Cell-Free Heme Exhibits Dose Dependent Lethality in a Murine Model of Sepsis

From the Washington University Office of Undergraduate Research Digest (WUURD), Vol. 13, 05-01-2018. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Lindsey Paunovich, Editor; Helen Human, Programs Manager and Assistant Dean in the College of Arts and Sciences Mentor(s): Kenneth Rem

Neurodegeneration with Brain Iron Accumulation: Two Additional Cases with Dystonic Opisthotonus

Background: Specific phenomenology and pattern of involvement in movement disorders point toward a probable clinical diagnosis. For example, forehead chorea usually suggests Huntington’s disease; feeding dystonia suggests neuroacanthocytosis and risus sardonicus is commonly seen in Wilson’s disease. Dystonic opisthotonus has been described as a characteristic feature of neurodegeneration with brain iron accumulation (NBIA) related to PANK2 and PLA2G6 mutations. Case report: We describe two additional patients in their 30s with severe extensor truncal dystonia causing opisthotonic posturing in whom evaluation revealed the diagnosis of NBIA confirmed by genetic testing. Discussion: Dystonic opisthotonus may be more common in NBIA than it is reported and its presence especially in a young patient should alert the neurologists to a possibility of probable NBIA

An Unusual Cause of Camptocormia

Background: Camptocormia is defined as forward flexion of the spine that manifests during walking and standing and disappears in recumbent position. The various etiologies include idiopathic Parkinson’s disease, multiple system atrophy, myopathies, degenerative joint disease, and drugs. Case Report: A 67-year-old diabetic female presented with bradykinesia and camptocormia that started 1 year prior to presentation. Evaluation revealed levosulpiride, a dopamine receptor blocker commonly used for dyspepsia, to be the culprit. Discussion: It is well known that dopamine receptor blockers cause parkinsonism and tardive syndromes. We report a rare and unusual presentation of camptocormia attributed to this commonly used gastrointestinal drug in the Asian population

An Unusual And Intriguing Presentation Of Sydenham’s Chorea

A 26-year-old male born of a non-consanguineous marriage with normal birth and developmental history presented with abnormal movements for the last 15 years. He first noticed changes in his handwriting. The movements were jerky, non-stereotyped, and were associated with violent flinging movements. They were not preceded by any premonitory urge and were only partially suppressible. The movements gradually progressed to involve the face and neck, and, over the next 5 years, became generalized. His parents also complained of behavioral disturbances such as hyperactivity, aggressiveness, and obsessive-compulsive behavior. There was no history of cognitive decline, psychosis, seizures, or myoclonic jerks. Family history was non-contributory. There was no history of rheumatic fever, vasculitis, or exposure to toxins. The patient suffered frequent throat infections until the age of 5 years. He had been previously prescribed multiple medications, without significant improvement (tetrabenazine, haloperidol, valproate, clonazepam in various combinations). This letter shows an unusual presentation of Sydenham’s chorea lasting more than 15 years and highlight the utility of antineuronal antibodies in such a scenario

Gall bladder stones: surgical treatment

Background: There is higher incidence of gall stones in Karnataka and more commonly seen in women aged between 25 to 55 years. In this study men are also encountered with gall stone. As all the gall stones cannot be removed by laparoscopic procedure, the complicated and adherent gall bladder with stones and where laparoscopic procedure is not available are removed by conventional open method of cholecystectomy and in this study open cholecystectomy procedure is dealt in detail.Methods: Open cholecystectomy through Right Kocher’s incision.Results: In this study of 10 cases with complications of gall stones dealt surgically by doing open cholecystectomy gave satisfactory postoperative results without much postoperative complications.Conclusions: Among 10 cases of open cholecystectomy 6 cases were done through duct first method and 4 cases were done through fundus 1st method, which gave good results and less postoperative complications

Appendicitis in pregnancy: management

Background:Acute appendicitis is an infrequent, yet one of the commonest surgical emergency encountered in pregnancy. Recorded incidence is about 1:1500 pregnancies. The aim of this study was to determine the risk factors associated with prenatal outcome in acute appendicitis during second and third trimester pregnancies. Open access surgery was done due to non-availability of laparoscopy.Methods:A total of 10 pregnant women who were diagnosed with acute appendicitis between Jan 2011 to Jan 2013 were presented and 7 of them operated by open access surgery.Results: Seven pregnant women who were diagnosed with acute appendicitis were operated upon during late pregnancy. The interval between symptom onset and surgery was the only predictive variable. A longer interval between symptom onset and surgery was associated with appendix perforation than with no appendix perforation. There was a significant difference in the rate of preterm labor (5.1% vs. 1.3%) and the rate of fetal mortality (25% vs. 1.7%) between patients with and without a perforated appendix.Conclusion:Delaying surgery correlates to more advanced disease with an increased risk of perforation. This contributes to an increased risk of further complications, including premature labor or abortion, and to higher maternal complication rates. Prompt diagnosis may improve the prenatal outcome.

Fecal Microbiota Transplantation Is Safe and Effective in Patients With Clostridioides difficile Infection and Cirrhosis

Background & Aims Clostridioides difficile infection (CDI) harms a large proportion of patients with cirrhosis. Fecal microbiota transplantation (FMT) is recommended for recurrent CDI, but its effects in patients with cirrhosis have not been established. We performed a multicenter observational study to evaluate the efficacy and safety of FMT for CDI in patients with cirrhosis. Methods We performed a retrospective study of 63 adults with cirrhosis (median model for end-stage liver disease score, 14.5; 24 patients with decompensated cirrhosis) who underwent FMT for CDI from January 2012 through November 2018 at 8 academic centers in the United States, Canada, and Italy. We collected data on patient demographics and characteristics of cirrhosis, CDI, and FMT from medical records and compared differences among patients with different severities of cirrhosis, and FMT successes vs failures at the 8-week follow-up evaluation. We also obtained data on adverse events (AEs) and severe AEs within 12 weeks of FMT. Results Patients underwent FMT for recurrent CDI (55 of 63; 87.3%), severe CDI (6 of 63; 9.5%), or fulminant CDI (2 of 63; 3.2%) primarily via colonoscopy (59 of 63; 93.7%) as outpatients (47 of 63; 76.8%). FMT success was achieved for 54 patients (85.7%). Among FMT failures, a higher proportion used non-CDI antibiotics at the time of FMT (44.4% vs 5.6%; P < .001), had Child–Pugh scores of B or C (100% vs 37.7%; P < .001), used probiotics (77.8% vs 24.1%; P = .003), had pseudomembranes (22.2% vs 0; P = .018), and underwent FMT as inpatients (45.5% vs 19%; P = .039), compared with FMT successes. In multivariable analysis, use of non-CDI antibiotics at the time of FMT (odds ratio, 17.43; 95% CI, 2.00–152.03; P = .01) and use of probiotics (odds ratio, 11.9; 95% CI, 1.81–78.3; P = .01) were associated with a greater risk of FMT failure. FMT-related AEs occurred in 33.3% of patients (21 of 63)—most were self-limited abdominal cramps or diarrhea. There were only 5 severe AEs that possibly were related to FMT; none involved infection or death. Conclusions In a retrospective study, we found FMT to be safe and effective for the treatment of CDI in patients with cirrhosis

Extracellular NAD and ATP: Partners in immune cell modulation

Extracellular NAD and ATP exert multiple, partially overlapping effects on immune cells. Catabolism of both nucleotides by extracellular enzymes keeps extracellular concentrations low under steady-state conditions and generates metabolites that are themselves signal transducers. ATP and its metabolites signal through purinergic P2 and P1 receptors, whereas extracellular NAD exerts its effects by serving as a substrate for ADP-ribosyltransferases (ARTs) and NAD glycohydrolases/ADPR cyclases like CD38 and CD157. Both nucleotides activate the P2X7 purinoceptor, although by different mechanisms and with different characteristics. While ATP activates P2X7 directly as a soluble ligand, activation via NAD occurs by ART-dependent ADP-ribosylation of cell surface proteins, providing an immobilised ligand. P2X7 activation by either route leads to phosphatidylserine exposure, shedding of CD62L, and ultimately to cell death. Activation by ATP requires high micromolar concentrations of nucleotide and is readily reversible, whereas NAD-dependent stimulation begins at low micromolar concentrations and is more stable. Under conditions of cell stress or inflammation, ATP and NAD are released into the extracellular space from intracellular stores by lytic and non-lytic mechanisms, and may serve as ‘danger signals–to alert the immune response to tissue damage. Since ART expression is limited to naïve/resting T cells, P2X7-mediated NAD-induced cell death (NICD) specifically targets this cell population. In inflamed tissue, NICD may inhibit bystander activation of unprimed T cells, reducing the risk of autoimmunity. In draining lymph nodes, NICD may eliminate regulatory T cells or provide space for the preferential expansion of primed cells, and thus help to augment an immune response

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an