Pathogenic Lesions Research Articles

Genetic characterization, antibiogram pattern, and pathogenicity of Clostridium perfringens isolated from broiler chickens with necrotic enteritis

The aims of this investigation were characterization, demonstration of the antibiogram pattern and detection of the pathogenicity of Clostridium perfringens (C. perfringens) strains isolated from broiler chickens in Damietta governorate, Egypt. A total of 357 samples representing 202 intestinal contents and 155 liver samples from freshly dead broiler chickens were collected from 18 broiler farms. Isolates of C. perfringens were identified morphologically, microscopically, and biochemically. Forty-seven C. perfringens isolates were recovered, which represented 20.3% of the intestinal contents and 3.8% of the liver samples. The toxins and virulence genes of C. perfringens were investigated using polymerase chain reaction. All of the toxigenic C. perfringens strains were type A and carried netB, tpeL, cpe, and plc genes. The in vitro antibiogram of C. perfringens strains revealed 100% sensitivity to gentamycin and levofloxacin and 100% resistance to nalidixic acid and ceftriaxone. The isolated C. perfringens strains were highly pathogenic and induced signs and lesions of necrotic enteritis as well as 43.3% mortalities in 20-day-old chicks. In conclusion, C. perfringens is an important pathogen that affects broiler chickens due to the presence of virulence genes and the pathogenicity in the inoculated birds.

Deficiency of thyroid hormone receptor protects retinal pigment epithelium and photoreceptors from cell death in a mouse model of age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. Progressive dystrophy of the retinal pigment epithelium (RPE) and photoreceptors is the characteristic of dry AMD, and oxidative stress/damage plays a central role in the pathogenic lesion of the disease. Thyroid hormone (TH) regulates cell growth, differentiation, and metabolism, and regulates development/function of photoreceptors and RPE in the retina. Population-/patient-based studies suggest an association of high free-serum TH levels with increased risk of AMD. We recently showed that suppressing TH signaling by antithyroid treatment reduces cell damage/death of the RPE and photoreceptors in an oxidative-stress/sodium iodate (NaIO3)-induced mouse model of AMD. This work investigated the effects of TH receptor (THR) deficiency on cell damage/death of the RPE and photoreceptors and the contribution of the receptor subtypes. Treatment with NaIO3 induced RPE and photoreceptor cell death/necroptosis, destruction, and oxidative damage. The phenotypes were significantly diminished in Thrα1−/−, Thrb−/−, and Thrb2−/− mice, compared with that in the wild-type (C57BL/6 J) mice. The involvement of the receptor subtypes varies in the RPE and retina. Deletion of Thrα1 or Thrb protected RPE, rods, and cones, whereas deletion of Thrb2 protected RPE and cones but not rods. Gene-expression analysis showed that deletion of Thrα1 or Thrb abolished/suppressed the NaIO3-induced upregulation of the genes involved in cellular oxidative-stress responses, necroptosis/apoptosis signaling, and inflammatory responses. In addition, THR antagonist effectively protected ARPE-19 cells and hRPE cells from NaIO3-induced cell death. This work demonstrates the involvement of THR signaling in cell damage/death of the RPE and photoreceptors after oxidative-stress challenge and the receptor-subtype contribution. Findings from this work support a role of THR signaling in the pathogenesis of AMD and the strategy of suppressing THR signaling locally in the retina for protection of the RPE/retina in dry AMD.

Magnetic Resonance Imaging Features on Deep Learning Algorithm for the Diagnosis of Nasopharyngeal Carcinoma.

The objective of this research was to investigate the application values of magnetic resonance imaging (MRI) features of the deep learning-based image super-resolution reconstruction algorithm optimized convolutional neural network (OPCNN) algorithm in nasopharyngeal carcinoma (NPC) lesion diagnosis. A total of 54 patients with NPC were selected as research objects. Based on the traditional CNN structure, OPCNN was proposed. Besides, MRI processed by the traditional CNN model and the U-net network model was introduced to be analyzed and compared with its algorithm. The used assessment parameters included volume transfer constant (Ktrans), rate constant (Kep), volume fraction (Ve), and apparent diffusion coefficient (ADC). The results showed that the values of Dice coefficient, peak signal-to-noise ratio (PSNR), and structural similarity (SSIM) of the OPCNN algorithm were significantly higher than those of the traditional CNN model and the U-net network model. Meanwhile, the difference was statistically significant (P < 0.05). Ktrans, Kep, and Ve in tumor lesions were significantly higher than those in the healthy side, while the ADC was significantly lower than that in the healthy side (P < 0.05). The sensitivity, specificity, and accuracy of dynamic contrast-enhancement magnetic resonance imaging (DCE-MRI) in the diagnosis of nasopharyngeal carcinoma staging were slightly higher than those in T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI). The diagnostic sensitivity of DCE-MRI was more than 85%, its diagnostic specificity was more than 75%, and its diagnostic accuracy was more than 90%. The AUC area of NPC diagnosed by combination of the three was significantly different from that diagnosed by single T2WI, DWI, and DCE-MRI (P < 0.05). The diagnostic accuracy of MRI based on the OPCNN algorithm for nasopharyngeal carcinoma (93.2%) was significantly higher than that of single MRI (76.4%). In summary, the OPCNN algorithm proposed in this study could improve the quality of MRI images, and the effect was better than the traditional deep learning model, which had the value of clinical promotion. The application value of DCE-MRI in the diagnosis of pathogenic lesions of nasopharyngeal carcinoma was better than conventional MRI. The combined application of T2WI, DWI, and DCE-MRI in the screening of nasopharyngeal carcinoma lesions could greatly improve the diagnostic accuracy of nasopharyngeal carcinoma.

РАСПРОСТРАНЕНИЕ ОИДИУМА НА РАСТЕНИЯХ РАЗЛИЧНЫХ СОРТОВ ВИНОГРАДА В УСЛОВИЯХ ДОНСКОЙ АМПЕЛОГРАФИЧЕСКОЙ КОЛЛЕКЦИИ

Information on the prevalence and harmfulness of oidium on grapevine plants of various varieties in the conditions of the Don ampelographic collection is presented. It was found that the corresponding meteorological conditions in 2019, 2020: moderate air temperature and high humidity in the spring months, as well as in July, the presence of foci of infection on the ampelocollection contributed to the epiphytotic development of oidium. The first signs of the pathogen were detected at the end of flowering - beginning of berry growth. During the growing season, despite the protective treatments against powdery mildew, the degree of pathogenic lesion exceeding 3.5 points was observed in 2019 in 88% of the studied varieties, in 2020 - in 20% of the varieties. The smallest degree of mildew infection (up to 1.5 points) in 2020 was noted in the varieties Tavrosi, Kumshatskiy beliy, Kumshatskiy cherniy.

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions.

We developed a new class of inhibitors of protein–protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2–20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein–protein interactions in the function of SHP2.

Evolution in Myeloid Neoplasms Clonal Architecture Post Allogeneic Hematopoietic Cell Transplantation

Relapse-related mortality remains one of the main causes of death in patients (pts) with myeloid neoplasms (MN) who undergo allogeneic hematopoietic cell transplantation (allo-HCT). Molecular mutations and cytogenetic abnormalities present in hematopoietic cells are important determinants of relapse risk, with MRD predictive of relapse after allo-HCT. We studied the clonal hierarchy of MN at diagnosis compared to the relapsed state, to determine the effects of the ancestral hit and subclones on the impact on post-transplant recurrence.DNA from marrow/PB samples of MN pts was subjected to analysis at the time of diagnosis, post, and at the time of relapse to evaluate clonal expansion or evolution using a targeted multi-amplicon deep NGS panel of all ORFs of the top 60 most commonly mutated genes in MDS.We identified 43 pts with MDS and MDS/MPN who underwent allo-HCT from 2000 to 2016, whom were assessed serially in non-relapsed MN (NR-MN) and relapsed (R-MN). Median age at diagnosis was 54 years (y, range, 22-69) and 54y (range, 22-70) at time of HCT; 56% were male. NR-MN vs. R-MN pts median IPSS and IPSS-R scores at the time of diagnosis, 1.0 vs. 1.25 (P=0.5) and 4.0 vs. 4.0 (P=0.6), respectively. 53% underwent MAC and 58% had a PBSC. Pre-HCT treatments included HMA (42%), ESA (29%), 7+3 (10%), IMiD (10%), and HU (10%). Serial cases had a median follow up of 4 y (range 0.7 - 14.8) from diagnosis (Dx) and 2.3 (0.1-10.7) y from HCT. Rates before HCT of CR (30% vs. 30%), progressive disease (13% vs. 5%), stable disease (25% vs 25%), and disease progression (35% vs. 40%) (P=0.89). Median follow up post allo-HCT was 1.6y vs. 2.5y (P= 0.26). The incidence of acute GVHD in NR-MN vs. R-MN was 43% vs. 65% (P= 0.269) and 39% vs. 15% for chronic GVHD (P= 0.156), respectively. No difference in median blast percentage pre allo-HCT 4% vs 3.5% (P=0.5722).In NR-MN pts (N=23) after transplant, their pre-HCT characteristics showed 45% (10/23) had abnormal cytogenetics, with the most common abnormalities being del17p, del7q, and/or monosomy 7. SNP analysis showed pathogenic lesions in 43% of assessable cases (6/14), with most frequent abnormalities being loss of 14q11.2 (N=3) and aberrations (loss/UPD) of chr 7 (N=3). Furthermore, 17/21 pts had ≥1 mutation in decreasing frequency TET2 (N=4) , BCOR/BCORL1 (3) , SRSF2 (3), STAG2 (3), ASXL1 (3) , TP53 (2). Post-HCT NGS analyses are ongoing.In R-MN pts (n=20) after transplant, their pre-HCT characteristics showed 65% had abnormal cytogenetics at diagnosis, with the most common chromosomal aberrations involving monosomy 7/7q, trisomy 8, del5q, and del20q. Pre-HCT, 14/20 pts had ≥1 mutation in decreasing frequency TP53 (N=4) , SF3B1 (3), U2AF1 (3) , DNMT3A (2) , NRAS (2), and ASXL1 (2) . NGS at disease diagnosis, post-HCT, and at relapse was performed for 9 pts. In 5 pts relapse of the original ancestral hit (PHF6, SF3B1, NRAS, TP53, and DNMT3A) evolution of additional mutations (ASXL1, KRAS, EZH2) (4 featured in Figure 1). Clinical management of relapsed pts included a 2nd allo-HCT in 7 pts (35%), of which 2 are alive, and DLI in 6 (30%), of which 3 are alive.Logistic regression analysis demonstrated that mutations in DNMT3A and TP53 were non-significantly associated with higher relapse rates (OR= 3.27; P=0.1403). Univariable analysis for time to relapse demonstrated a significant association with earlier relapse with chromosome 11 aberrations (HR=6.4; P=0.005), but DNMT3A and TP53 together (HR=2.285; P=0.1071), TP53 alone (HR=2.257; P=0.1576), and complex cytogenetics (HR=2.15; P=0.1733) with relapse did not reach statistically significance, due to limited sample size.In conclusion, serial analysis of R-MN pre and post-HCT indicated recurrences of the original ancestral mutation, but often included acquisition of new mutations. Retraction but not elimination of the initial ancestral clone in R-MN pts demonstrated the relevance of an earlier ontogenetic stage. The initial hit could potentially drive the phenotype and resultant characteristics of the disease of subsequent lesions or vice versa. We plan to apply ultra-deep sequencing followed by an in-house bio-analytical pipeline to exclude false positive low frequency hits thereby determining the true MRD for the mutation identified in the original MN pre allo-HCT. Deeper NGS of MN pts in the pre & post allo-HCT setting will expand understanding of primary clonal aberrations and their subsequent re-emergence or regression with disease evolution. [Display omitted] DisclosuresGerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Advani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Majhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity.

Understanding the role of common polymorphisms in modulating the clinical phenotype when they co‐occur with a disease‐causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild‐type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild‐type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis‐interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.

The incidence of brain lesions in central precocious puberty: The main cause for Chinese boys was idiopathic.

ObjectiveMany studies show that brain lesions are the main cause of central precocious puberty (CPP) in males. However, the association rate has not been reported in China. This study aimed to assess the frequency of both abnormal and likely pathologic brain lesions by magnetic resonance imaging (MRI) in Chinese boys with CPP.DesignThis is a retrospective cross‐sectional single‐centre study.Patients396 CPP boys were recruited from 2011 to 2019 in Children's Hospital, Zhejiang University School of Medicine, and 129 were eligible for our study.MeasurementsDiagnosis age, bone age, weight (kg), height (cm), puberty stage, MRI results and levels of sexual hormone were analysed.ResultsThe number of CPP boys is increasing from 2011 to 2019 in China. Brain MRI findings were normal in 83.7% of CPP boys. Only 21 (16.3%) CPP boys were found with abnormal MRI findings including hamartoma, pineal cyst and other minor changes.ConclusionIn China, there is an increasing trend of male CPP over the last decade and the main cause is idiopathic, rather than pathogenic brain lesions. Further investigations about the aetiology for CPP with pathological brain lesions are needed.

Comparison of the Hounsfield Unit Values Obtained From Cone-Beam Computed Tomography (CBCT) and Multidetector Computed Tomography (MDCT) Images for Different Bone Densities

Background and objective: In recent years, cone-beam computed tomography (CBCT) has become a key diagnostic tool in dentistry. CBCT can provide 3D images of the maxillofacial area to help dental practitioners in diagnosis and treatment, especially implant placement and treatment of pathogenic lesions. This study aimed to compare the Hounsfield Unit (HU) values obtained from CBCT images for bones of different densities with the corresponding HU values from MDCT images.&#x0D; Materials and methods: cube-shaped bone blocks of identical size were cut from the middle section of the cow ribs and femur area such that they had a layer of cortical bone in their buccal, lingual, and top surfaces and trabecular bone in the middle. MDCT scans were performed using a Somatom Sensation Ct Scanner. After determining HU from the results of these scans, nine suitable specimens from different ranges of HU were chosen for comparison. HU of the CBCT images was computed by the dedicated software of the CBCT machine. Finally, HU values obtained from MDCT and CBCT were compared. Data analysis was performed using SPSS version 25 at the 0.05 significance level.&#x0D; Results: The results showed a statistically significant difference between the mean HU from MDCT images and the mean HU from CBCT images (P&lt;0.05). For similar specimens, CBCT produced higher mean HU values than MDCT. The Pearson correlation test detected a significant direct relationship between the HU values of specimens in MDCT and CBCT (P&lt;0.05).&#x0D; Conclusion: For the tools and software used in this study, there was no significant difference between the HU values obtained from MDCT and CBCT, but the mean HU obtained from CBCT was higher than that from MDCT.

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis

IntroductionFibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple...

A Bama miniature pig model of monoallelic TSC1 mutation for human tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a dominant genetic neurocutaneous syndrome characterized by multiple organ hamartomas. Although rodent models bearing a germline mutation in either TSC1 or TSC2 gene have been generated, they do not develop pathogenic lesions matching those seen in patients with TSC because of the significant differences between mice and humans, highlighting the need for an improved large animal model of TSC. Here, we successfully generate monoallelic TSC1-modified Bama miniature pigs using the CRISPR/Cas9 system along with somatic cell nuclear transfer (SCNT) technology. The expression of phosphorylated target ribosomal protein S6 is significantly enhanced in the piglets, indicating that disruption of a TSC1 allele activate the mechanistic target of rapamycin (mTOR) signaling pathway. Notably, differing from the mouse TSC models reported previously, the TSC1+/− Bama miniature pig developed cardiac rhabdomyoma and subependymal nodules, resembling the major clinical features that occur in patients with TSC. These TSC1+/− Bama miniature pigs could serve as valuable large animal models for further elucidation of the pathogenesis of TSC and the development of therapeutic strategies for TSC disease.

Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms?

Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.

Abstract 3811: Circadian disruption enhances development of pancreatic inflammation and pancreatic cancer precursors

Abstract Introduction: Emerging data suggest a role for circadian disruption in tumor formation and progression. Yet little is known regarding the effects of circadian disruption on the oncogenesis of pancreatic ductal adenocarcinoma (PDAC). We sought to determine if circadian disruption enhances PDAC development through a genetically engineered mouse model, and evaluate possible mechanisms with transcriptomic analysis. Methods: KrasG12D/+ mice (K) were crossed with Pdx-1 Cre (C) mice on a C57BL/6 background to generate KC mice. At 4 weeks, mice were subjected to standard lighting conditions (KC normal circadian [KCNC]) or a chronic jet-lag protocol known to induce circadian disruption (KCCD), with light/dark cycles shifted 8 hours every 2-3 days. Mice were sacrificed at 9 months for histologic analysis, examining for PDAC and its precursor lesions (PanINs). Comparisons were made with Fischer's Exact Test. For pancreatic transcriptomic profiling, 144 4-week-old wild-type (WT) C57BL/6 mice underwent disruption (WTCD, n = 72) or standard lighting conditions (WTNC, n = 72) for 4 weeks to identify cycling genes over a 48 hour period. Four weeks was chosen to understand the effects of disruption on gene expression impacting tumor initiation. Standard gene cycling analysis was performed with meta2d utilizing a false discovery rate of q = 0.1, and comparisons were made with the Audic-Claverie Distribution tool. Results: All KC mice (27 KCNC &amp; 7 KCCD) exhibited chronic pancreatitis and PanIN-1 (p = 1). However, KCCD mice developed higher rates of acute pancreatitis (86% vs 4%; p &amp;lt; 0.01) and PanIN-2 (43% vs 7%; p = 0.04) versus KCNC mice. PanIN-3 (14% vs 7% p = 0.48) and PDAC (29% vs 16% p = 0.6) were also increased but did not reach statistical significance. Given this phenotype, we sought a mechanism through transcriptomic analysis. In total, we found 12.8% of the protein-coding pancreatic transcriptome was cycling in either WTNC or WTCD. Pathway enrichment analysis demonstrated genes important for circadian rhythm were cycling in WTNC, while those important for catabolism and protein localization were cycling in WTCD. Only 129 genes, shared between male and female mice, exclusively cycled following circadian disruption. Of those, roughly 15% have been implicated in PDAC development, reported as prognostic biomarkers in PDAC or possibly contribute to chemotherapeutic resistance in PDAC. Conclusion: Little is known about the effects of circadian disruption on PDAC. We have demonstrated histopathologic evidence of an increased incidence of pancreatic inflammation and pathogenic lesions following circadian disruption. Transcriptomic analysis of wild-type pancreas revealed an increased number of cycling genes involved in energy production following disruption. Future work will investigate the candidate genes identified to ascertain how circadian disruption leads to increased development of pancreatic lesions. Citation Format: Patrick Beard Schwartz, Morgan Walcheck, Noah D. Carrillo, Kristina A. Matkowskyj, Christopher A. Bradfield, Sean Ronnekleiv-Kelly. Circadian disruption enhances development of pancreatic inflammation and pancreatic cancer precursors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3811.

Primary Atopic Disorders.

Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector-related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors.

Swine proliferative enteropathy: pathogenic aspects and main diagnostic technics

Porcine proliferative enteropathy is an endemic worldwide disease, that causes enormous damage to the pig industry. Its agent is the bacteria Lawsonia intracellularis. This bacteria has several pathogenic mechanisms and, although well studied, many still remain unclear. Is can be manifested as acute, chronic or subclinical. This last one is usually underestimated but can cause average daily gain reduction and increase feed conversion ratio. Clinical signs may be very similar to other enteric diseases, requiring laboratory tests for diagnosis. To choose the best test, some points must be considered, as sample availability, laboratory capacity and infection stage of the animal. Then, this literature review was written about the disease, covering its main pathogenic aspects, clinical signs, lesions, and diagnostic technics.

Case Study: An Unusual Presentation of Smoldering Multiple Myeloma in a patient with End Stage Renal Disease

A 59-Year-Old Male patient presented to the benign hematology clinic with a chief complaint of persistent macrocytic anemia with mild thrombocytopenia of unclear etiology. The patient has an extensive medical history including end stage renal disease on hemodialysis post failed kidney transplant and recurrent gastrointestinal bleeds. Two colonoscopies have recently been unable to identify a bleeding source that would account for prolonged anemia. The degree of anemia that the patient was experiencing was disproportionate to clinical documentation of bleeding, and high MCV with normal TSH, Folate, B12 and no alcohol intake ruled out a deficiency as cause of anemia. Iron studies indicated that the cause was Anemia of Chronic disease. A Bone Marrow Biopsy was requested to rule out a Hematologic Malignancy. The Bone Marrow Biopsy came back with a reported diagnosis of Plasma Cell Myeloma as the core biopsy was fifty percent cellular and plasma cells made up fifteen to twenty percent of core biopsy cellularity. Paraprotein and radiologic studies were ordered to further differentiate between multiple myeloma, plasma cell leukemia and smoldering multiple myeloma. Radiologic studies were negative for pathogenic lesions, while paraprotein studies showed a monoclonal gammopathy of IgG Kappa and a bioclonal IgA region that couldn9t be further quantified. The patient was further refered to the malignant hematology Myeloma team. The patient hasn9t returned to make any further appointments with hematology, but has been admitted once for complications related to his end stage renal disease. Asymptomatic myeloma, also known as smoldering myeloma, is characterized by having a clonal plasma cell population in the bone marrow that is greater than 10 percent while having no organ damage. Some patients will start out asymptomatic before progressing to full blown disease. Treatment normally begins after symptoms evolve.

Molecular pathogenesis of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.

Case Study: An Unusual Presentation of Smoldering Multiple Myeloma in a Patient With End-Stage Renal Disease

<h3>ABSTRACT</h3> A 59-year-old male patient was presented to the benign hematology clinic with a chief complaint of persistent macrocytic anemia with mild thrombocytopenia of unclear etiology. The patient had an extensive medical history, including end-stage renal disease on hemodialysis after failed kidney transplant and recurrent gastrointestinal bleeds. Two colonoscopies had recently been unable to identify a bleeding source that would account for prolonged anemia. The degree of anemia that the patient was experiencing was disproportionate to clinical documentation of bleeding, and high mean corpuscular volume with normal <i>thyrotropin</i>, Folate, B12 and no alcohol intake ruled out a deficiency as cause of anemia. Iron studies indicated that the cause was anemia of chronic disease. A bone marrow biopsy was requested to rule out a hematologic malignancy. The bone marrow biopsy came back with a reported diagnosis of plasma cell myeloma, as the core biopsy was 50% cellular and plasma cells made up 15%–20% of core biopsy cellularity. Paraprotein and radiologic studies were ordered to further differentiate between multiple myeloma, plasma cell leukemia, and smoldering multiple myeloma. Radiologic studies were negative for pathogenic lesions, whereas paraprotein studies showed a monoclonal gammopathy of IgG Kappa and a bioclonal IgA region that could not be further quantified. The patient was further referred to the malignant hematology myeloma team. The patient has not returned to make any further appointments with hematology but has been admitted once for complications related to his end-stage renal disease. Asymptomatic myeloma, also known as smoldering myeloma, is characterized by having a clonal plasma cell population in the bone marrow that is greater than 10% while having no organ damage. Some patients will start out asymptomatic before progressing to full-blown disease. Treatment normally begins after symptoms evolve.

Molecular characterization and genotyping of recent isolate of Infectious Bronchitis Virus (IBV) in Egypt

In this study a total number of 22 organ samples (including trachea, lung and kidney) from 22 broiler farms from northern Upper Egypt were collected from Mars 2017 to June 2018 from chickens showing clear clinical and pathological signs of Infectious Bronchitis. The samples were prepared and examined by real time RT-PCR for diagnosis of IBV. A total number of 11 samples were positive (50%) which were used for further isolation on SPF eggs by three blind serial passages. Positive samples that showed the pathogenic lesions of IB (curling and dwarfing of embryos) were collected and tested with real time RT-PCR (rRT-PCR) for more confirmation then a part from S1 gene sequence was amplified by RT-PCR and the product was sequenced and the data have been compared with other related IBV strains. The results indicate that the Egyptian virus in this study has an identity percent reached up to 89% with other recent Egyptian isolates. However, it reached 67% with classical vaccine strains like H120 and variant I like CR88 strain. The lowest identity was observed with M41 strain (59%) in this study. The phylogenetic tree compared to other isolates from Middle East and worldwide showed that this isolate is related to the IBV variant 2 group closely related to IBVEg/1265B/2012 strain and the Israeli strain IS/1494/06.

Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies

The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.