revealed multiple old bone infarcts in both femurs as well as a new infarct with massive secondary osteomyelitis in the right femoral head, neck and trochanteric region, breaking through the medial cortex into the surrounding soft tissue Figure . With emInvasive disseminated Rhizopus-infections develop in fewer than ¼ of localized forms and have an estimated mortality rate of 78–100% in allo-HSCT recipients [Immunocompromised patients, particularly suffering from hematological diseases treated by allo-HSCT face a high risk of invasive fungal infections . InvasivCompared to focal RM fungal infections disseminated infections are even more seldom , 13, 14.Mucormycosis spreads from isolated infection hematogenously to other organs. The most common sites of origin are sinuses (39%), lungs 24%), and skin (19%) 4%, and s. DissemiFurthermore establishing the diagnosis of invasive fungal infections, primarily based on standard culture-based mycological methods is often difficult, especially in early stages . AccordiTherapy for mucormycosis infections includes systemic antifungal drugs and local surgical debridement . RegardiThis dramatic case of rapidly progressive and ultimately fatal RM infection of the bone illustrates the diagnostic and therapeutic challenges of mucormycosis in immunocompromised hosts. Amongst others, abscess formations should always be suspicious of invasive fungal infection under these circumstances. Rapid and exact diagnosis by both morphology and molecular techniques is crucial for starting early treatment of fungal infection. Amphotericine B should be used as soon as mucormycosis is suspected. If the patient’s condition is not improving, addition of posaconazole should be considered. At the same time, early and aggressive surgical debridement has to be performed first to detect the pathogen and second to establish local control. Comprehensive multimodal therapy for mucormycosis may create more opportunities to improve patient’s outcome despite the very low overall survival rate in disseminated cases.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.


A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient. In humans, ANCA associated systemic vasculitides clinically range from microscopic polyangiitis to granulomatosis with polyangiitis  to eosinophilic granulomatosis with polyangiitis . The systemic vasculitides mainly involve small vessels of the lungs and kidneys, causing compromised lung function and rapid progressive renal failure –4. ConveA 64-year-old male had progressive dyspnea over six-month duration. The patient had a history of asthma but never smoked. A recent cardiac evaluation included normal echocardiogram and stress test. Computerized tomography (CT) chest imaging without contrast revealed bilateral mild ground-glass opacities in the lungs, slightly greater within the middle and lower lobes on the right side, suggestive of mild interstitial lung disease. He was found to have positive serum p-ANCA at titer of 1 : 640 while the antiglomerular basement membrane antibody was negative. His serum test for myeloperoxidase was positive at greater than 8 units  while his serum level of proteinase-3 was negative. Wedge lung biopsies from the right upper, middle, and lower lobes were performed to reveal red to purple color from pleural surface and red color on the cross sections grossly. Microscopically, the biopsies mainly revealed diffuse hemorrhage and hemosiderosis  Figures , but no The patient's renal biopsy showed cellular crescents in 3 of 12 glomeruli and focal fibrinoid vasculitides in a small artery Figures  with milPulmonary hemosiderosis indicates chronic hemorrhage, as iron positivity is identified in hemosiderin-laden macrophages. Traditionally, the differential diagnosis for diffuse pulmonary hemosiderosis includes idiopathic pulmonary hemosiderosis versus Goodpasture's syndrome, which is supported by a positive test for antibasement membrane antibody , 16. GooUnlike Goodpasture's syndrome with one positive antibody and one main finding of pulmonary hemorrhage and hemosiderosis, ANCA associated vasculitis can range from microscopic polyangiitis to granulomatosis with angiitis and eosinophilic granulomatosis with polyangiitis in lung biopsies. Pathologic morphology of ANCA associated microscopic polyangiitis in lung biopsies is not well established , 9, but In summary, a positive ANCA test is an additional serology biomarker suggestive of systemic vasculitis. The criteria for ANCA associated variants of pulmonary vasculitis should be further investigated beyond traditional morphologic findings, which were established many years before ANCA test was discovered. The animal model of ANCA associated systemic vasculitides appears coupled with our findings after the current correlation between the lung biopsy and renal biopsy, implying that microscopic polyangiitis should be on the top differential diagnosis when diffuse pulmonary hemorrhage and hemosiderosis are the main findings in ANCA-positive patients.


About 90% of mortality associated with cancer is attributable to metastatic disease. Thus, our ability to treat cancer is largely dependent on the capacity to prevent metastasis. Metabolic reprogramming is recognized to support cellular transformation and tumor initiation; however, whether or how metabolism supports metastasis remains an open question. This study seeks to identify metabolic predictors of metastasis, with the rationale that understanding metabolic changes will lead to novel insights into metastasis and perhaps new therapies to treat metastatic disease.A patient-derived xenograft model was used in which metastasis in mice strongly correlates with metastatic history of patient donors. Tumor cells were originally obtained from melanoma patients and passaged exclusively in highly immunocompromised mice . In thisUnsupervised hierarchical clustering revealed that in every case, a given tumor biopsy was most closely related to all other biopsies descended from the same parental tumor. In addition, as a frequent mutation in melanoma, BRAF-mutant tumors were easily distinguished from BRAF-wild type tumors by their metabolomic signatures. More importantly, several metabolic pathways were found altered significantly when metabolomics profiles between melanoma lines with high or low metastatic potentials were compared.The MS-based metabolomic analysis of patient-derived melanoma xenografts demonstrates that tumors contain individual metabolomic identities that can be tracked. It may be possible to identify metabolomic features from primary tumors that predict various aspects of tumor biology, including the propensity to metastasize. The altered metabolic pathways in highly metastatic melanomas are potential therapeutic targets.


Depression and anxiety disorders are characterized by complex and idiopathic etiologies. One prominent hypothesis, termed “the neurogenesis hypothesis,” posits that stress-induced decreases in hippocampal neurogenesis underlie depressive episodes , the other brain structure that integrates new neurons in the adult mammalian brain, remains unspecified. Subventricular zone (SVZ) neuroblasts migrate to the OB along the rostral migratory stream (RMS). Chronic stress affects this migration  within the olfactory epithelium or OB sensory afferentation (OMP+ cells), suggesting deficits in odor processing rather than detection. Corticosterone administration decreased cell proliferation in the dentate gyrus (DG), but did not affect cell proliferation in the SVZ. These data suggest a different mechanism by which corticosterone affects neuroblasts destined for the OB. To investigate this, survival of newly born neurons maturing in the DG and OB was examined. Glucocorticoids decreased cell survival in both regions; this effect was prevented by co-administration of FLX. Additionally, dendritic complexity of newly integrated neurons increased following FLX administration, potentially contributing to the partially rescued phenotype. Taken together, these results link major depressive disorder and neurogenesis-dependent olfactory deficits within the DG and OB. Understanding the implications of impaired olfactory function and neurogenesis in depressed humans warrants further investigation; additional mechanisms by which glucocorticoids modulate neurogenesis and functional synapse formation should be examined.A new study Siopi et al.  provides+) in the SVZ and OB relative to psychiatrically healthy people (Maheu et al., + cells in the SVZ was reduced without simultaneous reductions in the OB. These data suggest that impaired migration and ectopic differentiation leads to neuroblast accumulation in the OB of unmedicated depressed individuals. Antidepressant treatment facilitates neuroblast migration out of the SVZ, but cells that differentiated ectopically prior to treatment persist (Maheu et al., The translational significance of these new data is worth considering in the context of vast species differences in rates of olfactory neurogenesis and reliance on olfaction. Rodents rely more heavily on olfaction than humans, and neurogenic rates in the OB are minimal in adult humans (Kam et al., Although stress-induced increases in glucocorticoids directly regulate neurogenesis, immune cells are also responsible for maintenance of the neurogenic niche (Ziv et al., In sum, Siopi and colleagues suggest that chronic elevated glucocorticoids reduce hippocampal and olfactory neurogenesis, leading to depressive-like states and impaired olfactory function Figure . FluoxetAll authors contributed equally to the writing and review of this manuscript.JB is supported by an OSU Presidential and Pelotonia pre-doctoral fellowship. YC was supported by National Institute of Dental and Craniofacial Research Grant T32DE014320.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.


Dear Editor,Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats . In this


Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy. Invasive fungal infections lead to significant morbidity and mortality in patients who are undergoing allogeneic stem cell transplantation (ASCT) –3. TreatA 58-year-old woman with intermediate risk acute myeloid leukemia in first complete remission underwent ASCT from an HLA-matched sibling. Her initial induction was complicated by hypoxia, pulmonary infiltrates, and fevers despite broad-spectrum antibiotics. She was treated with voriconazole with clinical improvement and was presumed to have invasive fungal infection. Voriconazole was continued throughout her transplant course given persistent chest CT abnormalities.At day 79 after ASCT, the patient complained of swelling in her left middle finger. Physical examination revealed discrete tender swelling of the middle phalanx on the third finger. This continued to worsen and one month later she was complaining of further swelling involving the fourth finger . In addiVoriconazole is a triazole antifungal that is indicated for the treatment of invasive aspergillosis. Common adverse effects include visual disturbances, hallucinations, QT prolongation, and hepatotoxicity. With prolonged use however, newly described adverse effects, including periostitis, alopecia, and development of skin cancers, have been noted . PainfulMost cases of voriconazole-induced periostitis have been reported in patients who have undergone solid organ transplantation –7. Few cThe clinical presentation and radiologic findings of patients who develop voriconazole-induced periostitis are nonspecific and insidious and may be confused with rheumatologic or endocrinologic disorders. In the setting of ASCT, symptoms may mimic cGVHD. Prior cases reported in the ASCT setting were also treated with corticosteroids for cGVHD, resulting in temporary symptom relief and a delay in discontinuing voriconazole –11. In oGiven that long-term voriconazole therapy is increasingly common, clinicians managing ASCT patients should be aware of this complication. We recommend periodic measurement of ALP and fluoride levels in patients on prolonged voriconazole therapy. In patients on voriconazole who report nonspecific musculoskeletal complaints following ASCT, drug-induced periostitis should be included in the differential diagnosis along with cGVHD.


Arthroscopic treatment of these disordersproduces more favourable results than open procedures.We report two patients who were not responding toconservative management and were treated with directarthroscopic distal clavicle excision and subacromialdecompression in single setting. Both patients gained goodpostoperative outcome in terms of pain score, function andstrength improvement assessed objectively with visualanalogue score (VAS) and University of California LosAngeles Score (UCLA).Shoulder impingement syndrome and acromioclavicularjoint osteoarthritis often occur simultaneously andeasily missed. Kay et al. reported excellent results withcombined arthroscopic subacromial decompression andresection of the distal end of the clavicle in patients withboth disordersAcromioclavicular joint arthritis, distal clavicle excision,Arthroscopy, Mumford operation. Resection of the distal clavicle, as described byMumford 2, is a reliable surgical option in acromioclavicularjoint (ACJ) osteoarthritis and shoulder impingementsyndrome. Symptom improvement has been satisfactory inmost reported series. Historically, distal clavicle resectionhas been performed using an open incision over the ACJ withdetachment of the deltoid and trapezius muscles. Significant morbidity may follow with these open procedures. Woundinfection, residual acromioclavicular joint instability,cosmetically unacceptable scar, postoperative shoulderweakness and stiffness are among the common complicationsreported from these open procedures 3.Symptomatic acromioclavicular osteoarthritis and distalclavicle osteolysis can be treated effectively with both nonoperativeand operative means. Non-operative treatmentsincluding physiotherapy, non-steroidal anti-inflammatorydrugs (NSAIDS) and corticosteroid injection may help torelieve the symptoms. However, surgical Patient OneAn active 64 year old lady with no previous history of traumawas referred for evaluation of persistent anterosuperiorleft shoulder pain for one year. The pain worsened whenshe tried to reach across the body or behind the back. Shealso experienced discomfort with rotational and overheadmovements of the left shoulder. Physical examinationrevealed tenderness over the left acromioclavicularjoint. Cross body adduction and active compression testsreproduced the symptoms at the acromioclavicular joint.Neer and Jobe impingement tests were positive. Plainradiographs revealed osteoarthritis of acromioclavicularjoint with narrowing of joint space The patient was put on beach chair position. Through astandard posterior portal, the arthroscope was insertedto screen for underlying pathology. Meanwhile, anotheranterior portal was made via outside in technique withspinal needle, in line with the AC joint (to facilitate the AC joint resection later). Osteophytes were shaved throughthe anterior portal first, and then switched to posteriorportal for bursectomy as this facilitated subacromialspace viewing and subacromial decompression. Lateralportal was created with spinal needle, 3cm to the lateral of acromion edge. By viewing the scope from the lateralportal, resection of inferior part of AC joint was performeddirectly from the anterior portal. Further resection of ACjoint, especially at the superior edge was achieved withthe 70-degree scope to shave from anterior portal. Using the 70-degree scope from the standard lateral portal andalso posterior portal, the entire AC joint could be viewedin detail which helped preserving the superior capsule andligament. Finally, we switched the scope to the anteriorportal for final checking for remnants of osteophytes anddistal clavicle.Postoperative, patient went through standard rehabilitationprotocol, with early range of movement exercises from dayone postoperatively. The shoulder was protected with armsling for 7 to10 days. The patient returned to her normalactivities at six weeks following surgery. Both VAS andUCLA scores showed improvements compared withpreoperative findings. During follow up at six months, sheremained pain free and achieved full range of movementsof the shoulder without impingement signs Patient TwoA 54 year old male presented with a 4 year historyof gradually worsening right anterosuperior shoulderpain. He had a history of a motor vehicle accident in2009, sustaining direct trauma to his right shoulder.Arthroscopic debridement had been carried out in 2010but the pain was only partially relieved. The patient hadsought to relieve his pain with anti-inflammatory drugs,corticosteroid injection and physiotherapy but to littleavail. Patient had limited range of movement of the rightshoulder especially adduction. He experienced difficultyreaching for his wallet and tucking his shirt behind his back. Physical examination revealed healed previousarthroscopic portals. Positive tests included cross-bodyadduction and active compression, with pain locatedspecifically at the acromioclavicular joint. There was noevidence of impingement signs or glenohumeral instability.Standard radiographs demonstrated maintenance of theacromioclavicular joint space, but marked hypertrophicdegenerative changes Postoperative radiographs demonstrated adequate boneresection and no obvious translation of the clavicle relativeto the acromion 4.Arthroscopic resection of the distal clavicle andsubacromial decompression can avoid complicationsarising from the open method. Preserving the posteriorand superior aspects of the acromioclavicular capsuleavoids creating iatrogenic distal clavicular anteroposteriorinstability. Moreover, arthroscopic excision provides theadvantage of evaluating glenohumeral joint at the time ofsurgery. Other shoulder joint pathology such as rotator cuffdisease, loose bodies, labral tears and chondral injurieswill not be missed. Hence, there will be only a singleprocedure needed to solve the patient’s shoulder problems.Arthroscopic subacromial decompression and arthroscopicresection of the acromioclavicular joint as separateprocedures have been well documented. However, there islittle documentation on the success rate of resection withconcomitant subacromial decompression. In our case, wefound excellent results with arthroscopic resection of theacromioclavicular joint and subacromial decompressionin a single setting. Maintaining the integrity of the capsular attachments minimizes the amount of bleedingand trauma into the subacromial space, thereby decreasingpostoperative pain while avoiding creating iatrogenic distalclavicular horizontal instability. When this procedure is performed on properly selected patients, there are fewerpostoperative complications. Patients return to activitiesearlier while achieving similar long-term outcomes asthe open procedure


Most healthcare professional training programs lack sufficient curricula on substance use-3, and eIn year two of the project, students training began integrating SBIRT into their clinical experiences. Implementation packets were distributed to students with resources and instructions tailored to fit the varied needs of the programs and clinical sites. Clinical practice was supervised by SBIRT-trained clinical preceptors when possible or self-evaluated by students using the Brief Intervention Observation Sheet fidelity scale. Qualitative feedback was collected from faculty, clinical preceptors, and students to identify facilitators and barriers to integration of SBIRT into clinical experience.Preliminary data showed that 56 students  practiced SBIRT at their clinical site during the first semester of implementation, with 9% completing screening only (no BI indicated) and 91% completing screening and BI. Fidelity ratings revealed strong completion of BI steps with no significant difference between the groups , although BSN students demonstrated stronger motivational style . Qualitative data revealed institutional barriers to integrating SBIRT into some nursing clinical sites, while MSW clinical sites generally facilitated student practice and some adopted SBIRT agency-wide.Students need opportunities to integrate SBIRT practice into clinical experience and receive supervised feedback to achieve competency. Plans must be tailored to meet the institutional needs of clinical sites, which can vary for BSN and MSW students.


Nephronophthisis is an autosomal recessive renal ciliopathy that constitutes the leading monogenic cause of end-stage renal disease in children. The KOUNCIL consortium is a collaboration between the UMC Utrecht, the Radboud UMC Nijmegen and UC London aimed at elucidating the genetic etiology and pathophysiological mechanisms underlying nephronophthisis and identifying drugs that prevent or delay renal insufficiency. Our goal is to improve genome diagnostics, genetic counselling and therapeutic options for nephronophthisis patients.in vitro and in vivo models. Genotypic and phenotypic patient characteristics are registered in a nephronophthisis database, facilitating correlation analyses and identification of early phenotypic markers. Newly identified nephronophthisis-genes are incorporated into diagnostic next-generation sequencing panels of ciliary genes. We use a systems-biology approach to identify and functionally characterize nephronophthisis-associated protein modules. Finally, we use high-throughput repurposing screens in zebrafish embryos to identify FDA-approved drugs that halt renal failure.We employ next-generation sequencing to identify novel disease genes in 100 nephronophthisis patients included within the AGORA biobank project. The functional effect of novel mutations is assessed using IFT172, WDR34 and WDR60) for nephronophthisis-related disorders. Clinical guidelines and new diagnostic tools for nephronophthisis are developed and implemented in diagnostics. We expect to identify drugs that can lead to novel therapies for nephronophthisis.With this approach, we expect to uncover the causal mutation in 60-90% of nephronophthisis patients. KOUNCIL members were involved in the recent identification of three novel genes (The KOUNCIL study is designed to advance understanding of renal ciliopathies and improve clinical care for nephronophthisis patients.


This survey sought to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among the senior North American Pediatric Neurosurgery membership.Surveys were sent to all active American Society of Pediatric Neurosurgeons (ASPN) members from September to November 2014. A total of 204 surveys were sent from which 130 responses were recorded, representing 64% of active ASPN membership. Respondents were asked 13 multiple choice and free response questions focusing on four problems encountered in shunted hydrocephalus management: Shunt malfunction, cerebrospinal fluid (CSF) overdrainage, chronic headaches and slit ventricle syndrome (SVS). Qualtrics® online survey software was used to distribute and collect response data.ASPN surgeons prefer three varieties of shunt valves: 41% differential pressure, 29% differential with anti-siphon device (ASD), and 27% programmable. Respondents agree shunt obstruction occurs most often at the ventricular catheter due to either in-growth of the choroid plexus (67%), CSF debris (18%), ventricular collapse (8%), or other reasons (9%). Underlying causes of obstruction were attributed to small ventricular size, catheter position, choroid plexus migration, build-up of cellular debris, inflammatory processes, or CSF overdrainage. The majority of respondents (>85%) consider chronic overdrainage a rare complication. These cases are most often managed with ASDs or programmable valves. Chronic headaches are most often attributed to medical reasons  and managed with patient reassurance. The most popular treatments for SVS include shunt revision (88%), cranial expansion (57%) and placement of an ASD (53%). SVS etiology was most often linked to early onset of shunting, chronic overdrainage and/or loss of brain compliance.This survey shows discrepancies in shunt-dependent hydrocephalus understanding and management style among a representative group of experienced North American pediatric neurosurgeons. In particular, there are differing opinions regarding the primary cause of ventricular shunt obstructions and the origins of SVS. However, there appears to be general consensus in approach and management of overdrainage and chronic headaches. These results provide impetus for better studies evaluating the pathophysiology and prevention of shunt obstruction and SVS.


The insular cortex (IC) is considered a rich hub for context-sensitive emotions/social cognition. Patients with focal IC stroke provide unique opportunities to study socio-emotional processes. Nevertheless, Couto et al.  have rec The insular cortex (IC), a brain region localized deep in the lateral sulcus, has been recently considered an interoceptive region , the right IC (whose lesion did not impair disgust recognition in Straube’s) is supposed to index negative emotions and disgust, as reported in several other studies  of the IC renders focal damage extremely infrequent in clinical practice , we assessed interoceptive sensitivity in the same two patients and found that interoceptive-related behavior was differentially impaired in each case: the insular lesion affected cardiac interoceptive measures whereas the subcortical lesion yielded preserved performance. Thus, the subcortical patient’s impairments in social cognition and negative emotion cannot be explained by canonical interoceptive signals running through autonomous  pathways. These factors notwithstanding, further studies would elucidate the relationship between interoceptive sensitivity and social cognition in subcortical lesions.The neuroanatomical and behavioral evidence offered by Couto et al.  also sugThe predictive coding approach is gaining acceptance within the neuroscience community Friston, . PredictPredictive coding principles apply not only to basic brain function but also to social cognition  by subcortical areas (lower in the hierarchy). PE-signals affecting the insular region would modulate connections, whereas PE-signals targeting more frontal areas would reach minimization.The above hypothesis suggests a two-sided explanation of the behavioral effects reported by Couto et al. On the one hand, PEs and response times are strongly correlated  suggest high variability in the patients’ performance. This variability can be interpreted in terms of preserved/affected hubs connecting the lesion sites with other ipsilateral regions and with their contralateral regions. Here, we have proposed that effective connectivity analysis constitutes a novel approach to examine functional connectivity and explain why only some stroke patients are impaired in these domains. Specifically, effective connectivity studies allow us to assess compensatory, contralateral, and subsidiary networks. Moreover, given the existence of transitory post-stroke deficits in empathy and other social cognition domains, this approach may be used to test the functional-remapping hypothesis in cases of IC damage and similar hypotheses in patients with lesions to other brain regions. Dynamic causal models of effective connectivity may provide an opportunity to achieve “effective” cross-talk between clinicians and basic neuroscientists (Kahan and Foltynie, 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.