The role of Fyn kinase in mediating microglial pro-inflammatory responses in Parkinson\u27s disease

Disparate lines of evidence including in vitro cell culture, ex vivo brain slice culture, and virtually every in vivo model system have clearly implicated microglial activation and neuroinflammation in the pathophysiology of the dopaminergic neuronal cell death in Parkinson’s disease (PD). The signaling pathways that lead to this chronic activation are still being elucidated. We show herein, the role of the non-receptor Src family tyrosine kinase Fyn in mediating pro-inflammatory signaling in microglia cells in response to various inflammogens. Our results from cell and animal models as well as postmortem brain tissues conclusively demonstrate that Fyn is preferentially activated in microglia post-stimulation with either Lipopolysaccharide (LPS) or Tumor necrosis factor alpha (TNFα). Activated Fyn then tyrosine-phosphorylates the known pro-inflammatory kinase PKCδ, mediating PKCδ-dependent activation of the NF-κB pathway, leading to pro-inflammatory cytokine and nitrite production. Both Fyn-/- and PKCδ-/- mice were remarkably resistant to LPS-mediated neuroinflammation, as well as neuroinflammation and dopaminergic neuronal loss induced by the Parkinsonian toxicant 6-hydroxydopamine (6-OHDA). Activation of the NLRP3 inflammasome, mediated by fibrillar amyloid-β, the major component of Alzheimer’s disease-associated senile plaques, has recently been shown to contribute to disease progression. Thus, we sought to validate whether the aggregated form of the PD-associated protein α-synuclein could activate the NLRP3 inflammasome within microglia. Our results conclusively demonstrate that α-synuclein can elicit the NF-κBdependent induction of the inflammasome components pro-IL-1β and NLRP3, as well as the Caspase-1- and ASC-dependent processing of pro-IL-1β to mature IL-1β. Remarkably, Fyn kinase was shown to contribute to both processes, via PKCδ-dependent NF-κB pathway activation to prime the NLRP3 inflammasome as well as to the uptake of α-synuclein into the cell, which leads to the assembly and activation of the inflammasome complex. Lastly, we demonstrate activation of the NLRP3 inflammasome in various α-synuclein-overexpressing PD model systems, as well as in post-mortem PD patient tissues. Fyn also contributes to microglial ASC speck formation in the adenoviral α-synuclein overexpression system. Overall, we identify Fyn kinase as a key upstream regulator of the microglia-mediated chronic neuroinflammatory cascade that is central to the pathophysiological process of nigral dopaminergic degeneration in PD

Triplet heterotopic pregnancy following ovulation induction with clomiphene citrate: a case report and review of literature

Heterotopic pregnancy, though rare is a combined pregnancy in which synchronous intrauterine and extra uterine pregnancy occur. An estimated incidence of between 1/8000 to 1/30,000 has been reported following spontaneous conception. After artificial reproductive techniques, the incidence is as high as 1/100 and after ovulation induction with clomiphene citrate, it is around 1/900. We are reporting a case of 26 year old gravida 2 who conceived after ovulation induction with clomiphene citrate and presented to the emergency department with acute abdominal pain. Ultrasound pelvis showed viable twin intrauterine gestation of 8 weeks along with ruptured ectopic pregnancy on the right tube. After stabilizing the patient, emergency laparotomy and right salpingectomy was performed. Fortunately, the intrauterine twin fetuses grew satisfactorily and patient was delivered by caesarean section at 36 weeks in view of previous lower segment caesarean section with preterm labour. Heterotopic pregnancy must be considered in a patient with amenorrhea, abdominal pain, adnexal mass and enlarged uterus particularly, conception following artificial reproductive techniques or fertility drugs, even though the intrauterine pregnancy has been documented. A high index of suspicion is important to avoid maternal morbidity, sometimes mortality and loss of intrauterine pregnancy

A Phenomenological Approach to Understand the Challenges Faced by Medical Students

Life in a medical school is more challenging, when compared to other disciplines like arts and engineering. The innate nature of the medical curriculum and the demands of the profession have created extensive pressure on its students, leading to the prevalence of high stress levels and stress related disorders in them. The mental health of future doctors is very important for quality patient care. Hence it is high time for medical institutions to design interventions to mitigate this situation. A significant amount of research has gone into identifying the predominant stressors of medical education and the prevailing stress levels amongst medical students. However, there is dearth in research efforts that explicitly explain: the manifestation of stressors in different stages of medical education; coping strategies of students; and the kind of support required by the students to cope up with these challenges. Hence this study uses a phenomenological approach to understand the phenomenon of stress amongst medical students of a private medical college in South India. The study found that academic pressure, homesickness, faculty and institution related factors challenge the students. It was also found that the students require support to handle these challenges. These findings have interesting and important implications for institutions and policy makers, with respect to designing interventions to provide a congenial learning environment for our future doctors

The Role of Pelvic Neurophysiology Testing in the Assessment of Patients with Voiding Dysfunction

PURPOSE OF REVIEW: The role of pelvic neurophysiology testing in the evaluation of patients with lower urinary tract (LUT) symptoms is explored in this review. RECENT FINDINGS: Different neurophysiology tests such as sphincter EMG and pudendal somatosensory evoked potentials are useful in evaluating the sacral somatic afferent and efferent innervation. S2 and S3 dermatomal evoked potentials assess individual sacral roots and are feasible to perform using standard neurophysiology machines. SUMMARY: The innervation of the LUT has a substantial contribution from splanchnic and somatic nerves arising from the sacral segments. Pelvic neurophysiology tests, which assess somatic nerve functions, are therefore a useful tool in assessing sacral nerve functions in patients presenting with unexplained voiding dysfunction. In this review, the commonly performed neurophysiology studies that assess the S2, S3 and S4 sacral afferent and efferent pathways are outlined, and their clinical applications reviewed

Review of 113 cases of autoimmune disorders in pregnancy

Background: Autoimmune disorders are chronic multisystem disorders affecting women of their reproductive age. Pregnancy among these women is complicated by the disease itself. Flaring up of disease, uteroplacental insufficiency due to vasculitis and drugs used for treatment are main reason for unfavourable pregnancy outcomes. The objective of this study was to analyze the pregnancy complications and outcome among 113 cases of autoimmune disorders.Methods: This study is a retrospective analysis of case records of pregnant women with autoimmune disorders. This study was conducted at PSG IMSR and Hospital, Coimbatore, and Tamil Nadu from July 2012 to June 2018. The case sheets were retrieved from medical record department and the details such as type of disease, maternal age, parity, status of disease at conception, treatment taken during pregnancy, maternal complications and fetal complications were collected and analyzed.Results: During 6-year period there were 113 pregnant women with autoimmune disorders, and they were studied of their previous and present pregnancy outcome. The disease incidence was 7.01% per 1000 deliveries. 40.7% were less than 25 years age group and 71.6% were multigravidae. We had forty-one patients (36%) who were positive for APLA syndrome which were the maximum number of patients with auto immune disorder in pregnancy and 37 patients (32.7) with SLE. We had significant numbers of maternal and fetal complications for common disorders. Most of the rare auto immune disorders were diagnosed before pregnancy and these pregnancies were managed by multi-disciplinary approach, and continued on immunomodulators throughout pregnancy, hence maternal and fetal complications were less for them.Conclusions: Adequate pre-conceptional counseling, vigilant monitoring during pregnancy and post-partum will avoid pregnancy related complications and have favorable outcomes

On The Application Of Log Compression and Enhanced Denoising In Contrast Enhancement Of Digital Radiography Images

Digital radiography (DR) is becoming popular for the point of care imaging in the recent past. To reduce the radiation exposure, controlled radiation based on as low as reasonably achievable (ALARA) principle is employed and this results in low contrast images. To address this issue, post-processing algorithms such as the Multiscale Image Contrast Amplification (MUSICA) algorithm can be used to enhance the contrast of DR images even with a low radiation dose. In this study, a modification of the MUSICA algorithm is investigated to determine the potential for further contrast improvement specifically for DR images. The conclusion is that combining log compression and its inverse at the appropriate stage with a multi-stage MUSICA and denoising is very promising. The proposed method resulted in an average of 66.5 % increase in the mean contrast-to-noise ratio (CNR) for the test images considered.Comment: 4 pages, 4 figure

On a sperm whale landed at Kalpeni island with notes on ambergris

In the Indian Ocean The sperm whale Physeter macrocephalus is found concentrated more in the Arabian Sea upto 20° N and between 50° and 80° E especially in the Gulf of Aden and approaches a little east of Minicoy Island and off Sri Lanka. The morphology of the sperm whales landed at various islands in the Lakshadweep are Total length 530; Distance from eye to snout 115 cm; Height of the body 98cm and Girth of the body 62cm. Ambergris is a valuable substance obtained from the sperm whale. In 1974 ambergris weighing 90 kg was found floating in the sea and it was auctioned at the rate of Rs. 1,160 per kg. Of this amount, 55% was paid to the fisherman who recovered it and 45% was credited to the Fisheries Department

An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro

Analysis of various types of ectopic pregnancies: a five-year review

Background: Ectopic pregnancy (EP) is a common, life threatening emergency during the first trimester and a significant cause for maternal morbidity and mortality. In any woman of reproductive age presenting with abdominal pain and vaginal bleeding, ectopic pregnancy should be considered. The objectives of the present study is to determine the incidence, risk factors, clinical presentation, type of ectopic pregnancy, treatment, morbidity and mortality.Methods: Retrospective analysis of case sheets of patients admitted with ectopic pregnancy at PSGIMSR, Coimbatore during the period July 2011 to June 2016 was done. The details noted were age, parity, risk factors {previous abortion, previous EP, previous pelvic surgery, intrauterine contraceptive device, tubectomy, history of pelvic inflammatory disease}, treatment for infertility, clinical presentation, ultrasound findings, investigations including beta HCG value and hemoglobin level, treatment offered, need for blood transfusion, operative findings and morbidity.Results: During the five year, there were 12,407 deliveries at our hospitals and 88 cases of ectopic pregnancies were managed. The incidence is 6.6/1000 deliveries. Among them 44% belonged to the age group of 25-30 years and multi gravida were 73.8%. Most common risk factors were previous abortion (23.8%) and previous surgeries including caesarean section, tubectomy, appendicectomy, tubal microsurgery (23.8%). Most common presentation was pain abdomen (85.2%). Out of the 88 cases, 73 patients were managed surgically (82.9%) and 11 cases were managed successfully with methotrexate (12.5%). Three of them underwent conservative management and one had Uterine Artery Embolization.Conclusions: Early diagnosis based on risk factors and timely intervention plays a main role in reducing morbidity and mortality associated with ectopic pregnancy