Distinct Disease States Research Articles

Diagnostic utility of hematological indices in predicting adverse outcomes and severity of acute pancreatitis based on BISAP and modified Glasgow score.

The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte-ratio (PLR), and red blood cell distribution width (RDW) are simple indicators of inflammatory status previously established as a severity indicator in distinct disease states. This study aimed to determine the impact of these simple hematologic indices with conventional inflammation markers such as C-reactive pro-tein (CRP) and white blood cells in acute pancreatitis (AP) patients and their relationship with AP risk stratification scores including Bedside Index for Severity of Acute Pancreatitis (BISAP) and modified Glaskow Prognostic score (mGPS) scores. This retrospective study was performed in the emergency department of Canakkale Onsekiz Mart University. A total of 171 patients (male/female: 68 [39.8%]/103 [60.3%]) with AP and 59 age and gender matched healthy subjects (male/female: 23 [39%]/36[61%]) as controls were enrolled in the present study. The patients were grouped according to severity and adverse outcomes according to BISAP and mGPS and a comparative analysis was performed to compare the NLR, PLR, and RDW between groups. The mean NLR values of AP patients and control group were 9.62±6.34 and 2.04±1.08, respectively (p<0.001), while the mean PLR values of AP patients and control group were 221.83±122.43 and 83.30±38.89, respectively (p<0.001). Except from RDW, all the other hematologic indices were found to be elevated (p<0.05 for WBC; NLR, PLR, and CRP) on both mild and severe disease at disease onset. NLR and PLR showed significant predictive ability for estimating serious complications associated with AP. The present study showed that NLR and PLR is increased in AP. Moreover, peripheral blood NLR and PLR values can predict disease severity and adverse outcomes associated with AP and can be used as an adjunctive marker for estimating disease severity.

Durable disease control with local treatment for oligoprogression of metastatic solid tumors treated with immune checkpoint blockade

BackgroundWhile the concept of oligometastatic disease is increasingly recognized as a distinct clinical disease state, the concept of oligoprogression is less well-characterized. Oligoprogression may be particularly relevant in the context of immune checkpoint inhibitors (CPI) given the underlying mechanism of action and insights regarding acquired resistance. In this study, we sought to characterize the incidence of oligoprogression in patients on CPI and explore the impact of local therapy. Materials and MethodsWe performed a retrospective analysis of all patients with advanced solid tumors (excluding glioblastoma multiforme) who received a PD-1, PD-L1, or CTLA-4 inhibitor at a single institution between 2011 and 2017. Oligoprogression was defined as progression at ≤3 metastatic lesions outside of the brain after achieving at least stable disease on CPI for 3 months. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. ResultsAmong 425 patients treated with CPI, 390 had advanced primary solid tumors outside of the central nervous system. 321 of these patients were evaluable for response, among whom 102 achieved at least stable disease. Oligoprogression was observed in 4.1% of the entire cohort and 15.7% of patients achieving at least stable disease on CPI. Among 16 patients experiencing oligoprogression, 15 received local therapy to the oligoprogressive lesions, many of whom continued CPI. At a median follow-up of 25.8 months, the median PFS for patients with oligoprogression after local therapy was 15.4 months. ConclusionsOligoprogression occurs in a subset of patients after an initial response to CPI. However, patients receiving local therapy to oligoprogressive sites may experience durable disease control. Further study is warranted. MicroabstractOligoprogression was observed in 4.1% of the entire cohort of patients on immune checkpoint inhibitors in this study and 15.7% of patients achieving at least stable disease. Among 16 patients experiencing oligoprogression, 15 received local therapy. At a median follow-up of 25.8 months, the median progression-free survival for patients with oligoprogression after local therapy was 15.4 months and zero patients had died. Oligoprogression occurs in a subset of patients after an initial response to CPI and local therapy to oligoprogressive sites may result in durable disease control.

Multinomial modelling of TB/HIV co-infection yields a robust predictive signature and generates hypotheses about the HIV+TB+ disease state.

BackgroundCurrent diagnostics are inadequate to meet the challenges presented by co-infection with Mycobacterium tuberculosis (Mtb) and HIV, the leading cause of death for HIV-infected individuals. Improved characterization of Mtb/HIV coinfection as a distinct disease state may lead to better identification and treatment of affected individuals.MethodsFour previously-published TB and HIV co-infection related datasets were used to train and validate multinomial machine learning classifiers that simultaneously predict TB and HIV status. Classifier predictive performance was measured using leave-one-out cross validation on the training set and blind predictive performance on multiple test sets using area under the ROC curve (AUC) as the performance metric. Linear modelling of signature gene expression was applied to systematically classify genes as TB-only, HIV-only or combined TB/HIV.ResultsThe optimal signature discovered was a 10-gene random forest multinomial signature that robustly discriminated active tuberculosis (TB) from other non-TB disease states with improved performance compared with previously published signatures (AUC: 0.87), and specifically discriminated active TB/HIV co-infection from all other conditions (AUC: 0.88). Signature genes exhibited a variety of transcriptional patterns including both TB-only and HIV-only response genes and genes with expression patterns driven by interactions between HIV and TB infection states, including the CD8+ T-cell receptor LAG3 and the apoptosis-related gene CERKL.ConclusionsBy explicitly including distinct disease states within the machine learning analysis framework, we developed a compact and highly diagnostic signature that simultaneously discriminates multiple disease states associated with Mtb/HIV co-infection. Examination of the expression patterns of signature genes suggests mechanisms underlying the unique inflammatory conditions associated with active TB in the presence of HIV. In particular, we observed that dysregulation of CD8+ effector T-cell and NK-cell associated genes may be an important feature of Mtb/HIV co-infection.

Five-parameter evaluation of dysphagia: A novel prognostic scale for assessing neurological decline in Gaucher disease type 2

BackgroundGaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2. MethodsA post-hoc analysis of modified barium swallow studies was performed. Six parameters of swallowing were scored in a retrospective chart review of eleven infants with GD2. Mixed effects regression, principal component analysis (PCA), and a transition analysis were used to evaluate swallow function and model disease progression. ResultsAll patients exhibited impaired swallow function. There was no association between any of the swallow parameters and age, indicating non-linear disease progression. PCA and transition analysis identified five parameters capturing multiple dimensions of swallowing which defined two distinct disease states. ConclusionA five-parameter swallow evaluation was sufficient to identify distinct states of GD2 and model prospective outcomes. This multi-dimensional evaluation could be a useful efficacy parameter for future therapeutic trials in GD2 and other neurodegenerative disorders of infancy.

A simple approximation to bias in the genetic effect estimates when multiple disease states share a clinical diagnosis.

Case-control genome-wide association studies (CC-GWAS) might provide valuable clues to the underlying pathophysiologic mechanisms of complex diseases, such as neurodegenerative disease and cancer. A commonly overlooked complication is that multiple distinct disease states might present with the same set of symptoms and hence share a clinical diagnosis. These disease states can only be distinguished based on a biomarker evaluation that might not be feasible in the whole set of cases in the large number of samples that are typically needed for CC-GWAS. Instead, the biomarkers are measured on a subset of cases. Or an external reliability study estimates the frequencies of the disease states of interest within the clinically diagnosed set of cases. These frequencies often vary by the genetic and/or nongenetic variables. We derive a simple approximation that relates the genetic effect estimates obtained in a traditional logistic regression model with the clinical diagnosis as the outcome variable to the genetic effect estimates in the relationship to the true disease state of interest. We performed simulation studies to assess the accuracy of the approximation that we have derived. We next applied the derived approximation to the analysis of the genetic basis of the innate immune system of Alzheimer's disease.

Current perspectives for the treatment of chronic myeloid leukemia

With an annual incidence of 1–2 in a million, Ph*(+) chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disease that makes myeloid neoplastic cells breed out of control. This BCR-ABL(+) myeloproliferative disease makes up about 15%–20% of all leukemia cases in adults. CML is seen more in males than females, with a rate of three to two. However, it does not show differences in prevalence in terms of age. CML consists of three clinical phases. The first one is the chronic phase, defined by rising white blood cell levels and also by myeloid proliferation and bone marrow maturation. While this phase does not exhibit complications, in diagnosis, it comprises most of the patients. The second phase is the accelerated phase, which the disease progresses to if it is not treated or does not respond to treatment. This usually takes about 3 years. The third phase is the blastic phase. The chronic phase can still progress to the next two phases within the first 2 years, with a rate of 10%. In the following years, the possibility increases by 15%–20% each year. Tyrosine kinase inhibitors (TKIs) are revolutionary drugs for the management of disease course in CML. The aim of this review is to assess current approaches to CML patients’ follow-up and treatment with TKIs. A literature search on CML and TKIs was made in PubMed, Web of Science, and Scopus with particular focus on randomized clinical trials, recommendations, guidelines, and expert opinions. In managing CML, various treatment methods have been utilized for many decades. Prior to the development of TKIs, interferon alpha was the primary tool, which was then complemented by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was successful in slowing the disease down in the long term and curing up to 50% of patients. Then the coming of the imatinib era opened up different treatment perspectives. For the patients resistant or intolerant to imatinib, second- and third-generation TKIs are successfully used in distinct CML disease states. The survival benefits of TKIs including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib for CML patients are outstanding. TKI-related adverse events could impact the clinical course, especially in long-term drug administrations. The current aim for CML disease management in the TKI era is to provide age- and sex-matched normal life duration to CML patients.

An Ambiguous Rash in an 11-Year-Old Boy

The varicella zoster virus is known for two distinct disease states, the primary varicella zoster virus and herpes zoster. Children who are vaccinated for varicella have a lower incidence of developing herpes zoster than those who have acquired the varicella virus. Regardless, vaccinated children are still at risk for developing herpes zoster and the diagnosis should be considered in patients with a clinical presentation of vesicular and erythematous lesions. An 11-year-old boy, with no significant past medical history, presented to his primary care physician for a rash on his lower back. A thorough history of possible contact exposures was ruled out and further review showed that the boy was up to date on all vaccines. The combination of his physical symptoms and appearance of the rash prompted a culture to be sent to the lab. These results returned positive for varicella zoster DNA on the corresponding polymerase chain reaction (PCR) and proper treatment was initiated. The manifestation of herpes zoster can vary in appearance and does not always present in a standard dermatomal pattern. When clinical diagnosis seems vague, pattern recognition of the distinct vesicular rash shared with a high index of suspicion due to associated symptoms should prompt the culturing of a vesicle for diagnosis of herpes zoster via DNA PCR. Early detection will help hasten appropriate treatment and education to reduce further spread of the virus. Int J Clin Pediatr. 2019;8(1):19-21 doi: https://doi.org/10.14740/ijcp334

PanoromiX: a time-course network medicine platform integrating molecular assays and pathophenotypic data

BackgroundNetwork medicine aims to map molecular perturbations of any given diseases onto complex networks with functional interdependencies that underlie a pathological phenotype. Furthermore, investigating the time dimension of disease progression from a network perspective is key to gaining key insights to the disease process and to identify diagnostic or therapeutic targets. Existing platforms are ineffective to modularize the large complex systems into subgroups and consolidate heterogeneous data to web-based interactive animation.ResultsWe have developed PanoromiX platform, a data-agnostic dynamic interactive visualization web application, enables the visualization of outputs from genome based molecular assays onto modular and interactive networks that are correlated with any pathophenotypic data (MRI, Xray, behavioral, etc.) over a time course all in one pane. As a result, PanoromiX reveals the complex organizing principles that orchestrate a disease-pathology from a gene regulatory network (nodes, edges, hubs, etc.) perspective instead of snap shots of assays. Without extensive programming experience, users can design, share, and interpret their dynamic networks through the PanoromiX platform with rich built-in functionalities.ConclusionsThis emergent tool of network medicine is the first to visualize the interconnectedness of tailored genome assays to pathological networks and phenotypes for cells or organisms in a data-agnostic manner. As an advanced network medicine tool, PanoromiX allows monitoring of panel of biomarker perturbations over the progression of diseases, disease classification based on changing network modules that corresponds to specific patho-phenotype as opposed to clinical symptoms, systematic exploration of complex molecular interactions and distinct disease states via regulatory network changes, and the discovery of novel diagnostic and therapeutic targets.

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder.

Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ2 (PLCγ2) gives rise to two distinct human disease states: acquired resistance of chronic lymphocytic leukemia cells (CLL) to inhibitors of Brutons´s tyrosine kinase (Btk) and dominantly inherited autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγ2S707Y mutation to other PLCG2 mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ2-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγ2S707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγ2Δ19 and PLCγ2Δ20-22. Combinations of CLL Btk inhibitor resistance mutations synergized to enhance PLCγ2 activity, with distinct functional consequences for different temporal orders of the individual mutations. Enhanced activity of PLCγ2S707Y was not observed in a cell-free system, suggesting that PLCγ2 activation in intact cells is dependent on regulatory rather than mutant-enzyme-inherent influences. Unlike the two PLAID mutants, PLCγ2S707Y was insensitive to activation by cooling and retained marked hyperresponsiveness to activated Rac upon cooling. In contrast to the PLAID mutants, which are insensitive to activation by endogenously expressed EGF receptors, the S707Y mutation markedly enhanced the stimulatory effect of EGF, explaining some of the pathophysiological discrepancies between immune cells of PLAID and APLAID patients in response to receptor-tyrosine-kinase activation.

Effect of Productive Human Papillomavirus 16 Infection on Global Gene Expression in Cervical Epithelium.

Human papillomavirus (HPV) infection is the world's most common sexually transmitted infection and is responsible for most cases of cervical cancer. Previous studies of global gene expression changes induced by HPV infection have focused on the cancerous stages of infection, and therefore, not much is known about global gene expression changes at early preneoplastic stages of infection. We show for the first time the global gene expression changes during early-stage HPV16 infection in cervical tissue using 3-dimensional organotypic raft cultures, which produce high levels of progeny virions. cDNA microarray analysis showed that a total of 594 genes were upregulated and 651 genes were downregulated at least 1.5-fold with HPV16 infection. Gene ontology analysis showed that biological processes including cell cycle progression and DNA metabolism were upregulated, while skin development, immune response, and cell death were downregulated with HPV16 infection in cervical keratinocytes. Individual genes were selected for validation at the transcriptional and translational levels, including UBC, which was central to the protein association network of immune response genes, and top downregulated genes RPTN, SERPINB4, KRT23, and KLK8 In particular, KLK8 and SERPINB4 were shown to be upregulated in cancer, which contrasts with the gene regulation during the productive replication stage. Organotypic raft cultures, which allow full progression of the HPV life cycle, allowed us to identify novel gene modulations and potential therapeutic targets of early-stage HPV infection in cervical tissue. Additionally, our results suggest that early-stage productive infection and cancerous stages of infection are distinct disease states expressing different host transcriptomes.IMPORTANCE Persistent HPV infection is responsible for most cases of cervical cancer. The transition from precancerous to cancerous stages of HPV infection is marked by a significant reduction in virus production. Most global gene expression studies of HPV infection have focused on the cancerous stages. Therefore, little is known about global gene expression changes at precancerous stages. For the first time, we measured global gene expression changes at the precancerous stages of HPV16 infection in human cervical tissue producing high levels of virus. We identified a group of genes that are typically overexpressed in cancerous stages to be significantly downregulated at the precancerous stage. Moreover, we identified significantly modulated genes that have not yet been studied in the context of HPV infection. Studying the role of these genes in HPV infection will help us understand what drives the transition from precancerous to cancerous stages and may lead to the development of new therapeutic targets.

Characterizing heterogeneity in the progression of Alzheimer's disease using longitudinal clinical and neuroimaging biomarkers

IntroductionModels characterizing intermediate disease stages of Alzheimer's disease (AD) are needed to inform clinical care and prognosis. Current models, however, use only a small subset of available biomarkers, capturing only coarse changes along the complete spectrum of disease progression. We propose the use of machine learning techniques and clinical, biochemical, and neuroimaging biomarkers to characterize progression to AD. MethodsWe used a large multimodal longitudinal data set of biomarkers and demographic and genotype information from 1624 participants from the Alzheimer's Disease Neuroimaging Initiative. Using hidden Markov models, we characterized intermediate disease stages. We validated inferred disease trajectories by comparing time to first clinical AD diagnosis. We trained an L2-regularized logistic regression model to predict disease trajectory and evaluated its discriminative performance on a test set. ResultsWe identified 12 distinct disease states. Progression to AD occurred most often through one of two possible paths through these states. Paths differed in terms of rate of disease progression (by 5.44 years on average), amyloid and total-tau (t-tau) burden (by 10% and 69%, respectively), and hippocampal neurodegeneration (P < .001). On the test set, the predictive model achieved an area under the receiver operating characteristic curve of 0.85. DiscussionProgression to AD, in terms of biomarker trajectories, can be predicted based on participant-specific factors. Such disease staging tools could help in targeting high-risk patients for therapeutic intervention trials. As longitudinal data with richer features are collected, such models will help increase our understanding of the factors that drive the different trajectories of AD.

Role of the CRISPR system in controlling gene transcription and monitoring cell fate (Review)

Even though the accrual of transcripts is implicated in distinct disease states, our knowledge regarding their functional role remains obscure. The CRISPR system has surged at the forefront of genome engineering tools in the field of RNA modulation. In the present review, we discuss some exciting applications of the CRISPR system, including the manipulation of RNA sequences, the visualization of chromosomal loci in living cells and the modulation of transcription. The CRISPR system has been documented to be very reliable and specific in altering gene expression, via leveraging inactive catalytically dead CRISPR-associated protein 9 (Cas9). In the present review, the CRISPR system is presented as an eminent tool for the meticulous analysis of gene regulation, loci mapping and complex pathways.

Cell Surface Proteomics of N-Linked Glycoproteins for Typing of Human Lymphocytes.

Lymphocytes are immune cells that are critical for the maintenance of adaptive immunity. Differentiation of lymphoid progenitors yields B-, T-, and NK-cell subtypes that individually correlate with specific forms of leukemia or lymphoma. Therefore, it is imperative a precise method of cell categorization is utilized to detect differences in distinct disease states present in patients. One viable means of classification involves evaluation of the cell surface proteome of lymphoid malignancies. Specifically, this manuscript details the use of an antibody independent approach known as Cell Surface Capture Technology, to assess the N-glycoproteome of four human lymphocyte cell lines. Altogether, 404 cell surface N-glycoproteins were identified as markers for specific cell types involved in lymphocytic malignancies, including 82 N-glycoproteins that had not been previously been described for B or T cells within the Cell Surface Protein Atlas. Comparative analysis, hierarchical clustering techniques, and label-free quantitation were used to reveal proteins most informative for each cell type. Undoubtedly, the characterization of the cell surface proteome of lymphoid malignancies is a first step toward improving personalized diagnosis and treatment of leukemia and lymphoma.

Systematic Identification of Pharmacological Targets from Small-Molecule Phenotypic Screens

Phenotypic drug discovery offers some advantages over target-based methods, mainly because it allows drug leads to be tested in systems that more closely model distinct disease states. However, a potential disadvantage is the difficulty of linking the observed phenotype to a specific cellular target. To address this problem, we developed DePick, a computational target de-convolution tool to determine targets specifically linked to small-molecule phenotypic screens. We applied DePick to eight publicly available screens and predicted 59 drug target-phenotype associations. In addition to literature-based evidence for our predictions, we provide experimental support for seven predicted associations. Interestingly, our analysis led to the discovery of a previously unrecognized connection between the Wnt signaling pathway and an aromatase, CYP19A1. These results demonstrate that the DePick approach can not only accelerate target de-convolution but also aid in discovery of new functionally relevant biological relationships.

A novel multiplex assay for simultaneous quantification of total and S129 phosphorylated human alpha-synuclein.

BackgroundAlpha-synuclein (asyn) has been shown to play an important role in the neuropathology of Parkinson’s disease (PD). In the diseased brain, classic intraneuronal inclusions called Lewy bodies contain abnormal formations of asyn protein which is mostly phosphorylated at serine 129 (pS129 asyn). This suggests that post-translational modifications may play a role in the pathogenic process. To date, several uniplex assays have been developed in order to quantify asyn not only in the brain but also in cerebrospinal fluid and blood samples in order to correlate asyn levels to disease severity and progression. Notably, only four assays have been established to measure pS129 asyn specifically and none provide simultaneous readout of the total and pS129 species. Therefore, we developed a sensitive high-throughput duplex assay quantifying total and pS129 human asyn (h-asyn) in the same well hence improving accuracy as well as saving time, consumables and samples.ResultsUsing our newly established duplex assay we measured total and pS129 h-asyn in vitro showing that polo-like kinase 2 (PLK2) can phosphorylate asyn up to 41 % in HEK293 cells and in vivo the same kinase phosphorylated h-asyn up to 17 % in rat ventral midbrain neurons. Interestingly, no increase in phosphorylation was observed when PLK2 and h-asyn were co-expressed in rat striatal neurons. Furthermore, using this assay we investigated h-asyn levels in brain tissue samples from patients with PD as well as PD dementia and found significant differences in pS129 h-asyn levels not only between disease tissue and healthy control samples but also between the two distinct disease states especially in hippocampal tissue samples.ConclusionsThese results demonstrate that our duplex assay for simultaneous quantification is a useful tool to study h-asyn phosphorylation events in biospecimens and will be helpful in studies investigating the precise causative link between post-translational modification of h-asyn and PD pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0125-0) contains supplementary material, which is available to authorized users.

The oncologists’ unmet clinical needs for imaging in advanced prostate cancer

The management of men with advanced prostate cancer has become a dynamic field due to the approval of several agents in the castration-resistant state of the disease (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, radium-223), the technical advances of radiation therapy (IMRT; stereotactic body radiation) and not at least due to significant innovations in the field of imaging modalities. Several distinct disease states of prostate cancer can be identified, with specific needs with regard to imaging modalities. The manuscript will discuss the following disease states: castration-naive metastatic prostate cancer, oligometastatic prostate cancer, castration-resistant prostate cancer (non-metastatic M0 and metastatic M1). Imaging in advanced prostate cancer generally consists of bone scintigraphy and contrast enhanced-computed tomography (CT). Increasingly more sophisticated technologies including multiparametric MRI, PET/CT (with different tracers) and hybrid PET/CT-MRI techniques are discussed and in larger centres available also outside of clinical trials. Many questions, however, are unsolved and as of now it is unclear whether the increased diagnostic sensitivity/specificity of these imaging technologies translates into a relevant clinical benefit for men with advanced prostate cancer in the sense of improvement of clinical outcome or guiding treatment decision. This opinion piece will reflect some of the areas of unmet needs in the management of men with advanced prostate cancer that oncologists face in daily practice as perceived by the authors.

Topological distortion and reorganized modular structure of gut microbial co-occurrence networks in inflammatory bowel disease.

The gut microbiome plays a key role in human health, and alterations of the normal gut flora are associated with a variety of distinct disease states. Yet, the natural dependencies between microbes in healthy and diseased individuals remain far from understood. Here we use a network-based approach to characterize microbial co-occurrence in individuals with inflammatory bowel disease (IBD) and healthy (non-IBD control) individuals. We find that microbial networks in patients with IBD differ in both global structure and local connectivity patterns. While a “core” microbiome is preserved, network topology of other densely interconnected microbe modules is distorted, with potent inflammation-mediating organisms assuming roles as integrative and highly connected inter-modular hubs. We show that while both networks display a rich-club organization, in which a small set of microbes commonly co-occur, the healthy network is more easily disrupted by elimination of a small number of key species. Further investigation of network alterations in disease might offer mechanistic insights into the specific pathogens responsible for microbiome-mediated inflammation in IBD.

Evaluation of Oxidative Stress in Women with Polycystic Ovarian Syndrome as Represented by Serum Ischemia Modified Albumin and Its Correlation with Testosterone and Insulin Resistance.

Objective Ischemia-mediated oxidative stress and inflammation have been reported to be important contributors to the pathogenesis of polycystic ovary syndrome (PCOS). Ischemia-modified albumin (IMA) is a novel marker generated under ischemic and oxidative conditions and may reflect disease activity in distinct disease states. Therefore, we investigated whether the serum IMA levels are affected in infertile PCOS patients. Methods Forty-six patients with infertile PCOS, 30 patients with unexplained infertility, and 31 age- and body mass index (BMI)-matched controls were included in this cross-sectional study. Biochemical parameters, serum IMA levels, and their correlations with serum testosterone and insulin resistance were determined for each subject. Results In patients with infertile PCOS, the serum IMA levels were significantly elevated (p=0.003) compared with unexplained infertility patients and controls. A correlation analysis suggested that the IMA levels only correlated with the serum free testosterone levels in PCOS patients (r=0.43, p=0.028). Conclusion Elevations in the serum IMA levels in infertile PCOS patients may suggest a possible additional role of oxidative stress mechanisms in disease pathophysiology. Moreover, correlation between serum IMA and testosterone levels may influence the quality of oocytes via alterations in the balance of critical follicular fluid factors in the follicular microenvironment.

Recurrent Idiopathic Catatonia: Implications beyond the Diagnostic and Statistical Manual of Mental Disorders 5th Edition.

We describe a case of recurrent, life-threatening, catatonic stupor, without evidence of any associated medical, toxic or mental disorder. This case provides support for the inclusion of a separate category of “unspecified catatonia” in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) to be used to classify idiopathic cases, which appears to be consistent with Kahlbaum’s concept of catatonia as a distinct disease state. But beyond the limited, cross-sectional, syndromal approach adopted in DSM-5, this case more importantly illustrates the prognostic and therapeutic significance of the longitudinal course of illness in differentiating cases of catatonia, which is better defined in the Wernicke-Kleist-Leonhard classification system. The importance of differentiating cases of catatonia is further supported by the efficacy of antipsychotics in treatment of this case, contrary to conventional guidelines.

Renal depletion of myo-inositol is associated with its increased degradation in animal models of metabolic disease.

Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.