TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2–ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene  Alternative mRNA isoforms have important roles in normal development and physiology. Almost every human gene produces more than one mRNA isoform, vastly expanding the information content of the human genome  and alternative utilisation of both 5′ and 3′ splice sites to insert exons of different sizes. Alternative mRNA isoforms can also be generated by the selection of different promoters and different polyadenylation sites. Each of these pathways produces mRNA splice variants that can impact on prostate cancer development or response to treatment . The prostate is a small gland located just below the bladder that produces seminal fluid components. Prostate cancers typically do not cause symptoms, but in some more advanced stages can block urine flow from the bladder, invade the adjacent seminal vesicles and metastasise more distantly to bone. Primary prostate cancer leads to a breakdown in the normal glandular structure of the prostate gland. Prostate cancer is classified histologically by morphological features using the Gleason scoring system  and one in the NDUFV3 gene that encodes a mitochondrial respiratory protein (this NDUFV3 exon was repressed by androgens). Although these ZNF121 and NDUFV3 exons changed splicing in response to androgens, their clinical importance is not known, nor if these genes are direct targets for the AR. However, this same study also identified a number of androgen-dependent mRNAs made from alternative promoters, including an alternative mRNA isoform of the normally tumour suppressor TSC2 (Tuberous Sclerosis 2) gene that is transcribed from an internal promoter (so only contains downstream TSC2 exons). The well-characterised full-length TSC2 protein represses cell growth via the mTOR pathway. The androgen-driven alternative TSC2 mRNA isoform encodes a shorter  TSC2 protein that promotes rather than represses cell growth  antigen  of the ST6GALNAC1 mRNA in the prostate. The presence of this extra exon causes an alternative start codon to be utilised, resulting in the shorter version of the ST6GalNac1 protein  are associated with more advanced forms of prostate cancer progression. ERG is a proto-oncogene that plays a key role in the pathology of prostate cancer. ERG encodes a transcription factor that controls the expression of many genes during normal development  and epithelial–mesenchymal transitions (EMT) crucial for prostate cancer cell metastasis  encodes an in-frame peptide sequence. Inclusion of this 72-nucleotide exon might affect the interactions of the encoded ERG protein with transcription factors and other nuclear proteins, since it is immediately adjacent to the region of the ETS gene that encodes a protein–protein interaction domain called the sterile alpha motif (SAM)/pointed domain (http://pfam.xfam.org/family/SAM_PNT).The The primary therapeutic strategy for advanced prostate cancer treatment is to block androgen signalling through androgen deprivation therapy or AR blockade, thereby halting tumour progression. Abiraterone is a drug that inhibits androgen biosynthesis and so reduces the levels of androgens within prostate cancer cells. Enzalutamide is a drug that antagonises the interaction of androgens with AR protein. Although prostate tumours initially respond to androgen deprivation therapy, later stages of the disease can develop into a treatment-resistant form of the disease called castration-resistant prostate cancer. Mechanisms of prostate cancer cell resistance cross over, so a prostate cancer cell developing resistance to enzalutamide will also show a reduced (~20%) response to abiraterone, and vice versa  that lack ligand-binding domains, frequently as a result of splicing inclusion of cryptic exons (abbreviated CE), making them independent of androgen control. Some AR-V protein variants translocate into the nucleus even in the presence of enzalutamide  site, thus creating a truncated AR mRNA that lacks coding information for the Ligand-Binding Domain (abbreviated LBD). As a result, ARv7 encodes a short yet constitutively active isoform of the AR (active in the absence of androgens). While full-length AR protein is dependent on androgen binding via its LBD to translocate into the nucleus and control transcriptional activity, ARv7 protein is constitutively present in the nucleus even in the absence of androgens and so can provide AR activity in androgen-depleted prostate cancer cells  patients, but less frequently in primary tumours  and NFκβ2, both of which increase expression in prostate cancer . The ARv567es protein isoform regulates the transcription of genes involved in cell cycle control and particularly activates the expression of the oncogene UBE2C. UBE2C is a ubiquitin-conjugating protein active during mitosis, as part of the anaphase-promoting complex (APC) that inactivates the mitotic checkpoint control. UBE2C protein is highly expressed in solid tumours and promotes cell proliferation. Transcriptional activation by the ARv567es AR isoform occurs via a DNA looping mechanism that involves interaction with the transcription factor MED1 , and within castration-resistant but not hormone-responsive prostate cancer  do increase in hormone-resistant prostate cancer compared to primary prostate cancer . However, it is worth noting that other HSP90 inhibitors have been reported to have different effects on ARv7 splice isoform variant production . SRRM4 is a splicing factor normally needed in the body (outside of the prostate gland) for neural differentiation. SRRM4 up-regulation drives splicing switches towards neuronal splicing patterns and the trans-differentiation of prostate cells towards neuroendocrine prostate cancer cells , BCLx (controlling splice isoforms important in cell death via apoptosis) and CCND1 (controlling splice isoforms important in the cell cycle) [Fig. CD44 pre-mRNA towards the production of more metastasis-associated splice isoforms [including CD44 exon v5  mRNA which is important for angiogenesis. SRSF1 switches VEGF splicing patterns between pro- and anti-angiogenic mRNA splice isoforms via selection of an alternative 3′ splice site  and the International Cancer Genome Consortia . Increased understanding of mRNA splice isoforms in prostate cancer will also come from integrating RNAseq data with peptide data from mass spectroscopy, thus enabling direct correlation of alternative isoforms and their encoded proteins (Evans et al. Investigation of splicing in prostate cancer is currently undergoing methodological change with the incorporation of analysis from big data sets, particularly with the global discovery of new splice isoforms. Future research in this area is likely to include comparison of large “-omics” level datasets to detect many splice isoform changes between different grades of prostate cancer tissue in parallel. Already, RNAseq datasets from patients with prostate cancer are available on sites like The Cancer Genome Atlas (TCGA, Integrating data from system-wide approaches will also be helpful for understanding how these splice isoforms are generated in prostate cancer cells. Transcriptome-wide binding maps of RNA splicing regulator proteins in cancer cells can be used to identify splicing targets important for therapy and diagnostics (Best et al. CHK1 mRNA might specifically kill cancer cells that rely on CHK1 in the absence of other checkpoints to control replication stress (Best et al. Although research in this area has been very productive, still remaining open in this field is a full understanding of how alternative splicing programmes impact on prostate cancer pathology. Research in the past few years shows that splicing patterns change during prostate cancer progression and in response to therapeutic intervention. Some splicing changes enable prostate cancer cells to grow in limiting concentrations of androgens, and some cause the production of more oncogenic proteins contributing to disease pathology. Understanding these splicing changes, and the mechanisms driving them, opens up new possibilities for developing diagnostic and therapeutic strategies to treat prostate cancer. As a result of these investigations, future therapies might aim to target specific splice isoforms, for example using antisense oligonucleotide and morpholino techniques that have been developed for other diseases including Duchenne muscular dystrophy and spinal muscular atrophy (Aartsma-Rus and Krieg


Purpose. To introduce a clinical sign on spectral domain optical coherence tomography (SDOCT), which may indicate high risk for full-thickness macular hole formation after internal limiting membrane (ILM) peeling. Methods. The preoperative SDOCT images of two patients—one with multilaminar hemorrhage from ruptured retinal artery macroaneurysm and one with serous retinal detachment and severe macular schisis from optic pit maculopathy—who developed full-thickness macular hole (FTMH) after ILM peeling were evaluated retrospectively. Results. On the preoperative SDOCT images of both patients there was a thin bridge of tissue on either side of the foveal center with an outer retinal defect. The photoreceptors were displaced laterally away from the foveal center to create an “omega-” shaped configuration of the remaining tissue. Conclusion. “Omega-” shaped configuration on SDOCT may represent a higher risk of FTMH following ILM peeling. Vitreoretinal surgeons may wish to consider this sign in the process of their surgical decision making. Peeling of the internal limiting membrane (ILM) has become a preferred technique in the surgical treatment of miscellaneous macular disorders . HoweverIn this report we introduce a clinical sign on spectral domain optical coherence tomography (SDOCT) which may indicate high risk for FTMH formation after ILM peeling.A 91-year-old hypertensive woman presented with sudden onset of central scotoma and 20/200 vision due to multilaminar hemorrhage from ruptured retinal artery macroaneurysm OD. Subretinal blood extended beneath the fovea. Arthritis limited face-down positioning for pneumatic displacement, so pars plana vitrectomy (PPV) and subretinal tissue plasminogen activator injection were performed. The ILM was peeled to liberate trapped sub-ILM hematoma. A 66-year-old woman presented with serous RD and severe macular schisis from optic pit maculopathy OD. Her visual acuity was finger counting and she complained of a central scotoma for several years. Pars plana vitrectomy, ILM peeling, and long-acting gas tamponade were performed with face-down positioning postoperatively. omega sign.” Preoperative recognition of this sign on SDOCT should warn surgeons against ILM peeling over the fovea, which may result in FTMH. Although the report of the bridging tissue is not novel, the risk of creating a macular hole by peeling it has not been well described. The more common situation for the bridging tissue is tractional foveoschisis in myopic eyes. In the study conducted by Kim et al., among the 17 eyes, macular hole was found in two eyes, where one of these eyes developed a macular hole with retinal detachment at 16 months after ILM peeling [Both cases demonstrate the necessity of the MCC for structural integrity of the fovea when a prominent outer retinal defect and localized serous or hemorrhagic RD are present. The bridging tissue over the foveola and lateral displacement of the photoreceptor band produced a horseshoe-shaped configuration that we termed the “ peeling . Similar peeling . Intraop peeling .Vitreoretinal surgeons may wish to consider “omega sign” in the process of their surgical decision making and surgical planning. This may reduce the threshold for ILM peeling in these patients.


Spinning top urethra (STU) denotes a particular urethral configuration that is a dilated posterior urethra mainly seen in young girls or women. STU deformity arises secondary to detrusor instability, leading to a rise the intravesical pressure against a closed sphincter. We describe a case of spinning top urethra in a 30-year-old woman who presented with lower urinary tract symptoms and left flank pain.


Recently developed high throughput molecular techniques such as massively parallel sequencing and phylogenetic microarrays generate vast datasets providing insights into microbial community structure and function. Because of the high dimensionality of these datasets, multivariate ordination analyses are often employed to examine such data. Here, we show how the use of phylogenetic distance based redundancy analysis provides ecological interpretation of microbial community differences. We also extend the previously developed method of principal response curves to incorporate phylogenetic distance measure, and we demonstrate the improved ability of this approach to provide ecologically relevant insights into temporal alterations of microbial communities. Because these experimental platforms generate large datasets of measured values such as sequence read counts or microarray probe hybridization signals, multivariate statistical analyses are usually employed to interpret the acquired data4. Unconstrained ordination analyses such as principal coordinate and component analyses are frequently used to assess the variability in the datasets and distribute samples in lower dimensional space according to the matrix of measured values. While useful, these exploratory techniques do not provide a direct assessment of how different explanatory variables such as environmental gradients, sample groups, or patient metadata  contribute to the observed patterns in microbial community variability. To provide such assessment, the use of constrained methods is advocated3. The two widely used approaches, redundancy analysis (RDA) and canonical correspondence analysis (CCA), utilize Euclidean and χ2distances, respectively, to calculate the relationships among samples6. Neither distance measure takes into consideration the phylogenetic makeup of microbial communities and thus is not able to take advantage of this ecologically important information. Phylogenetic trees closely resemble clusters obtained on the basis of shared gene content7, and the microbial phylogeny and function were shown to be linked for many microbial traits9 . Thus, the microbial community composition and function are dependent to at least some degree on the phylogeny of its members12. In this report we show that phylogenetic distance based constrained analyses provide ecological interpretation of microbial community datasets.Recent advances in high-throughput massively parallel sequencing and phylogenetic microarrays have led to a bloom of studies in the field of microbial ecology14 to utilize the phylogenetic UniFrac (UF) distance-based matrix of (dis)similarities among samples in a dataset as has been done in several previous studies18. UniFrac distance is computed by calculating the fraction of branch lengths of a combined phylogenetic tree that are not shared between two communities19. Thus, two communities that mostly have members of phylogenetically distinct clades would have large a UF distance, whereas communities that consist of different members of the same phylogenetic clade  would have a small UF distance. By incorporating the abundance estimates of each taxon in different samples, a weighted UniFrac measure (wUF) can also be calculated. To compare the performance of wUF-dbRDA with several other commonly used constrained ordination analysis including Euclidean and Bray-Curtis distance-based RDAs as well as CCA, we designed a small synthetic microbial community consisting of a dozen bacterial members known to reside in the human gastrointestinal tract. We chose to use a synthetic dataset at this stage over an actual example of microbial community in order to reduce overall dataset variance and limit noise arising due to many low-abundance members typically present in most microbial communities20. Response variables were counts of each species’ abundance simulated manually with random noise  as shown in Fig. Fusobacterium nucleatum, a gut bacterial species that has been associated with human colorectal cancer21. Within each group, we introduced further dichotomy between “genders” by varying which species of Clostridium and Bacteroides they harbored red Fig. . The oveups Fig. , and becups Fig. . Both caups Fig.  and instups Fig. . Thus, wet al. study22. The dataset comprised phylogenetic microarray based abundance values for 775 phylotypes of human gut microbiota profiled in two cohorts of teenagers: healthy group (designated kHLT) and those diagnosed with diarrhea-predominant irritable bowel syndrome (designated kIBS). Group , gender, and age served as explanatory variables in our UF-dbRDA analysis see Fig. . The fulsee Fig. . Bray-Cuges Fig. .Figure 229. The study described fecal microbiota changes in three patients with Clostridium difficile associated disease following fecal microbiota transplantation (FMT) from a healthy donor. The results of the wUF-dbPRC analysis are presented in Fig. et al. study based on the K-means cluster analysis29, and additionally provide the ability to quantitatively establish the main determinants of community alterations.We then applied the wUF-dbPRC analysis to the time-series measurements of microbiota composition taken from the study by Shankar and co-workersWhile our synthetic datasets were designed specifically to show the potential differences in outputs between traditional and weighted UniFrac distance-based RDA and PRC analyses, the above comparisons provide compelling evidence for the advantages of phylogenetic distance based constrained ordination analyses in the study of microbial communities.vegan package30. Specifically, distance-based redundancy analysis was performed using the vegan function capscale. Principal response curves analysis was performed using the prc function. Analysis of variance was performed using the anova.cca command. The R code to run both dbRDA and dbPRC analyses is provided in Supplementary File The constrained ordination techniques were performed in R using the Supplementary  Information


We report of a 57-year-old female patient who underwent a hemipelvectomy with a hemipelvic replacement in 1992. In 2013 the implanted material had to be partially removed due to a periprothetic infection. At that time a palacos spacer was implanted which penetrated two years later into the colon cavity.  Penetration of implanted material has been reported after different surgical procedures like endovascular aortic repair (aortoenteric fistula), gastric banding (penetration into the stomach) or total hip replacements (penetration into the pelvis). Here, we report a case of colon penetration after a total hip replacement.A 57-year-old female patient presented in 2/2015 in our outpatient clinic with mild, but therapy-refractory constipation since four weeks.This patient received a right inner hemipelvectomy with a hemipelvic replacement in 1992 because of a malignant schwannoma of the right iliac bone. In 1995, the patient suffered a traumatic right-sided femur fracture, which was treated with a plate osteosynthesis. During the following years she developed a non-irritated chronic fistula underneath her surgical scar. In 2013, the chronic fistula became infected and cumulated in a deep gluteal abscess (measuring 4x4 cm) extending to the hemipelvic prosthesis. An explantation of the pelvic replacement was recommended but was initially declined by the patient. She received antibiotics in concordance with the wound culture and sensitivity swab.® spacer, as well as a gentamycin chain , three wire cerclages, a Palacos® spacer inside her rectal cavity  showed the head of the implanted PalacosThe first step in our department was the removal of the foreign body under general anesthesia through the anus without complications  [A bowel perforation by implanted foreign material  is a rare complication. The complete absence of symptoms or only mild symptoms accompanying this process is even rarer. The penetration of foreign material into the gut usually causes severe complications like pain, melena respectively hematemesis or sepsis like in case of aortoenteric fistulas after endovascular repair via prosthesis . There a®) . HoweverThe authors declare that they have no competing interests.


A number of psychological symptoms have been found to predict psychosis. Many studies have found no specificity to separate symptoms predicting non-psychotic psychiatric disorders from those predicting psychotic disorders. We were able to conduct prospective study comparing adolescent symptoms predicting non-psychotic psychiatric disorders and psychotic psychiatric disorders.Members of the of the Northern Finland Birth Cohort 1986 were asked to fill in PROD-screen questionnaire at age 15–16 years. PROD-screen includes 21 items both measuring positive prodromal symptoms, negative prodromal symptoms and general symptoms.We were able to follow 6,514 participants using Finnish Hospital Discharge Register detecting new hospital treated mental disorders till 23 years.The highest prevalence of positive symptoms in the PROD-screen were in the group of subjects who developed psychotic disorder (65% over the cut off) compared to subjects who developed non-psychotic disorder , and to subjects without any disorder . Respective figures for negative symptoms were 55% in the group of psychotic subjects compared to 30% in subjects with non-psychotic disorder  and 24% in the ‘healthy’ .When comparing separate symptoms in those having psychiatric hospital treatments, we found four positive symptoms and one negative symptom predicting specifically psychotic disorders.In this large prospective population sample both positive and negative symptoms in adolescence associated specifically with development of first episode psychosis.


Influenza A virus (IAV) infection can be severe or even lethal in toddlers, the elderly and patients with certain medical conditions. Infection of apparently healthy individuals nonetheless accounts for many severe disease cases and deaths, suggesting that viruses with increased pathogenicity co-circulate with pandemic or epidemic viruses. Looking for potential virulence factors, we have identified a polymerase PA D529N mutation detected in a fatal IAV case, whose introduction into two different recombinant virus backbones, led to reduced defective viral genomes (DVGs) production. This mutation conferred low induction of antiviral response in infected cells and increased pathogenesis in mice. To analyze the association between low DVGs production and pathogenesis in humans, we performed a genomic analysis of viruses isolated from a cohort of previously healthy individuals who suffered highly severe IAV infection requiring admission to Intensive Care Unit and patients with fatal outcome who additionally showed underlying medical conditions. These viruses were compared with those isolated from a cohort of mild IAV patients. Viruses with fewer DVGs accumulation were observed in patients with highly severe/fatal outcome than in those with mild disease, suggesting that low DVGs abundance constitutes a new virulence pathogenic marker in humans. Influenza A viruses are the causative agents of annual epidemics, sporadic zoonotic outbreaks and occasionally pandemics. Worldwide, acute respiratory infections caused by influenza A viruses continue to be one of the main causes of acute illness and death. The appearance in 2009 of a new H1N1 pandemic influenza strain reinforced the search to identify viral pathogenicity determinants for evaluation of the consequences of virus epidemics and potential pandemics for human health. Here we identify a new general virulence determinant found in a cohort of severe/fatal influenza virus-infected patients, a reduced accumulation of viral defective genomes. These molecules are incomplete viral genome segments that activate the innate immune response. This data will contribute to the prediction of influenza disease severity, to improved guidance of patient treatment and will enable the development of risk-based prevention strategies and policies. Acute respiratory infections are a main cause of severe illness and death worldwide. Influenza A virus (IAV) causes annual epidemics and occasional pandemics with potentially fatal outcome ; the gloin vivo murine model  are shown in yellow. RNA viral promoter is shown in blue.(TIF)Click here for additional data file.S15 FigStructure of the dimer polymerase complex in Protein Data Bank (PDB) under accession 3J9B has been used as template for structural localization of PA mutations with UCSF Chimera 1.10.2. PA mutations described in the severe-fatal case viruses in the present study (PA 529 and PA 312) are shown in red. RNA viral promoter is shown in blue.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 TableEpidemiological data, including comorbidities information, reported by the National Epidemiological Influenza Center are shown for the 2012–2013 Spanish influenza seasons.(TIF)Click here for additional data file.S3 Table(TIF)Click here for additional data file.


Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS-induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors.  A repeated-measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild–moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS-evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. NCT02465034. The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with  Motor ir stroke . In roder stroke . In healr stroke . In indir stroke . Specifir stroke  and assor stroke . This exr stroke , 11. AltOne possible explanation for this limited progress in improving stroke rehabilitation outcomes is that abnormal IHI and hemispheric balance after stroke have been targeted indirectly and nonspecifically. Promising neuromodulatory rehabilitation approaches can elicit neuroplastic change using noninvasive brain stimulation TMS). However, traditional rTMS approaches target a single cortical site with limited effectiveness in restoring the balance of interhemispheric activity or meaningfully improving arm function in chronic stroke , 13. TheIf STDP can be induced noninvasively by targeting direct transcallosal connections between M1s in the human brain, then this approach could offer a neuromodulation approach to restore the balance of interhemispheric activity after stroke. Using an interhemispheric (ih)PAS paradigm to target transcallosal motor circuits in healthy individuals, STDP was induced in both local and interhemispheric neuronal circuits  and corrHAND representations will: (1) induce STDP that increases cortical excitability of the targeted region (iM1HAND) and reduces abnormal IHI from cM1HAND to iM1HAND and (2) enhance motor skill performance and learning of a modified serial reaction time task (SRTT) after STDP induction.In this early-stage clinical trial protocol, we will explore ihPAS as a novel noninvasive brain stimulation approach to induce STDP in interhemispheric motor connections to transiently modify IHI and ipsilesional cortical excitability targeting cortical pathways implicated in mediating chronic stroke-related arm motor impairment. The aims of the trial are to: (1) characterize STDP induction in intracortical and transcallosal circuits by ihPAS and (2) investigate the effect of ihPAS on motor skill acquisition and learning. We hypothesize that ihPAS of transcallosal connections between M1Twenty individuals with subcortical stroke aged 40–85 in the chronic stage of recovery (>6 months) with mild–moderate impairment of the paretic arm  scan and baseline assessments of cognition, upper extremity physical impairment, motor function, and hand dexterity. Next, enrolled participants will complete two sessions of ihPAS, each with a 24-hour retention test, over 2 weeks. Assessments of cortical excitability using electromyography (EMG) and electroencephalography (EEG) of TMS-evoked cortical responses and motor skill performance will be conducted before ihPAS and then at three time points following ihPAS to evaluate the immediate time course of effects . Followi1 scan  will be performed on a Siemens Trio TIM 3T whole-body MRI scanner housed within the Center for Systems Imaging, a core facility at Emory University. The study team will have direct and immediate access to the data using Emory University's secure network server.A high-resolution TArm motor behavior will be evaluated by a licensed physical therapist during the first visit with the Wolf Motor Function Test (WMFT), shown to be a valid and reliable test of motor function in stroke , the uppParticipants will be seated comfortably in an adjustable reclining chair for all procedures. To reduce within- and between-session variability, the coil location and trajectory for the M1 stimulation site will be recorded and monitored in real-time with a stereotactic neuronavigation system  using the T1-weighted anatomical scans acquired for each participant. TMS will be delivered using a 70 mm hand-held figure-of-eight coil over the iM1 and a 50 mm branding iron coil over the cM1. Each coil will be connected to a monophasic stimulator ) using navigated TMS and evoked responses in the FDI will be measured with EMG  . Resting motor threshold (RMT) (% of maximum stimulator output) will be determined bilaterally using standard protocols . If an MHAND and iM1HAND at a frequency of 0.2 Hz for ~8.3 min [HAND stimulation preceding suprathreshold (SP120) iM1HAND stimulation at a fixed interpulse interval of 8 ms [HAND) and decreased IHI from left M1HAND onto right M1HAND have been observed in healthy individuals [One hundred pairs of pulses will be delivered over cM1~8.3 min  with sub of 8 ms . This in of 8 ms . When apividuals . Controlividuals . The ordSingle TMS suprathreshold (SP120) pulses will be delivered over the M1 representation for the FDI (frequency jittered from 0.1–0.25 Hz) while the participant is seated quietly with eyes open and FDI at rest to assess general levels of corticospinal excitability . IHI wilSP120) will be the primary dependent measure of local iM1 excitability. For the IHI condition, MEP ratio (conditioned MEP/unconditioned MEP) will be calculated as the primary outcome measure characterizing IHI.For each TMS assessment, 30 pulses will be delivered to maximize within- and between-session reliability  and storμV/bit resolution) during TMS assessments of cortical excitability. TMS-induced auditory artifacts will be reduced by using earplugs and frequency-specific noise to mask the audible TMS coil click [Electroencephalography (EEG) data will be recorded during all TMS assessments. TMS-evoked cortical responses can be used to directly assess intracortical neuronal circuit excitability and connectivity between distinct cortical regions –34. Elecil click . CorrectTMS-evoked EEG responses will be used to quantify abnormal interhemispheric connectivity after ihPAS intervention via imaginary phase coherence analysis (as detailed in ). All daWe will assess motor skill performance of each participant using a serial reaction time task (SRTT). Paretic arm motor function will be evaluated on a 3-item abbreviated version of the WMFT. Each assessment will be performed at each time point .Participants will perform a modified version of the SRTT  while seSkill will be defined as the difference between the average RT during the last 50 sequential trials and average RT during the second set of random trials within each block  Figure . To evalDue to time constraints of the experimental design, three items of the WMFT will be used to evaluate functional motor performance at each assessment time point. Streamlined versions of the WMFT have been shown to be useful in evaluating poststroke motor function across the continuum of recovery , 42. TheStroke is the leading cause of adult disability in the U.S. and its prevalence is expected to rise by 20% over the next 20 years, with tripled stroke-related costs . InnovatNoninvasive brain stimulation (NIBS) using repetitive activation of circumscribed brain regions with magnetic or electrical stimulation has shown promise as a potential alternative and/or augmentative therapeutic approach to traditional physical therapy after stroke with few side effects , 47. HowTaken together, ihPAS may offer an innovative and promising neuromodulatory approach to target mechanisms fundamental to stroke recovery requiring systematic investigation. The proposed project will be the first step in determining the clinical utility of ihPAS to improve functional outcomes after stroke. If successful, ihPAS could provide a novel neuromodulation technology to augment current clinical rehabilitation strategies to improve stroke outcomes. Regardless of the outcome, findings from this study will provide important information for refining or reconceptualizing neurobiologically based models of persistent arm impairment after stroke. The principal long-term objective of this work is to conclusively define the salient neuroplastic signatures of stroke recovery that can be leveraged into improved therapeutic outcomes and quality of life for each stroke survivor.


Despite technical advances and accumulated experience, complications continue being aconcern for patients implanted with permanent pacemakers. Several leadless pacemakersystems have now been developed in order to reduce the rate of complications inpatients implanted with conventional transvenous pacemaker.A 75-year-old female patient with a background of systemic arterial hypertension,chronic atrial fibrillation with an episode of peripheral arterial embolism in theright upper limb and rheumatic valve disease, underwent mitral and aortic valvereplacement receiving two mechanical valve prosthesis in combination with leftatrial appendage occlusion. Six months after surgery, pharmacologic therapy toachieve heart rate control was very difficult and inadequate and the patient wasscheduled for permanent pacemaker implantation. In order to avoid lead or pocketcomplications, the Micra transcatheter leadless pacemaker  was implanted through the femoral vein using a steerablecatheter delivery system with the use of a 23-French introducer. The procedure wasperformed under uninterrupted acenocoumarol therapy with therapeutic internationalnormalized ratio (INR 2.5). Sedation and local anesthesia was applied and theimplant was successful upon initial device positioning at the mid-septum of theright ventricle with no complications. Access site closure was performed using asubcutaneous venous figure-of-8 suture. The pacing capture threshold at implant was0.38 V measured at 0.24 ms, the R-wave sensing amplitude was 8.8, and the pacingimpedance was 730 ohms. There were no complications and the patient was dischargedhome the next day after chest X-ray showed the device was positioned perfectly and elec1 They are particularly related to the device or as a result from transvenous leadplacement . Early performance and safety data for the Micratranscatheter leadless pacemaker are positive3 and leadlesspacemakers represent a promising alternative for many patients, eliminating the mainsources of complications associated with conventional transvenous pacemakerimplantation.In spite of technological advances and the enormous accumulated experience,conventional pacemaker therapy continues to be associated with a great variety ofpotential complications either in the short and long-term.Patients with mechanical heart valve prosthesis might represent a subgroup ofpatients for whom this new therapy can bring higher benefits due to the need forlifelong anticoagulation and the serious consequences of permanent transvenouspacemaker system infections.


Infection with human immunodeficiency virus (HIV) influences the outcome and natural disease progression of hepatitis C virus (HCV) infection. While the majority of HCV mono-infected and HCV/HIV co-infected subjects develop chronic HCV infection, 20–46% of mono- and co-infected subjects spontaneously clear HCV infection. The mechanism underlying viral clearance is not clearly understood. Analysis of differential cellular gene expression (mRNA) between HIV-infected patients with persistent HCV infection or spontaneous clearance could provide a unique opportunity to decipher the mechanism of HCV clearance.Plasma RNA from HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV was sequenced using Ion Torrent technology. The sequencing results were analyzed to identify transcripts that are associated with HCV clearance by measuring differential gene expression in HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV.We have identified plasma mRNA, the levels of which are significantly elevated  <0.05) before HCV infection in subjects who cleared HCV compared to those who remained chronically infected. Upon further analysis of these differentially expressed genes, before and after HCV infection, we found that before HCV infection 12 genes were uniquely upregulated in the clearance group compared to the chronically infected group. Importantly, a number of these 12 genes and their upstream regulators  are associated with innate immune response functions.These results suggest that subjects who spontaneously clear HCV may express these unique genes associated with innate immune functions. IL28B) and IP-10 have been implicated in mediating host susceptibility/resistance to HCV infection and disease progression [Hepatitis C virus (HCV) infection is the leading cause of hepatocellular carcinoma in the United States . Due to gression –17. In Hgression . HoweverDifferential cellular gene expression in HIV-infected subjects has been shown to be associated with HIV disease progression . TherefoPathogenic changes occurring in any tissues or organs are expected to leave footprints in the blood. Consequently, measurement of certain target RNA in the plasma has been explored or used for diagnosis of a number of diseases and cancers –24. We hIn this study we identified plasma mRNA, the levels of which are significantly increased  in the HCV clearance group compared to chronically HCV infected patients. Upon further analysis of these differentially expressed genes, we have identified 12 genes that are upregulated only in clearance group before HCV infection. Moreover, some of these 12 genes and their upstream regulators are associated with innate immune functions.Frozen plasma samples were obtained from 13 HCV seroconverters who were infected with HIV for more than 10 years before HCV seroconversion in the Multicenter AIDS Cohort Study (MACS) . MACS isTotal nucleic acids were extracted from l ml of frozen cryopreserved plasma using an automated NucliSens EasyMag nucleic acid extraction machine  followed by removal of DNA from the nucleic extract with Qiagen AllPrep DNA/RNA mini kit and ribosomal RNA by a Low Input RiboMinus System (Life Technologies). The cDNA Library was then constructed using an Ion Torrent Total RNA-Seq Kit (Life Technologies) for whole transcriptome libraries and Barcodes 1 through 8 from an Ion Xpress 1–16 barcoding kit were used (Life Technologies) for each individual sample. cDNA libraries were quantified by qPCR using an Ion Library Quantitation Kit (Life Technologies) to determine a suitable template dilution factor for subsequent emulsion PCR and sequencing.Four barcoded samples were combined for one sequencing reaction. Template preparation for sequencing was conducted using the OneTouch Ion™ Template Kit in the OneTouch machine (Life Technologies). Ion Torrent sequencing was conducted using the Ion Proton Sequencing Kit (Life Technologies) on an Ion Proton Machine (Life Technologies) using a P1(v2)-chip (Life Technologies). The constructed cDNA was also used for HIV viral load measurement using a quantitative-real time PCR for HIV gag RNA, with a sensitivity of 10 copies/mL .Raw sequencing reads in FastQ format were assessed for quality using CLC Genomics Workbench 7. Reads were accepted based on the length (longer than 25 nucleotides) and number of ambiguous bases . Quality trimming was performed. The mean numbers of reads from different groups after trimming ranged from 3.2 million to 8.4 million. The trimmed reads were then mapped to Homo sapiens gene sequences based on Homo sapiens (hg19) mRNA.www.genecards.org).Bioconductor edgeR in R package was employed to perform the differential expression analysis. A general linear model was applied on the subjects before and after HCV infection to accommodate the multifactor design of the experiment. The model incorporates the main effect for HCV infection plus interactions with patients and viral clearance, thus allowing us to identify genes differentially expressed in HCV cleared and chronically infected patients before and after HCV infection. To ensure there were sufficient counts for each gene in the test, genes with mean read counts higher than 10 were kept in the analysis. Genes with Benjamini-Hochberg adjusted FDR <0.05 and fold change greater than 1 were considered as significant genes. The significance and function networks of the detected differentially expressed genes were analyzed using Ingenuity Pathway Analysis software. The gene function information was obtained from GeneCards Human Gene Database ): six gene products (18%)  are related to signal transduction pathways and innate immune response,. eight gene products (24%)  are involved in metabolism and protein trafficking, and five gene products (15%)  are RNA/DNA binding proteins involved in gene regulation  before HCV infection, 19 DEGs have known biological functions  are RNA/DNA binding proteins involved in gene regulation   are known to participate in, or to be related to, signal transduction pathways and innate immune responses, twelve DEG gene products (21%)  are involved in metabolism and protein trafficking and eight DEG gene products (14%)  and cytotoxic NK-cells (P = 0.005), compared to patients who became chronically infected [The availability of sequential plasma samples with defined onset and disease outcomes of HCV infection in highly characterized HIV-infected subjects from the MACS  providedinfected . In addiinfected . FurtherPlasma RNA sequencing has identified the transcripts that are significantly associated with HCV clearance and are found to be expressed prior to infection. Some of the transcripts are involved in innate immune function. These results suggest that subjects who spontaneously clear HCV may have the transcripts that modulate forms of immunity that confer resistance to chronic infection with HCV. Further studies with longitudinal samples from HCV infected patients who cleared HCV infection, and those who became chronically infected may provide more definitive information about the nature of these inherited traits.


OtheWe addressed this possibility by examining the distributions of fiber-types and MU fibers in small muscles of the rat hindlimb for comparison with those in large muscles. Six months after nerve transection and repair, all the nerve fibers reinnervated the denervated rat muscle but, in contrast to the restored mosaic distribution of reinnervated MU fibers and fiber-types in well reinnervated large cat muscles, the reinnervated rat MU muscle fibers were mostly confined within 1-3 muscle fiber clumps; the MU fibers were clumped in parallel with a corresponding fiber-type grouping in the muscle cross-sections .both small and large muscles [Each MU muscle fiber is normally surrounded by an average of 6 non-MU muscle fibers and all the MU muscle fibers are confined to a ‘muscle territory’ that is bounded by the outermost MU fibers Figure . The ter muscles . The siznot increase in size from normal [It is only when few nerve fibers regenerate into a denervated large muscle and each nerve fiber branches to reinnervate 5-8 times as many muscle fibers as normal, that each motor nerve fiber innervates adjacent muscle fibers; MU fibers and fiber-types exhibit clumping within MU territories which do m normal . This pam normal . The cluis also indicative of extensive partial denervation as in large muscles [both sprouting after extensive nerve damage and muscle reinnervation after damage that severs all the nerve supply whether or not all the nerves regenerate and reinnervate the denervated muscle. In large muscles on the other hand, fiber-type grouping indicates sprouting after extensive nerve damage whether or not there is partial or complete nerve injury.These findings and arguments indicate that fiber-type grouping in reinnervated muscles is not inevitable as has been generally supposed. Fiber-type grouping only occurs in large muscles after extensive partial denervation and when fewer than 20% of the original nerve supply reinnervate muscle after complete nerve transection and surgical repair . In smal muscles  but, clu muscles . Hence fThe enlarged MUAPs that are frequently recorded from muscles have been and continue to be used as indicators of muscle reinnervation , 3. It i


Purpose: To present a case with posterior segment findings in a patient with cloudy corneas secondary to immunotactoid glomerulonephritis (ITG).Methods: A 57-year-old female was known to have bilateral cloudy corneas diagnosed 12 years ago secondary to immunotactoid glomerulonephritis. Clinically, fundus examination was difficult to visualise due to the density of her corneal opacities. Results: B-scan ultrasound revealed significant retino-choroidal & non-inflammatory scleral thickening. The macula also showed signs of thickening in both eyes. Optical coherence tomography (OCT) showed thinning of the inner retinal layers and significant choroidal folds in both eyes. Electrodiagnostic tests (EDT) concluded loss of retinal ganglion cells with preservation of retinal function in both eyes.Conclusion: This case widens the spectrum of findings seen in patients diagnosed with Immunotactoid Glomerulonephritis and alerts us to undertake detailed posterior segment examination where possible. Ocular coherence tomography (OCT) and B-scan ultrasonography are important adjuvants to help assess the posterior segment in patients with corneal opacities secondary to ITG.  Corneal involvement in patients diagnosed with immunotactoid glomerulonephritis (ITG) is well described in literature. ITG is characterised by deposition of abnormal monoclonal protein in patients with paraproteinemia and lymphoproliferative disorders. We present interesting posterior segment findings in a patient with cloudy corneas secondary to immunotactoid glomerulonephritis.A 57-year-old female was referred to the corneal clinic with a one-week history of seeing a ‘black spot’ in front of her right eye. Her past ocular history revealed bilateral cloudy corneas diagnosed 12 years ago secondary to ITG. She was reviewed on an annual basis but as she was asymptomatic with visual acuity 6/6 (LogMAR 0.0) both eyes and the appearance of her corneas had remained unchanged over seven years; she was discharged back to primary care. Her medical history revealed ITG following a renal biopsy carried out 20 years ago. 6 years ago, she was diagnosed with end stage renal failure and was on haemodialysis and continuous ambulatory peritoneal dialysis. She was also known to suffer with haemolytic anaemia and hypertension.On examination, her best-corrected visual acuity was recorded as 6/7.5 (logMAR 0.2) and near vision N6 in both eyes. Corneal examination revealed full thickness limbal to limbal opacification in both eyes Figure 1 . The cenOCT examination showed a hazy view but thinning of the inner retinal layers and choroidal folds was noted in both eyes. Photoreceptor layer appeared to be intact including the outer nuclear layer Figure 2 . B-scan In both eyes, visual evoked potential (VEP) to flash stimulus was essentially normal. Her visual field testing showed non-specific defects and Ishihara colour vision test was normal. The patient refused penetrating keratoplasty due to the risks attached but elected to consider this option at a later stage. We decided to observe this patient on a regular basis and carry out serial OCT scans. The patient was asked to report any changes to her vision. At 6-month follow-up, patient was asymptomatic and visual complaints of seeing a ‘black spot’ in her right eye resolved completely.Immunotactoid glomerulonephritis (ITG) is a rare renal deposition disease and the diagnosis is based on analysis of renal biopsies. The primary differential diagnosis of this condition includes membranoproliferative or mesangiocapillary glomerulonephritis (MPGN). Both these glomerular diseases typically present with nephrotic syndrome. In ITG, the exact mechanism is unknown but deposition of immunoglobulin, particularly IgG κ and λ light chains and complement, suggests an immune system dysfunction. MPGN is a group of immune complex-mediated disorders characterized by subendothelial and mesangial deposition of immune complexes. Most of these patients progress to develop end stage renal failure. Corneal involvement in various systemic paraproteinemias or monoclonal gammopathies is well established and various morphological characteristics mimicking hereditary and degenerative corneal disorders have also been described , 2]. Th. Th2]. TThe choriocapillaris, Bruch’s membrane and RPE complex have been proven to have similar morphological characteristics as the glomerulus and there is histopathological evidence that immune complexes can get deposited at these sites , 5]. Mo. Mo5]. MIn our patient, renal biopsy showed deposits of IgG kappa and C3 at the tips of some glomerular loops and based on electron microscopy, a diagnosis of ITG was made. Subsequently, our patient developed generalized full thickness cloudiness of both her corneas. As her visual acuity continued to remain stable and the patient was asymptomatic, the need for detailed fundus examination was overlooked and patient was discharged to primary care. Her recent presenting complaint of ‘black spot in vision’ did not correlate with her cloudy corneas and it was then that the patient underwent an OCT scan. Choroidal folds seen on OCT both eyes are presumably a result of retino-choroidal & scleral thickening as confirmed by B-scan. We feel that this is an immune related process related to ITG as there were no signs of intraocular inflammation & ‘T-sign’ was absent on B-scan. One could argue that choroidal thickness is possibly altered as a result of chronic renal failiure and following haemodialysis but evidence shows that the average choroidal thickness decreases significantly in such patients  whereas To our knowledge, this is the first case describing retino-choroidal & scleral thickening in a patient with ITG. This case widens the spectrum of findings seen in patients diagnosed with ITG and alerts us to undertake detailed posterior segment examination in patients with corneal opacities. Corneal changes might not be the only cause of visual symptoms in patients with ITG. OCT and B-scan USG are useful tools for posterior segment assessment in these patients. This case also highlights the need for further studies on a cohort of patients diagnosed with ITG to assess their posterior segment findings.The authors declare that they have no competing interests.


Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within six hours following blood transfusion. In most cases, donor antibodies are suggested to be involved, however, the pathogenesis is poorly understood. A two-hit model is generally assumed to underlie TRALI pathogenesis where the first hit consists of a patient predisposing factor such as inflammation and the second hit is due to donor antibodies present in the transfused blood. We recently demonstrated that the acute phase protein C-reactive protein (CRP) could enhance murine anti-major histocompatibility complex (MHC) class I-mediated TRALI. Whether CRP is increased in human TRALI patients which would support its role as a risk factor for human TRALI, is currently unknown. For that purpose, we measured CRP levels in the plasma of human TRALI patients and found CRP levels to be significantly elevated compared to transfused control patients. These data support the notion that CRP may be a novel first hit risk factor in human TRALI and that modulation of CRP levels could be an effective therapeutic strategy for this serious adverse event of transfusion. Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality and is characterized by acute respiratory distress within six hours following blood transfusions , 2. AparWe recently demonstrated that C-reactive protein (CRP), an acute phase protein widely used as a clinical biomarker of infections and inflammation, enhances anti-major histocompatibility complex (MHC) class I-mediated TRALI in BALB/c mice . MechaniIn light of these findings in mice, we assessed whether CRP levels are indeed increased in human TRALI patients which is an essential step to establish if CRP may be a risk factor for TRALI induction and if modulation of CRP levels in humans could be a therapeutic approach to combat TRALI.CRP levels were measured in plasma samples from human TRALI patients n=12) and in control orthopedic surgery patients that had not been hospitalized nor had infections within one month prior to surgery and received allogeneic blood transfusions post-operatively without any pulmonary transfusion reactions (n=10). TRALI samples were collected for CRP analysis within 24-48 hours upon transfusion and for the control group blood samples were collected within 24 hours following transfusion (which occurred on post-operative days 3-4). The patient characteristics and clinical features are listed in Table 2 and in The finding that CRP levels are significantly elevated in human TRALI patients Figure  suggestsCRP is member of the pentraxin family and is composed of 5 identical, nonglycosylated 206 amino acids protomers which together form a noncovalently linked annular symmetrical pentameric molecule . PentamePlatelets are classically known for their hemostatic function but have been suggested to play a pathogenic role in TRALI , 24. It In summary, our data indicate that CRP levels are significantly upregulated in the plasma of TRALI patients and thus monitoring CRP levels prior to transfusion may be useful and down-regulating CRP levels could be a novel therapeutic approach to explore in TRALI.Human TRALI samples were diagnosed and obtained with approval from Sanquin Diagnostic Services, Amsterdam, The Netherlands (Dr. L. Porcelijn). All TRALI samples were obtained and collected strictly under the following conditions : 1) Newly developing acute respiratory distress: PaO2/FiO2 ratio  < 300 mmHg or arterial oxygen saturation < 90% at room air; 2) Newly developed or worsened bilateral pulmonary infiltrates indicative of pulmonary edema on chest X-ray; 3) Emergence of all symptoms within 6 hours upon blood transfusion; 4) Exclusion of cardiac ischemia and transfusion associated circulatory overload (TACO).If patients had major risk factors for acute lung injury, such as pneumonia, sepsis, aspiration, multiple fractures or pancreatitis, they were excluded from this study except if the patient was stable and the risk factor did not appear to cause acute lung injury and the onset of acute lung injury was triggered by the blood transfusion.Human transfused control samples were obtained from Dr. M. T. Rondina . Patient characteristics and clinical features for both TRALI and transfused control samples are described in Table TRALI samples were collected for CRP analysis within 24-48 hours upon transfusion and for the control group blood samples were collected within 24 hours following transfusion, which occurred 3-4 days after the orthopedic surgery. CRP was measured from plasma using a standardized immunoturbidimetric assay, in which the human CRP from the samples agglutinates when incubated with latex particles coated with polyclonal rabbit anti-human CRP antibodies . The aggregrates were subsequently determined turbidometrically using the Beckman AU680, Beckman Coulter, USA.


This study used the Deese-Roediger-McDermott paradigm [34] to investigate the direction and the extent to which emotional valence in semantic word lists influences the formation of false memories (FM). The experimental paradigm consisted of 1) a study phase , 2) a free recall phase, and 3) a recognition phase. Participants had to indicate whether the displayed item was "new" (new item or non-studied CL) or “old” (studied list item). CL associated with negative word lists elicited significantly more FM than CL associated with neutral word lists. This finding is in contrast to previous work showing that emotional words elicit fewer FM than neutral words. The results of our study also suggest that valence is capable of influencing emotional memory in terms of encoding and retrieval processes.


Independent replication is vital for study findings drawn from Electronic Health Records (EHR). This replication study evaluates the relationship between seasonal effects at birth and lifetime cardiovascular condition risk. We performed a Season-wide Association Study on 1,169,599 patients from Mount Sinai Hospital (MSH) to compute phenome-wide associations between birth month and CVD. We then evaluated if seasonal patterns found at MSH matched those reported at Columbia University Medical Center. Coronary arteriosclerosis, essential hypertension, angina, and pre-infarction syndrome passed phenome-wide significance and their seasonal patterns matched those previously reported. Atrial fibrillation, cardiomyopathy, and chronic myocardial ischemia had consistent patterns but were not phenome-wide significant. We confirm that CVD risk peaks for those born in the late winter/early spring among the evaluated patient populations. The replication findings bolster evidence for a seasonal birth month effect in CVD. Further study is required to identify the environmental and developmental mechanisms. External replication and validation are essential to medical research145Recently, two of the co-authors (Boland and Tatonetti) developed a method called SeaWAS: Season-Wide Association Study that reveals relationships between birth month  and lifetime disease riskTo perform a proper replication study, we sought to follow the original SeaWAS study as closely as possibleWe extracted all individuals born between 1926 and 2000 inclusive  who were treated at MSH (between 1979–2015), demographics given in We are especially interested in cardiovascular condition – birth month associations because they represent the novel findings from the original SeaWAS studyhttps://github.com/maryreginaboland/SeaWAS) to fit the database schema of MSH. We first performed a phenome-wide exploration of all birth month – disease associations for conditions with at least 1000 patients (1433 conditions). We employed the Benjamini-Hochberg method to correct for multiple hypotheses and control for the false discovery rate (FDR)We modified the SeaWAS algorithm obtained from the public domain . We assess statistical significance by comparing the actual correlation between the two institutions to an empirically derived null distribution. We generated empirical null distributions for each condition by randomizing the birth month–disease risk curve from MSH. We then computed the Pearson correlation for the random curve and CUMC’s birth month-disease risk curve. We repeated this procedure 1000 times producing 1000 random correlation results. We determined the empirically derived p-value as the proportion of random correlations greater than the actual correlation between true MSH data and true CUMC data divided by 1000. If this value is zero then the p-value is reported as “p < 0.001.”et al. 2004To place our findings in the context of biological mechanisms deemed important in birth month associations, we obtained peak flu season data obtained from the Centers for Disease Prevention and Control (CDC) data on flu activity from 1982–83 through 2013–14We used SeaWAS to mine birth month associations at MSH for all 1433 conditions with at least 1000 individuals born between 1926 and 2000, inclusive. We applied multiplicity correction using FDR to adjust the p-values. We limited our analysis to only the circulatory system conditions (as defined by the ICD-9 codes) that were found in both datasets, allowing us to compare the patterns of birth month-disease risk between the two institutions. SeaWAS-CUMC analysis found 9 circulatory system conditions were associated with birth month at an FDR threshold of 0.05 computed phenome-wide (1433 conditions) . Four ofWe performed pattern analysis of the birth month – disease risk curves for the circulatory system conditions between MSH and CUMC (set of 108 conditions). This was done to ascertain whether or not the birth month – disease relationship was the same between the two institutions. We found that seven of nine CUMC findings had significantly similar patterns at MSH . More dehttp://www.cdc.gov/flu/about/season/flu-season.htm) containing the number of times each month was the peak month for a given flu season. This data was aggregated from 1982–83 through 2013–14We overlaid data on seasonal variation in vitamin D levels and flu diagnosis levels to identify trends that could imply a biological rationale for observed cardiovascular – birth month association patterns. Replication of novel research findings is critical to biomedical research1457Coronary arteriosclerosis, essential hypertension, angina and pre-infarction syndrome were all significantly associated with birth month at the phenome-wide level at both MSH (after adjusting for 1433 tests) and CUMC (after adjusting for 1688 tests). Their seasonal patterns were also significantly correlated , Fig. 2 Three conditions, atrial fibrillation, cardiomyopathy, and chronic myocardial ischemia, were significantly correlated between CUMC and MSH but were not significantly associated with birth month at the phenome-wide level at MSH. These conditions could be associated with birth month through their common comorbidities, namely essential hypertension, angina, coronary arteriosclerosis and pre-infarction syndromeThere are several additional reasons why results from CUMC and MSH may differ. Firstly, many of these circulatory system conditions are comorbid with one another Several mechanisms have been proposed previously that could explain the relationship between cardiovascular conditions and birth month24et al.et al.A limitation of our approach includes the exclusive use of diagnosis codes collected during the clinical encounter and recorded in EHRs. Therefore, we know that these patients were diagnosed with a cardiovascular condition, but they may not necessarily have had cardiovascular disease. We used only diagnosis codes in order to properly validate the original results presented in Boland The condition most correlated between MSH and CUMC was coronary arteriosclerosis , which iIn this replication study, we study the cardiovascular condition – birth month relationship at another institution (MSH) with the same climate and urban setting as CUMC (both located in NYC). We found that seven of nine cardiovascular conditions associated with birth month at CUMC were also significantly correlated with the patterns revealed at MSH. These findings support the relationship between risk for cardiovascular conditions and birth month. We describe two leading putative mechanisms behind this relationship: maternal infection and low vitamin D levels. We also discuss the possibility of a combined mechanism  underlying the disease – birth month observations. Further study is required to identify the particular environmental and developmental mechanisms driving the observed associations.How to cite this article: Li, L. et al. Replicating Cardiovascular Condition-Birth Month Associations. Sci. Rep.6, 33166; doi: 10.1038/srep33166 (2016).


Despite a vast literature examining semantic impairment in Alzheimer's disease (AD), consensus regarding the nature of the deficit remains elusive. We re-considered this issue in the context of a framework that assumes semantic cognition can break down in two ways: (1) core semantic representations can degrade or (2) cognitive control mechanisms can become impaired [1]. We hypothesised and confirmed that the nature of semantic impairment in AD changes with disease severity. Patients at mild or severe stages of the disorder exhibited impairment across various semantic tasks but the nature of those deficits differed qualitatively for the two groups. Commensurate with early dysfunction of the cognitive control, temporoparietal-frontal-cingulate network, characteristics of deregulated semantic cognition were exhibited by the mild AD cases. In contrast, the severe AD group reproduced features of additional degradation of core semantic representations. These results suggest that spread of pathology into lateral anterior temporal lobes in later stage AD produces degradation of semantic representations, exacerbating the already deregulated system. Moreover, the dual nature of severe patients’ impairment was highlighted by disproportionately poor performance on tasks placing high demand on both conceptual knowledge and control processes–e.g., category fluency.


Legionella pneumophila we uncovered that the host metabolic checkpoint kinase Mechanistic target of rapamycin (MTOR) is a central regulator of the pathogen niche expansion program.A ruptured bacteria-containing organelle within the cytosol of an infected eukaryotic cell frequently initiates host defense responses that restrict pathogen replication. Therefore, source for lipids must be found to accommodate the organelle membrane expansion required to support bacterial replication. How host cells are manipulated to provide lipids for the expansion of pathogen-occupied organelles is not well understood. By investigating the interaction between macrophages and the human pulmonary pathogen  Legionella suppress MTOR to promote inflammation through a host-driven mechanism. In our recent study :e1006088) we identified the Toll-like Receptor (TLR) adaptor Myeloid differentiation primary response gene 88 (Myd88) as a critical factor mediating the host-induced MTOR suppression in Legionella infected BMMs. Deletion of Myd88 unmasked an unexpected ability of L. pneumophila to activate and sustain MTOR function even in the absence of growth factors or TLR stimulation. BMMs harboring pathogenic L. pneumophila elicited robust phosphorylation of the ribosomal S6 protein (a downstream substrate of the MTOR pathway) that was sustained for the entire intracellular replication cycle of the bacterium. In sharp contrast, uninfected neighboring cells remained quiescent . Further investigation revealed that one or more protein(s) encoded by L. pneumophila is translocated through the bacterium Type IVb secretion system (T4bSS) directly into the host cytosol to activate MTOR in a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-dependent manner. The Legionella T4bSS manipulates host functions through delivery of ~300 bacterial effector proteins into the host cytosol and is critical for virulence. Thus, it appears that in L. pneumophila-infected macrophages the host and the pathogen are locked in a molecular tug-of-war over MTOR function, where suppression favors the host and activation likely favors the pathogen.Previously, we uncovered that mouse bone marrow-derived macrophages (BMMs) infected with pathogenic Legionella was revealed in part because in MTOR studies cells are generally serum-starved prior to stimulation. Under those conditions, membrane biogenesis requires de novo lipogenesis or lipids recycling through autophagy. Blocking MTOR function in Legionella infections through various approaches destabilized the Legionella-containing vacuole (LCV), led to its premature rupture and the release of bacterial products into the host cytosol, which in turn activated a host cell death response. Culture supplementation with serum but not delipidated serum maintained LCV integrity and blocked the host cell death response implicating a lipids shortage as the likely cause for the loss of LCV integrity under MTOR suppression conditions. Because Legionella efficiently blocks autophagy through LC3 delipidation, the role of MTOR-dependent de novo lipogenesis was investigated. The transcription factors Serum Response Element Binding Protein 1 and 2 (SREBP1/2) are key lipogenesis regulators downstream of MTOR. Legionella infection induced Srebf1 expression as well as SREBP1/2-regulated genes in infected macrophages. Similarly to MTOR suppression, SREBP1/2 inhibition produced a LCV instability phenotype, which was complemented by dietary lipids. Taken together these data indicates that Legionella manipulates the PI3K-MTOR-SREPB1/2 axis to sustain MTOR-dependent lipogenesis to accommodate LCV expansion for optimal intracellular replication.The benefit of sustained MTOR activity for de novo lipogenesis are functionally redundant for LCV growth in mammalian macrophages one might wonder why Legionella has retained the capacity to activate MTOR? MTOR anabolic regulation is conserved in unicellular amoebae, the natural hosts for Legionella, which inhabit aquatic environments and lack constant source of dietary lipids. MTOR inhibition reduced Legionella intracellular replication in Acanthamoeba castellanii but only moderately. This observation raises the question if Legionella could manipulate host lipogenesis independent of MTOR and SREBPs or perhaps LCV expansion can be accommodated from pre-existing membranes . In principle, fusion with other membrane-bound organelles could facilitate LCVs expansion. Indeed, Legionella T4bSS effectors repertoire include proteins that promote recruitment and fusion of the LCV with the early secretory pathway as well as the endoplasmic reticulum. The ER is a major biosynthesis compartment for most cellular lipids and its large membrane reservoir could potentially accommodate some LCV expansion even in the absence of de novo lipogenesis. Considering that we identified a number of Legionella species that replicate intracellularly but do not activate MTOR it would be important to determine the different mechanisms by which LCV compartments expand.If dietary lipids and Legionella infections could be an excellent model system to decipher how MTOR controls SREBP1/2 and lipogenesis - a key cellular process that is still poorly understood in primary macrophages. Our work points to a rapamycin-insensitive MTOR-dependent mechanism although additional work is needed to elucidate which MTOR complex is involved and the precise mechanism. Host membranes are key features for successful intracellular survival of vacuolar pathogens and we uncovered that subversion of MTOR by L. pneumophila is one mechanism by which the host membrane biogenesis program can be manipulated for niche homeostasis.


Cardiac MRI is frequently used in the diagnosis of cardiac amyloidosis. Feature tracking is a novel method of analyzing myocardial strain at the myocardial borders. We investigated myocardial deformation mechanics of both the right and left ventricles in patients with Multiple myeloma with suspected cardiac amyloidosis.Comprehensive strain analysis was performed in 46 patients with multiple myeloma with suspected cardiac amyloidosis. MRI strain by feature tracking was measured using 2D cardiac performance analysis MR software . Global longitudinal strain (GLS) was obtained obtained from averaging longitudinal strains of apical 4-, 2- and 3-chamber views. Global circumferential strain (GCS) was obtained from averaging circumferential strains of the basal, mid and apical short axis views. Endocardial and epicardial contours were analyzed separately. Right ventricular GLS was derived from apical 4 chamber view, only endocardial contour was analyzed.Table 1 depicts the MR characteristics of the cohort. Normal LV wall thickness was present in 47% with biopsy proven cardiac amyloidosis. GLS and strain rate were significantly reduced in the epicardial and endocardial layers. There was no statistically difference in radial and circumferential strain as well as right ventricular GL strain. Segmental GL strain analysis showed typical apical sparing pattern in the endocardium but not in the epicardium.This feature tracking MRI analysis sheds light on strain mechanics in a cohort of early cardiac amyloidosis with a significant number of cases with normal LV wall thickness. Global longitudinal strain was affected earlier than radial and circumferential strain. Based on the pattern of apical sparing, amyloidosis affects epicardial strain earlier and without segmental variation compared to endocardial strain.


Investigators from four European tertiary care hospitals  performed a case-control study of children and adolescents aged 6 to 17 years diagnosed with primary headaches in the emergency department by a pediatric neurologist using the validated ICHD-3 criteria. Investigators from four European tertiary care hospitals  performed a case-control study of children and adolescents aged 6 to 17 years diagnosed with primary headaches in the emergency department by a pediatric neurologist using the validated ICHD-3 criteria. They enrolled 648 controls and 424 cases (257 patients with migraine and 167 with tension-type headache). Investigators masked to a patient’s group allocation diagnosed functional gastrointestinal disorders using the Rome III diagnostic criteria. Eighty-three (32%) children and adolescents in the migraine group were diagnosed with functional gastrointestinal disorders compared with 118 (18%) in the control group (p<0·0001). Multivariable logistic regression showed a significant association between migraine and three gastrointestinal disorders: functional dyspepsia, irritable bowel syndrome and abdominal migraine. The authors concluded that correct recognition would have an impact on the diagnosis and therapeutic management of these pediatric gastrointestinal disorders. [COMMENTARY. This well conducted multicenter trial included all functional gastrointestinal disorders defined according to ROME III criteria. However, among digestive afflictions, celiac disease (CD) deserves particular attention. CD patients may exhibit a myriad of extra-intestinal symptoms, which includes neurological symptoms such as migraine. Studies report a high frequency of migraines in patients with CD and vice versa, and describe the beneficial effect of a gluten-free diet in these cases . Also, tOn the other hand, recent findings regarding the role of the gastrointestinal microbiota in the gut-brain axis suggests that an unbalanced gut flora (i.e. dysbiosis) can be associated with neurological diseases like migraine. Enhanced pro-inflammatory immune responses have been reported with intestinal disorders associated with dysbiosis and increased intestinal permeability (just like IBS and celiac disease) as well as in migraine patients . Evidenc


A 60-year-old Polish male was admitted into our hospital with complaint of right-sided lower extremity weakness. CT of head showed a left frontal 2.6 × 1.5 cm mass. Staging work-up did not show any other associated lesions in the chest or abdomen. Brain tumor was resected with histology consistent with large cell neuroendocrine carcinoma with most likely lung primary because of TTF-1 positivity. Following recovery from surgery, he had external beam radiation therapy to the brain and systemic chemotherapy with four cycles of cisplatin/etoposide. Patient is alive and doing well 6 months post diagnosis with no evidence of recurrence. Large cell neuroendocrine carcinomas (LNECs) are rare malignant high-grade neuroendocrine tumors with clinical outcomes that mirror that of small cell carcinomas. LNEC of the lung is still classified under non-small lung cancers according to WHO classification but they are managed in a similar manner as small cell lung cancer (SCLC) because of poor clinical outcomes compared to other non-small cell lung cancer (NSCLC).There are few case reports of metastatic neuroendocrine tumor of the brain without radiologically detected primary. These together with metastatic neuroendocrine tumors of other sites with unknown primary are said to arise from occult clinically undetected primary sites like lung and GI.This case highlights the different ways of presentation of these tumors and also management challenge in terms of further systemic chemotherapy for resected oligometastatic disease with no primary lesion detected.A 60-year-old Polish male presented to our hospital because of worsening right lower extremity weakness for about a month. He has had chronic low back pain ongoing for a couple of years. No problems with bowel or bladder movement were found. He has 20-pack-pear history of cigarette smoking.Physical examination was significant for mildly reduced power in his right lower extremity with positive Babinski bilaterally.CT of head showed a left frontal 2.6 × 1.5 cm mass , 2. MRI Further staging work-up which includes CT of chest and abdomen, MRI of cervical and thoracic spine and CT of lumbar spine was unremarkable aside degenerative disease of lumbar and cervical spine. He was also noted to have an elevated PSA of 55 ng/mL as part of outpatient work-up for chronic lower back pain.He was started on intravenous steroids and eventually had MRI-guided stereotactic left parietal craniotomy with tumor resection.Pathologic examination of resected tumor showed large cells growing in sheets and nests  There waThis patient, however, did not have any lung lesion noted on imaging. He did not have any significant pulmonary symptoms either.He had external beam radiation therapy once recovered from surgery. He also had four cycles of cisplatin/etoposide after completion of radiation therapy.MRI of brain done 3 and 6 months post diagnosis has not shown any evidence of recurrence.The patient also had prostate biopsy which showed prostatic adenocarcinoma Gleason 4 + 3 = 7. He was started on androgen deprivation therapy while being treated for metastatic neuroendocrine tumor and will start radiation therapy soon for prostate cancer.LNEC is a rare high-grade neuroendocrine tumor that has been described in the lungs and other extra pulmonary sites -3. In 19Neuroendocrine tumors of unknown primary constitute less than 5% of all cancer of unknown primary sites and 10-13% of all neuroendocrine tumors -11. MostFew cases of metastatic neuroendocrine tumor of the brain without radiologically detected primary have been described in the literature -14. SomeMetastatic neuroendocrine tumors of unknown primary are said to be from occult clinical undetectable primary sites like lung, GI and other sites. Some patients with these kinds of tumors (isolated lymph node metastasis) constitute a distinct group with unknown primary carcinoma with relatively favorable prognosis .Survival after diagnosis of cerebral metastasis is dependent on some parameters that include age, performance status, extent of extracranial disease as well as the primary diagnosis . The lat


Interventricular septal hematoma is a rare complication of retrograde chronic total occlusion (CTO) percutaneous coronary interventions (PCI) with a typically benign course. Here we report two cases of interventricular septal hematoma and coronary-cameral fistula development after right coronary artery (RCA) CTO-PCI using a retrograde approach. Both were complicated by development of ST-segment elevation and chest pain. One case was managed actively and the other conservatively, both with a favorable outcome. Interventricular septal hematoma is a rare complication of retrograde chronic total occlusion (CTO) percutaneous coronary interventions (PCI) with a typically benign course . Here weA 46-year-old female with Canadian Cardiovascular Society (CCS) class IV angina symptom despite maximal medical therapy was referred for coronary angiogram and was found to have right coronary artery (RCA) chronic total occlusion (CTO) .RCA CTO percutaneous intervention was performed using right radial and right femoral artery dual catheter approach. The RCA was engaged with 6 French Judkins right guide catheter; the right femoral artery was cannulated with a 6 French sheath and the left main was engaged with a 6 French XB 3.5 guide catheter. With standard antegrade wire escalation technique, the CTO could not be crossed . The treAfter removal of retrograde Corsair and guidewire, angiogram of the LAD and RCA revealed Ellis Type III cavity spilling perforation of the second septal branch into the right ventricle (RV) Figures . The patThe next morning, she was taken back to the cardiac catheterization lab and repeat coronary angiography appeared unchanged. Given the patient's symptom and tachycardia, the decision to proceed with exclusion of the septal artery to RV perforation was made. Bilateral femoral access was obtained and similar guide catheters were used to engage the left and right coronary systems. The perforated collateral septal branch was accessed with workhorse type coronary guidewires from the LAD and RCA. Corsairs were then advanced into the proximal segment of the collateral vessel and negative suction was applied for approximately ten minutes . This maA 66-year-old male with known coronary artery disease and a chronically occluded mid right coronary stent presented with non-ST-segment elevation myocardial infarction. The culprit lesion was the RCA proximal to the remotely deployed and chronically occluded bare metal stent resulting in right ventricular ischemia. An attempt to recanalize the RCA was unsuccessful. He was treated medically but had persistent Canadian Cardiovascular Society (CCS) class III angina and was referred for RCA CTO-PCI.The antegrade approach was unsuccessful because the wire repeatedly tracked beside the stent; therefore, the retrograde approach was used. The in-stent lesion was successfully crossed with reverse cart technique in the proximal RCA . The RCAOn the night after his PCI, he developed severe chest pain, anterior ST-segment elevation, and nonsustained ventricular tachycardia . Repeat The following day, a contrast enhanced transthoracic echocardiogram confirmed a new large interventricular hematoma. The end systolic dimensions were 5.3 × 2.6 cm . There wTen days after PCI he was clinically stable and angina-free. An echocardiogram revealed a smaller intramyocardial septal hematoma (3.6 × 1.3 cm) with a fistulous tract in the septum that entered the apical right ventricle. At 3 months a subsequent echocardiogram showed resolution of the interventricular septal hematoma  and the CTO-PCI frequency is increasing . In a reSeptal collateral perforation and hematoma formation is a rare complication after retrograde CTO-PCI  and beliWhile the management of these cases remains controversial and undefined by large experience some guidance is needed as the frequency of CTO-PCI and the retrograde approach increases. Taking our observations together with previous reports we suggest the following when retrograde CTO-PCI results in septal hematoma formation . InpatiePatients who remain asymptomatic can be managed conservatively and dismissed 24–48 hours after CTO-CPI. Among those with symptoms of hematoma expansion, those without hemodynamic compromise can also be monitored with serial echocardiography and dismissed after 3-4 days of additional observation in the absence of additional evidence of hematoma expansion or significant shunt formation. We recommend more aggressive management with hematoma exclusion for those with hemodynamic compromise, evidence of additional hematoma expansion, pericardial effusion, tamponade, or significant shunt development (Qp/Qs > 1.5 : 1). Early dismissal after definitive management is not unreasonable and may be useful in avoiding prolonged inpatient observation, but the long term outcome of this approach is unknown. After successful CTO-PCI, exclusion of septal hematoma can be accomplished by local occlusion of the contributing septal perforator or occlusion of the origin of the septal with a covered stent. Both the donor and recipient vessel side of the collateral must be occluded to prevent flow into the hematoma. After unsuccessful CTO-PCI only the donor limb of the collateral needs to be occluded. Local occlusion of either limb of the septal can be accomplished with aspiration (as in Case 1) through a microcatheter or coiling with a bailout strategy of covered stenting. We preferentially use aspiration and coils in an effort to avoid the long term risk of covered stent restenosis or thrombosis which is as high as 30% in some series . AdditioSeptal hematoma formation is an unusual but potentially dangerous complication of the increasingly used technique of retrograde CTO-PCI. The case reports to date provide some clues as to the best management of this event. We propose an observation and treatment algorithm and recommend serial imaging with contrast echocardiography to assist in the decision-making during these rare but important events.RCA CTO PCI was complicated by large interventricular septal hematoma “5.3 × 2.6 cm” at end systole (video 1), with coronary-ventricular fistula (5 mm in diameter) (Video 2). At 3 months post PCI a subsequent echocardiogram showed resolution of the hematoma (Video 3).


Two patients with longitudinally extensive myelopathy were initially biopsied for suspected spinal cord tumors. Both patients were later diagnosed with neuromyelitis optica spectrum disorders (NMOSD) supported by their AQP4-seropositivity. Pathological review of both biopsies revealed demyelinated lesions with thickened vessel walls and tissue rarefaction. Immunohistochemical staining demonstrated findings compatible with acute NMOSD lesions in one case while the other case exhibited findings consistent with chronic NMOSD lesions. A pre-biopsy differential diagnosis of longitudinally extensive spinal cord tumors should include NMOSD. Specific biopsy features, such as cystic changes with vascular wall thickening and astrocyte injury, should raise suspicion for NMOSD. No clinical response was observed with high-dose methylprednisolone.A 14-year-old girl presented with bilateral lower limb paresthesia and weakness that progressed over a few days. Nine months later, she developed upper extremity weakness with sensory dysfunction at the level of C7 that worsened in a step-wise manner over a period of 3 months to paraplegia, sensory loss and sphincter dysfunction. Spinal MRI  showed tRe-assessment of the biopsied spinal cord specimen  revealedA 47-year-old woman presented with left shoulder pain, motor weakness and paroxysmal spasms in her left upper extremity over a month period. Spinal cord MRI demonstrated an edematous T2 hyper-intense lesion extending from the medulla to C7 with central contrast enhancement. Brain MRI was normal. She was treated with high-dose methylprednisolone for five days with a partial recovery. Four months later, acute transverse myelopathy developed over a few days with paraparesis, loss of sensation in both legs and sphincter dysfunction. A second spinal MRI revealed a caudal extension of the lesion to the T2 level with marked swelling and gadolinium enhancement . The patRe-assessment of the spinal cord specimen  revealedThese two case reports highlight the importance of a proper diagnostic work-up in patients with acute LETM to differentiate inflammatory myelitis from spinal tumors. Serum testing for AQP4 antibodies should be considered before invasive procedures.7 Spinal cord-biopsied lesions in patients with NMOSD are uncommon for obvious reasons, and the opportunity to evaluate NMOSD pathology features in vivo is rare. We identified only one prior case report of a biopsied patient with LETM and AQP4 antibodies, and these authors did not perform a detailed pathological study to analyze features of NMOSD.8Most of our understanding of NMOSD pathology derives from post-mortem studies.7 NMOSD findings are quite distinct from multiple sclerosis (MS) lesions and clearly indicate immune-mediated astrocytopathy.9 The pathological findings in the first case are good examples of the active NMO lesions associated with complement activation and granulocyte infiltration described in a recently published study identifying six lesion types.10 In contrast, the second case only demonstrated pathological findings compatible with the chronic NMOSD lesions in post-mortem cases, and the differential diagnosis of NMOSD based solely on the pathological findings is challenging because of the similarity of chronic NMO lesions to another demyelinating diseases such as MS. The elevated expression of AQP4 in the demyelinated lesions is indicative of reactive fibrous astrogliosis that can also be observed in MS, whereas speckled necrotic spots with decreased AQP4 staining and vascular hyalinization are consistent with astrocyte dystrophy found in NMO. This sample may have been taken from the periphery of the active lesion, or the biopsied area may have been affected by a previous attack.Acute NMOSD lesions are characterized by an extensive loss of AQP4 and GFAP staining with activated complement and IgG deposition in perivascular regions, in addition to relatively preserved myelinated fibers. In regions with severe inflammation, necrotic changes and perivascular cuffing are observed, predominantly including neutrophils, eosinophils, lymphocytes and macrophages.Although we do not under any circumstances recommend using spinal cord biopsy as a substitute for AQP4-antibody testing to diagnose NMOSD, the AQP4-antibody result may be false negative with some assays and the diagnosis may be arrived at incidentally during the work-up of spinal tumors. NMOSD should be suspected in biopsies with features such as cystic changes with vascular wall thickening and astrocyte rarefaction. The findings can range from the very acute to chronic inactive lesions depending on the evolutionary stage of the biopsied area. Nevertheless, additional immunohistochemistry staining is required to identify other features compatible with the typical pathological findings described in NMOSD.


Tuberculosis (TB) occurring in solid organ transplantation (SOT) is associated with significant morbidity and mortality usually due to delays in diagnosis, drug toxicity encountered with antimycobacterial therapy, and drug-drug interactions. TB in SOT patients may mimic other infectious and noninfectious posttransplant complications such as posttransplant lymphoproliferative disorder (PTLD) and systemic cytomegalovirus infection. Immune reconstitution inflammatory syndrome (IRIS) is a host response resulting in paradoxical worsening of an infectious disease which occurs after the employment of effective therapy and reversal of an immunosuppressed state. We describe the development of immune reconstitution inflammatory syndrome (IRIS), a unique complication occurring during the treatment of extrapulmonary tuberculosis occurring after transplant which resulted from decreasing immunosuppression in a patient who received Alemtuzumab induction therapy. Although (IRIS) has been originally described in HIV/AIDS patients receiving highly active antiretroviral therapy (HAART), solid organ transplant recipients with diagnosed or occult TB whose immune system may undergo immune reconstitution during their posttransplant course represent a new high risk group. SOT recipients have a high risk of developing TB during the posttransplant period usually due to reactivation of latent infection , 2. ExtrA 32-year-old Asian woman received a successful two-antigen mismatched deceased donor renal transplant. She underwent Alemtuzumab and Methylprednisone induction. The immediate posttransplant course was uncomplicated. She was discharged with a nadir serum creatinine of 0.9 mg/dL. Immunosuppression consisted of Mycophenolic acid delayed release (MMF) 720 mg twice daily and Tacrolimus therapy (target trough 9–12 ng/mL). Three months after transplant the patient developed elevated liver enzymes associated with fever of 102°F. Initial blood cultures, CMV, parvovirus B-19 and EBV by quantitative polymerase chain reaction were negative. Computed tomographic imaging studies (CT) revealed periaortic lymphadenopathy . Liver bFever, abdominal pain, and fullness slowly resolved over the course of therapy. Repeat CT imaging of the abdomen revealed resolving iliopsoas fluid collections . After 4SOT recipients have a high risk of developing TB during the posttransplant period usually due to reactivation of latent infection , 2, 4. MRifampin induces hepatic and intestinal CYP3A4 resulting in protracted difficulty in maintaining therapeutic drug levels of calcineurin inhibitors (CNI), inhibitors of the mammalian target of Rapamycin (MTOR), and corticosteroids , 12. RifIRIS can be described as a pathological hyperinflammatory host response when reversal of either pathogen or iatrogenic immunosuppression occurs resulting in paradoxical worsening of disease during effective antimicrobial therapy . IRIS haIn SOT undergoing treatment for active TB, IRIS usually occurs within 3 months . Risk faAlthough a working paradigm of the pathophysiology of IRIS occurring in the posttransplant setting has not been established, current evidence suggests an imbalance between pathogen directed host inflammatory Th1, Th17) and anti-inflammatory  effector cells resulting in hyperinflammatory response to a pathogen with ensuing tissue damage . Both MT and antiIt is important to also consider epidemiological data involving TB to further examine high risk population subgroups within which our patient resides. According to the Centers for Disease Control and Prevention (CDC), one-third of the world's population is infected with TB . In 2015Immune Reconstitution Inflammatory Syndrome (IRIS) has primarily been studied in the context of HIV/AIDS-associated paradoxical exacerbation of infection symptoms after recovery of an immunosuppressed state. Although there have been increasing reports of IRIS occurring in the setting of SOT and infections with MTB and a variety of opportunistic infections, we believe that IRIS is an underrecognized complication in this high risk group. This report demonstrates the difficulties encountered when IRIS develops in a SOT recipient during the management of extrapulmonary MTB infection by reduction in immunosuppression and institution of appropriate antimycobacterial therapy. It is possible that decreasing immunosuppression may have further exacerbated the development of IRIS in this patient. The potential for the development of IRIS in SOT with MTB may have an impact on treatment strategies for physicians managing transplant immunosuppression. Clinicians should therefore be cognizant of the potential of IRIS not only in HIV/AIDS cases but also in solid organ transplant patients. Caution should be used in decreasing immunosuppression in SOT patients undergoing treatment for MTB. Developing greater awareness among treatment providers about the paradoxical nature of IRIS is essential for the safe and proper management of patients that have undergone therapeutic immunosuppression for transplantation. What is clear is that further investigation into IRIS associated with solid organ transplantation must be completed to develop not only our understanding but also appropriate treatment protocol for this complex phenomenon.