bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive effect of methanol leaf extract of Azadirachta indica was mediated through suppression of renal caspase 3 expressions on Nω‐Nitro‐L‐Arginine Methyl Ester (L‐NAME) induced hypertension
Authors: Ogunpolu Blessing Seun , Omobowale Temidayo Olutayo , Ugbor Fisayo Olutayo , Adejumobi Olumuyiwa Abiola , Oyagbemi Ademola Adetokunbo , Falayi Olufunke Olubunmi , Adedapo Adeolu Alex , Yakubu Momoh Audu
Published: April 2020

In the last two decades, the incidence of hypertension has increased significantly both in developed and developing countries. Moreover, hypertension is known as a major risk factor in the development of cardiovascular diseases. Azadirachta indica Adr Juss (AI) known as neem, has been used traditionally for the treatment of various cardio‐metabolic diseases such as type 2 diabetes, obesity and hypertension. This study investigated the possible antihypertensive effects of the methanol leave extract of Azadirachta indica on Nω‐nitro‐L‐arginine methyl ester (L‐NAME) induced hypertension in Wistar rats. Fifty rats were selected into five groups, ten animals in each group, for this study. Group A (Control) received only clean water; group B received L‐NAME at 40 mg/kg; groups C and D were administered Azadirachta indica at 100 and 200 mg/kg, respectively, with L‐NAME at 40 mg/kg; and group E received enalapril at 25 mg/kg and L‐NAME at 40 mg/kg. All administrations were done for 21 days consecutively. Treatment with L‐NAME led to significant (p <0.05) increases in systolic, diastolic, mean arterial blood pressure and markers of oxidative stress in hypertensive rats. Immunohistochemistry showed increased renal expressions of Caspase‐3 in hypertensive rats compared to the control. Treatment with methanol leaf extract of Azadirachta indica caused significant improvement in antioxidant defense systems, reduction in markers of oxidative stress, restoration of blood pressure parameters and suppression of renal caspase‐3 expressions when compared to enalapril, standard antihypertensive drug. This study suggests that Azadirachta indica leaf extract can exert antihypertensive effect on L‐NAME induced elevation of blood pressure.
Structure‐Activity Relationships of a Negative Allosteric Modulator of the D3 Dopamine Receptor and Investigation of its Binding Site
Authors: Moritz Amy E. , Inbody Laura R. , Gandhi Disha M. , Akano Emmanuel , Fearce Chelesa , Free R. Benjamin , Barnaeva Elena S. , Hu Xin , Southall Noel T. , Ferrer Marc , Keck Thomas M. , Frankowski Kevin J. , Sibley David R.
Published: April 2020

Dopamine receptors (DARs) are G protein‐coupled receptors (GPCRs) that regulate diverse physiological functions including movement, cognition, mood, and reward‐related behaviors, and are involved in the treatment or etiology of many neuropsychiatric disorders including schizophrenia, substance use disorder (SUD), and Parkinson’s disease. DARs are classified as either D1‐like (D1R and D5R) or D2‐like (D2R, D3R, and D4R) based on structural homology and pharmacological properties. Antagonists of D2‐like DARs are currently used as drug therapies for many psychiatric disorders. While the D2R is highly expressed in the dorsal striatum, which regulates movement, the D3R has a more limited distribution to limbic regions associated with the control of mood and emotion. D3R‐selective antagonists may therefore be useful as schizophrenia or SUD therapeutics as they could attenuate psychotic or drug craving symptoms without the motor side effects frequently produced by D2R‐preferring antagonists. Discovery of subtype selective compounds for the D3R and D2R has been challenging due to high sequence homology within their orthosteric binding sites. However, compounds that modulate receptor activity through interactions with a less conserved allosteric site of the receptor have the potential to be highly selective. To find highly selective allosteric antagonists of the D3R, our lab utilized a high‐throughput screen of the NIH Molecular Libraries Program 400,000+ small molecule library using a D3R‐mediated β‐arrestin recruitment assay. We found one compound, MLS6357, that was selective for the D3R versus the D2R in several functional outputs including β‐arrestin recruitment and G‐protein activation. Further, radioligand binding and functional assays using closely related GPCRs revealed that MLS6357 has very limited cross‐reactivity with other GPCRs. Additionally, Schild‐type functional assays found that MLS6357 is a purely non‐competitive negative allosteric modulator of the D3R. We synthesized 46 analogs of MLS6357 using iterative medicinal chemistry and tested them for activity which revealed structure activity‐relationships and enabled further refinement of the scaffold. These efforts produced modulators that are 5‐ to 9‐fold more potent than the original hit compound. To identify the allosteric site on the D3R, we utilized D3R/D2R chimeras which revealed receptor regions necessary for compound efficacy. Further refinement of the binding pocket for MLS6357 will inform future medicinal chemistry efforts. Ultimately, this novel scaffold may be of benefit as a pharmacological probe or therapeutic lead for D3R‐related pathophysiology.

Support or Funding Information

NINDS Intramural Research Program
Development of ELLA Approach to Measure Kidney Injury Molecule‐1
Authors: Krandel Jessica , Scheetz Marc H. , Gilchrist Annette
Published: April 2020

Antibiotics with high nephrotoxic potential, such as polymyxins, are being used with increased frequency because of antibiotic resistance and few novel antibiotic agents. Dose escalation of polymyxins is limited by the kidney injury. The objective of this study was to develop a novel ELISA‐based assay using the ELLA instrument in an effort to increase sensitivity and decrease the amount of time required to detect sensitive biomarkers such as Kidney Injury Molecule‐1 (KIM‐1). KIM‐1 is a transmembrane glycoprotein expressed on the proximal convoluted tubule, shed into the urine and blood, and can be detected by ELISA as soon as 6 hours after cell injury, while remaining undetectable in persons with healthy kidneys. The FDA has qualified KIM‐1 for pre‐clinical and clinical study of drug‐induced nephrotoxicity. The ELLA platform has been reported to be more sensitive than MAGPIX for several biomarker assays such as IL‐1beta, PD‐L1, IL‐4, and TNF‐alpha. Improved sensitivity for KIM‐1 is needed for a blood assay as concentrations are considerably lower than the urinary assay counterpart. The ELLA platform is also reported to have better reproducibility given the reduction in manual steps. Each cartridge is manually loaded and then run hands‐off for approximately 1.5 hours.

Using the ELLA open cartridge system we examined several commercially‐available monoclonal and polyclonal antibodies to human KIM‐1. Capture antibodies were digoxigenin‐labeled and detection antibodies were biotinylated. A standard curve was created by spiking diluent with known concentrations of rhKIM‐1. Two diluents were tested – SD13 (Biotechne) and PBS.

Curves for rhKIM‐1 were run ranging from a minimum of 0.49 pg/mL to a maximum of 10000 pg/mL. Quality control urine and plasma samples of known concentrations were included with runs of unknown urine samples from patients treated with vancomycin. Results were analyzed using Graphpad Prism.

We determined the optimum concentration for the detection and capture antibodies, and identified in which position
monoclonal and polyclonal antibodies performed better, providing the most sensitive and accurate assay. Currently measurement of KIM‐1 is done using an ELISA or MAGPIX approach. Thus, we compared the ELLA assay to a MAGPIX assay and found that the ELLA is quicker and provides a lower LLOQ. Further development of the ELLA approach may provide a test that can be rapidly employed in a hospital setting for blood or urine to examine KIM‐1 levels and identify patients at risk for acute kidney injury.

Support or Funding Information

Funding: Kenneth A. Suarez Fellowship from Midwestern University, Biotechne, Intramural grant from Midwestern University (Chicago College of Pharmacy Pilot Grant, awarded to Dr. Gilchrist)
Dynamics of cytokines and heat shock proteins mRNA expression in thermally manipulated chicken challenged with intraperitoneally injection of Lipopolysaccharide (LPS).
Authors: Al-Zghoul Moh’d Borhan , Gerrard David , Dalloul Rami
Published: April 2020

Heat stress is known to significantly affect broiler immunity and cytokine expression, but it is not yet clear how embryonic thermal manipulation (TM) might help alleviate the aforementioned effects. The aim of the present study was to evaluate the effects of TM on the splenic mRNA expressions of IL‐1β, IL‐6, TNF‐α, IFN‐α, IFN‐β, IFN‐γ, IL‐4, IL‐8, IL‐15, IL‐16, IL‐17, IL‐18, Hsp70 and HSF‐3 in broilers intraperitoneally injected with lipopolysaccharide (LPS). TM was performed by elevating the incubation temperature to 39°C at 65% relative humidity for 18 h daily during embryonic days 8 to 16. Whereas, control group was incubated at standard condition during the whole incubation period (37.8°C and 56% relative humidity). LPS was intraperitoneally injected at a dose of 0.5 mg/kg body weight (BW) on post‐hatch days 10 and 24. spleens was collected from all groups to evaluate mRNA expression by relative‐quantitative real‐time RT‐qPCR. TM results in alteration in the mRNA expression dynamics of cytokine and heat shock protein following intraperitoneally injection of LPS. The results of this study provided us with a valuable information about the mechanisms by which thermal manipulation may modify the immune system response in the thermally manipulated chicken.

Support or Funding Information

Deanship of Research/ Jordan University of Science & Technology for its financial support of this work (Grant#: 44/2019).
Ultrasound’s limitations in investigating dynamic ligamentous ankle anatomy
Authors: Nix Jessica , McCullough Reid , Throckmorton Zachary
Published: April 2020

The distal tibiofibular joint, or tibiofibular syndesmosis, is supported by the anterior and posterior inferior tibiofibular ligaments, tibiofibular interosseous membrane and ligament, and inferior transverse ligament. As a component of the ankle complex, the tibiofibular syndesmosis exhibits little mobility, with the fibula translating not only laterally (Harris 1991), but also posteriorly, with external rotation (Malhotra et al. 2019), during ankle dorsiflexion to accommodate the foot’s internal rotation and talar wedging. The mobility of the tibiofibular syndesmosis is relevant in both clinical and evolutionary contexts; disruption of the syndesmosis results in a high ankle sprain, one of the most recalcitrant orthopedic injuries (Gerber et al. 1998), and flexibility of the syndesmosis is thought to be critical to arboreal resource acquisition via tree climbing (Venkataraman, Kraft, and Dominy 2013). While Mei‐Dan et al. (2009) argued dynamic ultrasound investigation of the anterior inferior tibiofibular ligament could be used to diagnose distal tibiofibular syndesmotic injury after analyzing 47 professional athletes, to our knowledge no studies have sought to quantify basic normal variation of the tibiofibular interosseous ligament in non‐professional athletes (i.e., most people). We hypothesized the length of the tibiofibular interosseous ligament measured via ultrasound would be greater during closed‐packed dorsiflexion than closed‐packed standing in adults lacking a prior history of an ankle injury. Data were collected after obtaining informed consent from a mixed‐sex and mixed‐ancestry population of young adults (n = 78), via ultrasounding the distal tibiofibular joint during standing with the knee in closed‐packed position, measuring the tibiofibular interosseous ligament within the tibiofibular clear space, then measuring the same structure within the tibiofibular clear space during squatting with the ankle in closed‐packed position. We found approximately 25% of subjects’ tibiofibular interosseous ligaments decreased in length as measured by ultrasound – which we attribute to registration error inherent to the non‐reproducibility of consistent ultrasound probe placement throughout the ankle’s range of movement. These results cast doubt on the utility of ultrasound in investigating dynamic ligamentous ankle anatomy, consistent with the findings of Prakash (2018), and likely a consequence of the fibula’s complex pattern of motion relative to the tibia during ankle movement.

Support or Funding Information

This work was supported by the Arkansas College of Osteopathic Medicine.
Multiparametric cardiac magnetic resonance imaging of the heart in people with spinal cord injury
Authors: Scott Berkeley A. , Soriano Jan E. , Rosentreter Ryan E. , Satriano Alessandro , Dufour Antoine , Charbonneau Rebecca , Feuchter Patricia , Rivest Sandra , Sandonato Rosa , Flewitt Jacqueline , Garcia Julio , West Christopher , White James , Phillips Aaron
Published: April 2020

Cardiovascular disease is the foremost cause of death for individuals with spinal cord injuries and is a patient priority in this population. To reduce cardiovascular disease, health care costs, and address key patient‐centered priorities, we must understand how and why heart health deteriorates after high‐level spinal cord injuries. Using high‐resolution cardiac magnetic resonance imaging and analysis approaches (ie., 4D strain analysis, 4D flow imaging, late gadolinium enhancement), our objective was to evaluate the impact of high‐level spinal cord injury on cardiac structure and function. Cardiac dimensions including chamber wall thickness were reduced in people with cervical spinal cord injury compared to matched controls and fibrosis was more apparent. Furthermore, we observed changes in global markers of strain in the heart including both longitudinal and circumferential strain after spinal cord injury. Cardiac magnetic resonance imaging revealed deficits in structure and function of the left ventricle after SCI. The next steps are to establish the risk factors leading to abnormal hearts after spinal cord injury, and develop strategies for prevention and treatment.

Support or Funding Information

Natural Sciences and Engineering Research Council of Canada, Canadian Institutes of Health Research, Stephenson Cardiac Imaging Centre, University of Calgary, Libin Cardiovascular Institute, Hotchkiss Brain Institute, Campus Alberta Neuroscience, Clinical Neurosciences Pilot Research Fund Program, Compute Canada, Rick Hansen Institute, Wings for Life Foundation
Anti‐inflammation Ameliorates Repairment of Frostbite‐induced Skin Injuries
Authors: Tu Huiyin , Zhang Dongze , Wadman Michael C. , Muelleman Robert L. , Li Yu-Long
Published: April 2020

Frostbite occurs when tissues freeze with cold external temperature. Freeze (ice crystals) destructs the cells and blood vessels, increases permeability in vessel walls and blood leaks into the tissues, and causes inflammation‐related further tissue damage. A mouse model of skin frostbite injuries was used to observe the effect of dexamethasone (Dex) on morphological recovery of damaged skin.

Under anesthetized condition, C57/BL6 mice were subjected to 5 minutes of the freezing by placing magnets pre‐frozen in dry ice (−20°C) to create frostbite injuries on back skin within 3‐cm diameter circle. Dex treatment (1 mg/kg/day, i.p.) began on the day of frostbite induction and lasted for 7 days. Histological data demonstrated that frostbite resulted in swelling and severe skin damage from the first day, including epidermal necrosis and loss, blood vessel breaking, liquid leakage, degeneration of the panniculus adiposus and carnosus. Pro‐inflammatory factors (IL‐1β and TNFα) were elevated from day 3 to day 14 after frostbite (p < 0.05, compared to control), reaching the maximum level at day 7 after frostbite. After 7 days of frostbite, the skin tissue starts to regenerate. Treatment with Dex attenuated the elevation of TNFα and IL‐1β (p<0.05, compared to frostbite group), promoted CD31 expression (a marker for vascularization; p<0.05, compared to frostbite group), and accelerated collagen deposition and wound closure. These results suggest that Dex treatment attenuates frostbite‐induced inflammation and improves the tissue repairment.
What We Can Do About Maternal Mortality—And How to Do It Quickly
Authors: Mann Susan , Hollier Lisa M. , McKay Kimberlee , Brown Haywood
Published: April 2020

(Abstracted from N Engl J Med 2018;379(18):1689–1691)

Women in the United States are more likely to die from childbirth- or pregnancy-related causes than women in any other high-income country, with black women dying at a rate 3 to 4 times that of white women. The Centers for Disease Control and Prevention identifies 3 types of complications as the most common potentially preventable causes of pregnancy-related death: postpartum hemorrhage, severe hypertension, and venous thromboembolism.
The Transition From Latent to Active Labor and Adverse Obstetrical Outcomes
Authors: Rosenbloom Joshua I. , Woolfolk Candice L. , Wan Leping , Stout Molly J. , Tuuli Methodius G. , Macones George A. , Cahill Alison G.
Published: April 2020

(Abstracted from Am J Obstet Gynecol 2019;221:487.e1–487.e8)

Previously defined time limits for latent labor (defined as ending at 6 cm) have been removed by recommendations on preventing primary cesarean delivery (which also urge clinicians to avoid cesarean delivery for labor abnormalities in the latent phase). However, relatively little is known about the implications of labor curve abnormalities from 4 to 6 cm and subsequent outcomes.
Chromosomal Microarray vs. NIPS: Analysis of 5541 Low-Risk Pregnancies
Authors: Sagi-Dain Lena , Vig Lital Cohen , Kahana Sarit , Yacobson Shiri , Tenne Tamar , Agmon-Fishman Ifat , Klein Cochava , Matar Reut , Basel-Salmon Lina , Maya Idit
Published: April 2020

(Abstracted from Genet Med 2019;21:2462–2467)

Prenatal genetic testing is conducted today using a variety of methods: noninvasive prenatal screening (NIPS) and invasive prenatal testing with karyotyping and/or chromosomal microarray analysis (CMA). While NIPS can detect some genetic aberrations without an invasive procedure, karyotyping and CMA require amniocentesis or chorionic villi sampling.
The Orthopaedic Trauma Service and COVID-19: Practice Considerations to Optimize Outcomes and Limit Exposure
Authors: Stinner Daniel J. , Lebrun Christopher , Hsu Joseph R. , Jahangir A. Alex , Mir Hassan R.
Published: April 2020

The COVID-19 pandemic has presented challenges to healthcare systems, including the cancellation and then staged resumption of elective procedures. The orthopaedic trauma community has continued to provide care to patients with acute musculoskeletal injuries that cannot be delayed in all scenarios. This article summarizes and provides relevant information (orthopaedic trauma service, outpatient fracture clinic, inpatient surgery) to the practicing orthopaedic traumatologist on maximizing outcomes while limiting exposure during the pandemic.

Level of Evidence:

Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.
Intracapsular pressure in children with septic arthritis of the hip
Authors: Gutiérrez Carbonell Pedro , Ruiz Piñana Enrique , Valiente Valero Jose Manuel
Published: April 2020

Elevated intracapsular pressure in the hip causes occlusion of the retinacular vessels and may result in avascular necrosis of the proximal femoral epiphysis (ANPFE) and growth disturbances. Our goal is to study intraarticular pressure in children with septic arthritis of the hip and its potential correlation with body weight, systemic blood pressure and the volume of synovial fluid aspirated from the joint. Thirteen septic arthritis of the hip were studied. Inclusion criteria: pain, limping, fever, leukocytosis, elevated C-reactive protein and ultrasonographic effusion >5 mm. Traumatic, inflammatory, rheumatic or tumoral origin were excluded. Mean age was 3.7 years. Girls were 58%. Mean time to articular drainage was 15 h. Arthrocentesis was performed. An STIC self-calibrating monitoring system with an error of ±1 mmHg was used. Measurements were taken: intracapsular pressure, volume of fluid aspirated, systolic and diastolic pressures and weight. Follow-up was 6.3 years. Descriptive and nonparametric tests were performed: U Mann–Whitney and Kruskal–Wallis. Statistical significance was P <0.05. Mean intracapsular pressure was 50.5 mmHg; fluid aspirated was 2.9 ml; systolic and diastolic pressures were 107.5 and 44.3 mmHg, respectively; weight was 16.2 kg. Intracapsular pressure exceeded 30 mmHg in eight children (61.5%) and was lower than 50 mmHg in 73%. Variables studied had no significance on intracapsular pressure. Complications: coxa magna in three patients (23%) and Harris lines in three (23%). Surgical drainage of septic arthritis of hip must be performed urgently, within the first 24 hours, to reduce the time with high intracapsular pressure and to avoid risk of ANPFE.
Morbidity and Mortality in Critically Ill Children. I. Pathophysiologies and Potential Therapeutic Solutions*
Authors: Pollack Murray M. , Banks Russell , Holubkov Richard , Meert Kathleen L. ,   and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network
Published: April 2020

Objectives:

Developing effective therapies to reduce morbidity and mortality requires knowing the responsible pathophysiologies and the therapeutic advances that are likely to be impactful. Our objective was to determine at the individual patient level the important pathophysiological processes and needed therapeutic additions and advances that could prevent or ameliorate morbidities and mortalities.

Design:

Structured chart review by pediatric intensivists of PICU children discharged with significant new morbidity or mortality to determine the pathophysiologies responsible for poor outcomes and needed therapeutic advances.

Setting:

Multicenter study (eight sites) from the Collaborative Pediatric Critical Care Research Network of general and cardiac PICUs.

Patients:

First PICU admission of patients from December 2011 to April 2013.

Interventions:

None.

Measurements and Main Results:

Two-hundred ninety-two patients were randomly selected from 681 patients discharged with significant new morbidity or mortality. The median age was 2.4 years, 233 (79.8%) were in medical/surgical ICUs, 59 (20.2%) were in cardiac ICUs. Sixty-five (22.3%) were surgical admissions. The outcomes included 117 deaths and 175 significant new morbidities. The most common pathophysiologies contributing to the poor outcomes were impaired substrate delivery (n = 158, 54.1%) and inflammation (n = 104, 35.6%). There were no strong correlations between the pathophysiologies and no remarkable clusters among them. The most common therapeutic needs involved new drugs (n = 149, 51.0%), cell regeneration (n = 115, 39.4%), and immune and inflammatory modulation (n = 79, 27.1%). As with the pathophysiologies, there was a lack of strong correlations or meaningful clusters in the suggested therapeutic needs.

Conclusions:

There was no single dominant pathophysiology or cluster of pathophysiologies responsible for poor pediatric critical care outcomes. Therapeutic needs often involved therapies that are not close to implementation such as cell regeneration, improved organ transplant, improved extracorporeal support and artificial organs, and improved drugs.
Reducing Cardiac Arrests in the PICU: Initiative to Improve Time to Administration of Prearrest Bolus Epinephrine in Patients With Cardiac Disease*
Authors: Ferguson Lee P. , Thiru Yamuna , Staffa Steven J. , Guillén Ortega Margarita
Published: April 2020

Objectives:

To evaluate the effectiveness of a quality-improvement initiative in reducing cardiac arrests in infants and children in the cardiac ICU.

Design:

Prospective observational before-after cohort study.

Setting:

Single pediatric cardiac ICU in the United Kingdom.

Patients:

All patients less than 18 years old admitted to the ICU.

Intervention:

Initial interdisciplinary training in cardiac arrest prevention followed by clinical practice change whereby patients with high-risk myocardium were identified on daily rounds. High-risk patients had bolus epinephrine preordered and prepared for immediate administration in the event of acute hypotension.

Measurements and Main Results:

Interrupted time series analysis was used to compare the cardiac arrest rate in the 18 months before and 4.5 years after implementation. Mean monthly cardiac arrest rate was 17.2 per 1,000 patient days before and 7.6 per 1,000 patient days after the initiative (56% decrease). Patient characteristics and ICU interventions were similar in the control and intervention periods. In the time series analysis, monthly cardiac arrest rate in the ICU decreased by 12.4 per 1,000 patient days (95% CI, –1.5 to –23.3; p = 0.03) immediately following the intervention, followed by a nonsignificant downward trend of 0.36 per 1,000 patient days per month (95% CI, –1.3 to 0.6; p = 0.44). Bolus epinephrine was administered during 110 hypotension events in 77 patients (eight administrations per 1,000 ICU days); responder rate was 77%. There were no significant changes in ICU and hospital mortality.

Conclusions:

Implementation of the initiative led to a significant, sustained reduction in ICU cardiac arrest rate.
Relationship Between Preoperative Gait Speed and Discharge Disposition After Open Heart Surgery: An Observational Study
Authors: Wilson Christopher M. , Willett Darian , Kostsuca Stephanie
Published: April 2020

Purpose:

To examine the relationship between gait speed before open heart surgery and discharge disposition. The hypothesis was that slower gait speeds before surgery may increase the likelihood of discharge to a skilled nursing facility after surgery and faster gait speeds may predict that patients were more likely to discharge home.

Methods:

Retrospective analysis of 720 medical records. Gait speed was measured through a 5-m walk test before cardiac surgery. Discharge disposition was examined for a relationship to gait speed.

Results:

Slower gait speeds before surgery increased the likelihood of discharge to a rehabilitation facility or a skilled nursing facility while faster gait speeds increased the likelihood of discharge home. Mean gait speed for discharge home (5.2 seconds) was statistically significantly different from discharge to rehab or institution (6.9 seconds, P < .0001). There was also a significant correlation between discharge disposition and preoperative assistive device use (P < .0001).

Conclusions:

Slower gait speeds before surgery showed an increased likelihood of discharge to a skilled nursing facility after surgery, and faster gait speeds lead to patients being able to go home after the surgery.
Occupational Contamination with a Highly Enriched Uranium Solution
Authors: Mullinax Ross A. , Iddins Bart O. , Alday Michael A. , McLaughlin David A.
Published: April 2020

This medical case report describes the first reported instance of occupational skin contamination with a uranyl nitrate solution containing highly enriched uranium. The report provides an overview of the unique medical treatment and management considerations in such a case. Internal dose assessment is covered in detail. The discussion covers key points regarding uranium characteristics, chemical and radiological damage to body tissues from HEU exposure, and resources available for assistance with a case of radiological contamination. This information adds to the limited medical literature on this topic and provides a valuable reference for medical personnel when dealing with this uncommon problem.
CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA
Authors: Nguyen Xuan-Thanh-An , Talib Mays , van Cauwenbergh Caroline , van Schooneveld Mary J. , Fiocco Marta , Wijnholds Jan , ten Brink Jacoline B. , Florijn Ralph J. , Schalij-Delfos Nicoline E. , Dagnelie Gislin , van Genderen Maria M. , de Baere Elfride , Meester-Smoor Magda A. , De Zaeytijd Julie , Balikova Irina , Thiadens Alberta A. , Hoyng Carel B. , Klaver Caroline C. , van den Born L. Ingeborgh , Bergen Arthur A. , Leroy Bart P. , Boon Camiel J.F.
Published: April 2020

Purpose:

To investigate the natural history of RHO-associated retinitis pigmentosa (RP).

Methods:

A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP.

Results:

Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor–retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001).

Conclusion:

Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies.
Atypical Corneal Ectasia Associated With Vitamin C Deficiency
Authors: Clijsters Leen , Van Wijngaerden Eric , Delbeke Heleen
Published: April 2020

Purpose:

To demonstrate a possible correlation between corneal ectasia and vitamin C deficiency.

Methods:

Case series.

Results:

This case series covers 3 patients with atypical features of corneal ectasia. All 3 had a peculiar general history and visited our tertiary ophthalmology department complaining about decreased visual acuity. Corneal tomography by Scheimpflug imaging (Pentacam) indicated an irregular astigmatism congruent with a corneal ectasia. A blood test diagnosed vitamin C deficiency.

Conclusions:

To the best of our knowledge, this is the first time a possible correlation between corneal ectasia and vitamin C deficiency is established. Although more research is of course of the essence, it proves useful to determine vitamin C plasma levels in patients presenting with atypical ectasia. To the extent that vitamin C deficiency is indeed diagnosed, it should be substituted orally.
Risk Factors for Carriage of Antibiotic-resistant Bacteria in Healthy Children in the Community
Authors: Messina Nicole L. , Williamson Deborah A. , Robins-Browne Roy , Bryant Penelope A. , Curtis Nigel
Published: April 2020

Background:

In addition to health care settings, antibiotic resistance has also been increasing in the community. Healthy children represent an important potential reservoir of antibiotic-resistant (AR) bacteria. However, strategies to reduce the spread of AR bacteria often fail to specifically address the factors that promote the carriage of AR bacteria in this population.

The objective of this review was to Identify risk factors for carriage of AR bacteria by healthy children.

Methods:

We did a systematic search of MEDLINE, Embase and PubMed for studies in developed (OECD) countries that assessed risk factors for carriage of AR bacteria in healthy children in the community. We excluded studies done before 1998 and studies of AR Streptococcus pneumoniae carriage in the absence of pneumococcal conjugate vaccination.

Results:

Of 1234 studies identified, 30 were eligible for inclusion. These studies assessed the impact of 49 risk factors on AR strains of S. pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. The majority of these risk factors were assessed in 2 or fewer studies per bacteria. Recent antibiotic consumption was associated with carriage of resistant respiratory bacteria (S. pneumoniae, H. influenzae); however, it was not consistently associated with carriage of AR bacteria in skin or stool (S. aureus and E. coli). For AR S. aureus, transmission within households appeared to have a greater impact than individual antibiotic use.

Conclusions:

The factors that promote carriage of AR bacteria by healthy children differed between bacterial species. To reduce reservoirs of AR bacteria in the community, it is essential for intervention strategies to target the specific risk factors for different bacteria.
The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli
Authors: Kucharczyk Mateusz W. , Chisholm Kim I. , Denk Franziska , Dickenson Anthony H. , Bannister Kirsty , McMahon Stephen B.
Published: April 2020

Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurons innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 after surgery, designated “late”-stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal–Wallis H for independent samples; CIBP vs sham-operated, day 14;P< 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, dorsal root ganglia in vivo imaging of genetically encoded calcium indicators and Markov Cluster Analysis were used to analyse 1748 late-stage CIBP (n = 10) and 757 sham-operated (n = 9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour, (1) 3 times as many sensory afferents responded (repeated-measures analysis of variance:P< 0.0001 [vs sham]); (2) there were significantly more small neurons responding (Kruskal–Wallis for independent samples (vs sham):P< 0.0001); and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats, and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.
Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models
Authors: Stine Carrie , Coleman Deziree L. , Flohrschutz Austin T. , Thompson Austen L. , Mishra Sanket , Blagg Brian S. , Largent-Milnes Tally M. , Lei Wei , Streicher John M.
Published: April 2020

Heat shock protein 90 (Hsp90) is a ubiquitous signal transduction regulator, and Hsp90 inhibitors are in clinical development as cancer therapeutics. However, there have been very few studies on the impact of Hsp90 inhibitors on pain or analgesia, a serious concern for cancer patients. We previously found that Hsp90 inhibitors injected into the brain block opioid-induced antinociception in tail flick, paw incision, and HIV neuropathy pain. This study extended from that initial work to test the cancer-related clinical impact of Hsp90 inhibitors on opioid antinociception in cancer-induced bone pain in female BALB/c mice and chemotherapy-induced peripheral neuropathy in male and female CD-1 mice. Mice were treated with Hsp90 inhibitors (17-AAG, KU-32) by the intracerebroventricular, intrathecal, or intraperitoneal routes, and after 24 hours, pain behaviors were evaluated after analgesic drug treatment. Heat shock protein 90 inhibition in the brain or systemically completely blocked morphine and oxymorphone antinociception in chemotherapy-induced peripheral neuropathy; this effect was partly mediated by decreased ERK and JNK MAPK activation and by increased protein translation, was not altered by chronic treatment, and Hsp90 inhibition had no effect on gabapentin antinociception. We also found that the Hsp90 isoform Hsp90α and the cochaperone Cdc37 were responsible for the observed changes in opioid antinociception. By contrast, Hsp90 inhibition in the spinal cord or systemically partially reduced opioid antinociception in cancer-induced bone pain. These results demonstrate that Hsp90 inhibitors block opioid antinociception in cancer-related pain, suggesting that Hsp90 inhibitors for cancer therapy could decrease opioid treatment efficacy.
The Citrullinated and MMP-degraded Vimentin Biomarker (VICM) Predicts Early Response to Anti-TNFα Treatment in Crohn’s Disease
Authors: Mortensen Joachim H. , van Haaften Wouter T. , Karsdal Morten A. , Bay-Jensen Anne-Christine , Olinga Peter , Grønbæk Henning , Hvas Christian L. , Manon-Jensen Tina , Dijkstra Gerard , Dige Anders
Published: April 2020

Background:

In Crohn’s disease (CD), 10% to 40% of patients do not respond to anti-tumor necrosis factor-α (TNFα) treatment. Currently, there are no biomarkers with adequate sensitivity to separate responders from nonresponders at an early stage.

Aim:

The aim of this study was to investigated whether early changes in the VICM (citrullinated and matrix metalloproteinase-degraded vimentin) biomarker were associated with response to anti-TNFα treatment in patients with CD.

Methods:

Serum VICM levels were measured by ELISA in 2 independent cohorts of CD patients (n=42) treated with anti-TNFα (infliximab or adalimumab). Response was determined by achieving clinical remission (Harvey Bradshaw Index<5).

Results:

Compared with baseline, VICM serum levels were reduced by anti-TNFα in the infliximab cohort (week 6 and 14) and in the adalimumab cohort (week 8). VICM was lower in the responders compared with the nonresponders [infliximab: week 6, P<0.05; area under the curve (AUC)=0.90; adalimumab: week 1, P<0.01 (AUC=0.91), and week 8, P<0.05 (AUC=0.86)], and were able to predict response to treatment after 1 week of treatment with an odds ratio of 42.5.

Conclusions:

The VICM biomarker was time dependently reduced in CD patients responding to anti-TNFα treatment. We suggest that VICM may be used as a marker for monitoring early response to anti-TNFα in patients with CD.
Reducing Hospitalization in Mild Acute Pancreatitis
Authors: Ahmed Awais , Kothari Darshan J. , Wardlaw Scott , Freedman Steven D. , Sheth Sunil G.
Published: April 2020

Goals and Background:

Acute pancreatitis (AP) is a common emergency department (ED) diagnosis, amounting to enormous costs. Our previous pilot study demonstrated the feasibility of reducing hospitalization using an ED-based observation pathway. In this follow-up study, we hypothesize that the pathway is durable in clinical practice, outside of research supervision, and patients can safely be managed without hospitalization.

Study:

We reviewed patients prospectively enrolled in the observation pathway after the end of the pilot study. We compared outcomes to patients enrolled in our pilot study and with a historic cohort of patients admitted with mild AP. Our primary outcome was hospitalization rate during the enrollment period and secondary outcomes included length of stay, 30-day readmissions, mortality, and health care utilization.

Results:

Over a 2-year period 165 patients met criteria for AP with 118 (71.5%) having mild AP. Fifty-four of 118 patients (45.8%) were enrolled in the observation pathway and of these, 45 patients were discharged from the ED, reducing hospitalization by 31.2%, compared with pilot study (22.2%) and historic cohort (0%) (P<0.05). Median length of stay was shorter [19.9 (observation) vs. 72.0 h (historic cohort), P<0.01]. There were fewer radiographic examinations in the observation cohorts (pilot and current study) than in the historic cohort (P<0.05), with similar 30-day readmissions, and no reported deaths.

Conclusions:

This follow-up study demonstrates the durability of an observation-based pathway to manage mild AP outside of a research protocol and maintain its ability to reduce hospitalizations without affecting readmission rates or mortality.
Thermal Ablation Versus Cryotherapy or Loop Excision to Treat Women Positive for Cervical Precancer on Visual Inspection With Acetic Acid Test: Pilot Phase of a Randomized Controlled Trial
Authors: Pinder Leeya F. , Parham Groesbeck P. , Basu Partha , Muwonge Richard , Lucas Eric , Nyambe Namakau , Sauvaget Catherine , Mwanahamuntu Mulindi H. , Sankaranarayanan Rengaswamy , Prendiville Walter
Published: April 2020

(Abstracted from Lancet Oncol 2020;21:175–184)

Cervical cancer has a long and treatable precancerous phase, is easily screened for, and is common enough to justify population-based screening even in low- and middle-income countries (LMICs). The standard treatment in high-income countries is large loop excision of the transformation zone (LLETZ).
A Modified Histopathologic Staging in Penile Squamous Cell Carcinoma Predicts Nodal Metastasis and Outcome Better Than the Current AJCC Staging
Authors: Sali Akash P. , Menon Santosh , Murthy Vedang , Prakash Gagan , Bakshi Ganesh , Joshi Amit , Desai Sangeeta B.
Published: April 2020

Recently, the American Joint Committee on Cancer (AJCC) updated the staging system for penile squamous cell carcinoma. According to it, unlike its previous version, the involvement of urethra does not upstage the tumor; however, the involvement of corpora cavernosa (CC) does. The tumors involving CC are now staged pT3, whereas those involving corpora spongiosa (CS) are staged pT2, irrespective of the involvement of the urethra. In the current study, we sought to validate these recent modifications and in-process also attempted to improvise upon it. The histopathology slides were reviewed in 142 cases of penile squamous cell carcinoma. The histopathologic variables noted were tumor grade, anatomic level of invasion (CC/CS), lymphovascular invasion (LVI), and perineural invasion (PNI). Metastases to the lymph nodes were confirmed. Tumors were staged pT2/pT3 according to AJCC 8th edition and this staging system was further improvised by incorporating histopathologic variables similar to pT1 tumors in AJCC 8th edition. Accordingly, pT2 tumors invaded CS/CC without LVI or PNI and were not grade 3, whereas pT3 tumors invaded CS/CC, showed LVI and/or PNI, or were grade 3. Both the staging models were then correlated with nodal metastasis and disease-free survival. The new staging model (P=0.001) and not the AJCC pT2/pT3 stages (P=0.2) showed a statistically significant correlation with nodal metastasis. Similarly, only the proposed model significantly impacted disease-free survival (P=0.011). To conclude, we were unable to validate the prognostic difference between the pT2/pT3 stages according to AJCC 8th edition. The staging system can be improvised by incorporating histopathologic variables similar to pT1 tumors.
Gastrointestinal Malakoplakia
Authors: Zhang Yang , Byrnes Kathleen , Lam-Himlin Dora , Pittman Meredith , Pezhouh Maryam , Gonzalez Raul S. , Alruwaii Zainab , Larman Tatianna , Miller James A. , Matoso Andres , Oshima Kiyoko , Epstein Jonathan I. , Montgomery Elizabeth A. , Voltaggio Lysandra
Published: April 2020

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.
Anticipatory oculomotor responses in parents of children with attention deficit hyperactivity disorder
Authors: Chamorro Yaira , Ramírez-Dueñas María de Lourdes , Matute Esmeralda
Published: April 2020

Objective

Diminished inhibitory control has been proposed as a core characteristic and potential endophenotype of attention deficit hyperactivity disorder (ADHD). If this is the case, one would expect to find this trait among first-degree relatives of individuals with ADHD. The aim of this study, therefore, was to determine whether the oculomotor measures typically related to inhibitory control failures in individuals with ADHD are also observed among those relatives.

Methods

Using prosaccadic and antisaccadic tasks in gap and overlap conditions, we assessed a group of unaffected parents of children with ADHD symptoms and compared them to a group of unaffected parents of children with typical development. Direction errors, anticipatory errors and saccadic reaction times were analyzed. We also determined the presence of ADHD behaviors (in adulthood and childhood) in all participants.

Results

No between-group differences were observed for the antisaccadic measures, but the group of parents of children with ADHD made more anticipatory responses on the prosaccadic-gap task than the parents of controls. A moderate association between these anticipatory errors and dimensional inattention scores was also found.

Conclusions

Saccadic performance differed between the two groups of parents, as those with children with ADHD showed a failure to withhold the initiation of responses in the absence of external control references (gap condition) on tasks with low cognitive load (prosaccadic). These anticipatory responses were related to inattention traits. Our results support the familial compound of ADHD as a multifactorial disorder.