bluuebunny/crossref_metadata_2025 huggingface dataset:
ACE2 gene therapy leads to Ang‐(1‐7)‐mediated restoration of glucose metabolism in diabetic mice
Authors: Bindom Sharell M , Lazartigues Eric D
Published: June 2021

We previously demonstrated that pancreatic ACE2 overexpression is able to improve glucose tolerance and reduce fasting blood glucose in diabetic mice. We hypothesized that ACE2 overexpression improves glucose homeostasis by enhancing pancreatic beta cell function. Diabetic db/db and lean mice (n=10/group) were infected with Ad‐hACE2 or a control adenovirus (Ad‐eGFP) and glucose homeostasis assessed after 7 days. Insulin sensitivity (area under the curve, AUC) was not different between Ad‐hACE2‐ and Ad‐eGFP‐treated db/db (50 ±3 vs. 54 ±4) and lean (31 ±9 vs. 35 ±9) mice, respectively. Ad‐hACE2 increased islet insulin content (arbitrary units) in db/db mice (92 ±7 vs. 49 ±6, P<0.01) but had no effect on lean mice (109 ±17 vs. 124 ±9) compared to Ad‐eGFP. Infusion with an Ang‐(1‐7) receptor antagonist [D‐Ala7‐Ang‐(1‐7), 600 ng/kg/min, 7 days sc], prevented Ad‐hACE2‐mediated normalization of fasting blood glucose (247 ±31 vs. 135 ±11 mg/dl, P<0.01) but had no effect on Ad‐eGFP‐treated diabetic mice (224 ±26 vs. 191 ±12 mg/dl). D‐Ala7‐Ang‐(1‐7) also prevented the Ad‐hACE2‐mediated improvement in glucose tolerance (AUC: 67 ±2 vs. 51 ±5; P<0.05) but did not affect Ad‐eGFP‐treated db/db mice (AUC: 68 ±3 vs. 72 ±2). These data indicate that ACE2 gene therapy improves pancreatic beta cell function and restores glucose homeostasis by increasing Ang‐(1‐7) receptor‐mediated signaling pathways. (NIH NS052479 and RR018766)
Pseudomonas aeruginosa toxin (Cif) induces lysosomal degradation of CFTR
Authors: Bomberger Jennifer , Ye Siying , O'Toole George , Stanton Bruce
Published: June 2021

P. aeruginosa is an opportunistic pathogen critical to the pathogenesis of nosocomial infections, chronic obstructive pulmonary disease, ventilator‐associated pneumonia, cystic fibrosis, and bronchiectasis. Cif, a bacterial toxin secreted by clinical isolates of P. aeruginosa, reduces CFTR‐mediated chloride secretion by decreasing endocytic recycling of CFTR. The aim of the current study was to investigate the mechanism by which Cif reduces the endocytic recycling of CFTR. Experiments in polarized human airway epithelial cells showed a reduction of CFTR in the plasma membrane with Cif exposure, followed by an increase in CFTR labeling in the late endosomes, then lysosomes. Moreover, lysosomal inhibitors blocked the degradation of CFTR by Cif. Concomitant to the Cif‐mediated degradation of CFTR, we measured an increase in the ubiquitination of CFTR. Employing a deubiquitinating enzyme (DUB) activity assay, we identified USP10 as a DUB that is inactivated by Cif in the early endosomes. siRNA‐mediated knockdown or a dominant‐negative USP10 was capable of recapitulating the Cif‐mediated increase in CFTR ubiquitination and degradation. These studies demonstrate that Cif inactivates USP10 and thus, triggers a redistribution of CFTR from recycling endosomes to the lysosomal degradation pathway. These data suggest that chronic infection of P. aeruginosa will result in diminished mucociliary clearance, severely compromising the immune defenses of the lung.
Potassium‐Sensitive Hyperaldosteronism in Kcnmb1−/− Mice (β1 KO)
Authors: Grimm Paul Richard , Irsik Debra L. , Settles Deann C. , Sansom Steven C.
Published: June 2021

Hypertension often results from elevated aldosterone (Aldo), which promotes renal Na reabsorption and K secretion (ROMK and BK). β1KO have defective renal K secretion and exhibit hypertension ‐ the latter thought to result from vascular smooth muscle dysfunction. BK are also in the zona glomerulosa cells, where they help regulate Aldo production. We hypothesized that the hypertension of β1KO results from inappropriate Aldo production in response to plasma [K]. Wild type (WT) and β1KO were fed a control (CK; 0.8%) or a high K (HK; 5.0%) diet for 10d. Additional groups were fed HK + Eplerenone (E; Aldo antagonist) or vehicle. Mean arterial blood pressure (mmHg) was greater in β1KO ‐ CK (134±17 vs 111±14) and was further increased in the β1KO ‐HK (149±12 vs 114±14) but reversed in β1KO ‐ HK+E (121±16 vs 113±16, p=NS). Compared to WT, β1KO ‐ CK had increased plasma [Aldo] (147±14 vs 107±6 pg/ml) which was further increased by HK (216±20 vs 145±17). β1KO ‐ HK (but not HK+E) exhibited volume expansion by increased body weights and reduced hematocrits. Plasma [K] (mM) was significantly increased in β1KO ‐ CK (4.4±0.1 vs 4.1±0.1) and ‐ HK (4.8±0.2 vs 4.3±0.3) compared to WT. HK+E increased plasma [K] in both WT and β1KO (6.0±0.2 vs 6.1±0.2, p=NS). The slope of the plasma [K] vs. [Aldo] relation was increased by 2‐fold in β1KO vs. WT. Conclusion: The hypertension of β1KO is partially due to elevated [Aldo], a condition that is exacerbated by HK diet.
Ca2+ entry via α1G and TRPV4 channels differentially regulates alveolar capillary endothelium
Authors: Townsley Mary , Jian Ming‐Yuan , Xu Yan‐Chun , Zhou Chun , Al‐Mehdi Abu‐Bakr , Liedtke Wolfgang , Shin Hee‐Sup , Wu Songwei
Published: June 2021

In this study, we addressed the discrete functional role of Ca2+ influx via the α1G T‐type Ca2+ channel and the transient receptor potential channel TRPV4 expressed in pulmonary capillary endothelium. In isolated, perfused mouse lung, we assessed endothelial cytosolic Ca2+ using real‐time fluorescence imaging, surface expression of P‐selectin using immunohistochemistry, and lung endothelial permeability using the filtration coefficient. The α1G T‐type channel or TRPV4 were activated by membrane depolarization (high K+, 25 mM) or 4α‐phorbol‐12,13‐didecanoate (4αPDD, 10 μM), respectively. Both high K+ and 4αPDD induced Ca2+ entry into alveolar septal endothelium. However, only high K+ elicited surface expression of P‐selectin and only 4αPDD increased lung endothelial permeability. Pharmacologic blockade or knockout of α1G abolished high K+‐induced Ca2+ entry and surface expression of P‐selectin, but did not prevent either the 4αPDD‐induced Ca2+ entry nor the resultant increase in permeability. Blockade or knockout of TRPV4 specifically abolished Ca2+ entry and increased permeability elicited by 4αPDD, but had no effect on the response to high K+. We conclude that in alveolar septal capillaries, Ca2+ entry through the α1G and TRPV4 channels differentially regulates discrete facets of lung endothelial function: P‐selectin expression and barrier integrity, respectively. Supported by HL066299.
Intrauterine growth restriction inhibits cell proliferation within the subventricular zone and white matter of rat offspring
Authors: Campbell Leigh Rhodes , Zheng Baoying , Ojeda Norma B , Royals Thomas P , Rhodes Philip G , Pang Yi , Alexander Barbara T
Published: June 2021

Our laboratory has developed a unique rat model of placental insufficiency that results in intrauterine growth restriction (IUGR). Many studies demonstrate an association of IUGR with atypical white matter development and abnormal neurologic outcome. We hypothesize that IUGR will affect cerebral development, and this insult will result in histopathologic changes. At postnatal day 6 (P6) and 14 (P14), rat pups were sacrificed. The brains were fixed with 4% paraformaldehyde and frozen sections prepared. There was no evidence of brain damage in the basic hematoxylin and eosin staining of IUGR rat pups at P6 and P14. However, immunohistochemistry with Ki‐67 demonstrated a significant decrease in cell proliferation within the subventricular zone (SVZ) and the surrounding white matter (719.7±119.7 vs. 339.4±55.3 cells/mm2; female control vs. female IUGR, respectively, P<0.05), but not in the cortex of P6 female IUGR rat pups. The decreased number of Ki‐67 + cells in the SVZ and white matter suggests possible damage or delay in brain development of the female IUGR rat.
Sympathetic or parasympathetic involvement in the postprandial gastrointestinal hyperemia of rainbow trout (Oncorhynchus mykiss)?
Authors: Seth Henrik Karl , Axelsson Michael
Published: June 2021

There is a limited knowledge concerning how the postprandial hyperemia, seen in fish as well as in mammals, is regulated. To investigate the possible involvement of both parasympathetic as well as sympathetic nerves in the postprandial hyperemia of rainbow trout, we sectioned both the vagal and splanchnic branches innervating the gastrointestinal tract before injecting a predigested diet into the intestine. After sectioning the extrinsic nerves innervating the gastrointestinal tract there was still a significant hyperemia. The response was, however, delayed compared to the response seen in the untreated animals. A potential explanation for this is that sectioning the splanchnic nerve leads to an altered tonus of the coeliacomesenteric artery, which would indicate that the splanchnic nerve is important in maintaining the routine blood flow of the gastrointestinal tract. The scope for increasing the gastrointestinal blood flow was nevertheless still substantial. In conclusion, the extrinsic innervation of the gastrointestinal tract is not a prerequisite for a postprandial hyperemia in rainbow trout. The splanchnic nerve is, however, potentially important in maintaining the routine tonus of the coeliacomesenteric artery and its branches.
CHARACTERIZATION OF MYOCARDIAL CONTRACTILE DYSFUNCTION IN TYPE 2 DIABETES MOUSE MODEL
Authors: Fricovsky Eduardo Santiago , Ihm Sang , Suarez Jorge , Scott Brian , Belke Darrell , Oyeleye Mary , Villarreal Francisco , Dillmann Wolfgang H
Published: June 2021

CHARACTERIZATION OF MYOCARDIAL CONTRACTILE DYSFUNCTION IN TYPE 2 DIABETES MOUSE MODEL

Eduardo Fricovsky, Sang Ihm, Jorge Suarez, Brian Scott, Francisco Villarreal, , Darrell Belke, Mary O. Oyeleye, Wolfgang Dillmann

Universitty of California, San Diego, La Jolla California.

Type 2 diabetes mellitus (DMII) contributes to cardiac dysfunction. Characterization of the development of cardiac dysfunction in DMII animal models has been incompletely explored. Currently, it is unknown if cardiac dysfunction occurs in DMII mouse even with mild hyperglycemia and insulin resistance. DMII was induced in mice by feeding a high fat diet (60% fat) and administering a single low dose of streptozotocin (75 mg/Kg). Echocardiography was performed at 2, 4, and 6 months post treatment and diastolic and systolic parameters, as well as biochemical analysis were assessed. Our results show that DMII mice have slightly increased fasting blood glucose compared with control mice (DMII: 124±13 vs. Control: 90±2.0mg/dL). Insulin serum levels were 3 fold increased starting at 2 months in DMII mice suggesting insulin resistance. At 6 months of DMII SERCA2a protein levels was significantly decreased by 50% in hearts. Echo results also showed that at 6 months of DMII mouse hearts already exhibited significant cardiac dysfunction. Fractional Shortening was significantly reduced (DMII: 30.8±6.1% vs. Control: 40.8±4.5%) and LV diastolic (DMII: 3.59±0.16mm vs. Control: 4.03±0.14mm) and systolic (DMII: 2.13±0.2mm vs. Control: 2.79±0.3mm) dimensions were decreased. In conclusion, this data indicates that cardiac dysfunction can develop in DMII mouse hearts even with mild hyperglycemia.
NOX2 is the primary source of superoxide in the macula densa in angiotension II induced hypertension
Authors: Zhang Rui , Lu Deyin , Fu Yiling , Juncos Luis , Liu Ruisheng
Published: June 2021

Tubuloglomerular feedback (TGF) is one of the main mechanisms that regulate the renal microcirculation, NaCl excretion, and ultimately blood pressure. Superoxide (O−2) in the macula densa (MD) enhances TGF by scavenging nitric oxide. MD expresses NOX2 and NOX4 isoforms of NAD(P)H oxidase. We hypothesize that NOX2 is the primary isoform for O−2 in angiotensin II (Ang II) induced hypertension.

MD like cell line, MMDD1, was used. O−2 was measured using lucigenin chemiluminescence with a luminometer and expressed by units/min/106 cells.

To measure whether Ang II induces O−2 production in MMDD1 cells, we stimulated the cells with Ang II (106 M) for 30 min. O−2 production increased from 198.4 ± 14.7 to 447.6 ± 21.2 units/min/105 cells. To determine if the Ang II induced O−2 is mediated through AT1 or AT2 receptors, we used specific receptor antagonists. In the presence of AT1 receptor antagonist losorten (10−6 M), O−2 was from 198.4 ± 14.7 to 214.7 ± 35.4 unit/min/106 cells. In the presence of AT2 receptor antagonist PD‐123319 (10−6 M), O−2 was from 198.4 ± 14.7 to 435.1 ± 25.3 unit/min/105 cells. To study which NOX is the primary source of Ang II induced O−2 , we knocked down NOX2 or NOX4 with siRNA and measured O−2. In the cells treated with siRNA‐NOX2, Ang II induced O−2 was from 163.9 ± 32.6 to 239.5 ± 51.8 unit/min/105 cells. In the cells treated with siRNA‐NOX4, O−2 was from 117.2 ± 19.3 to 422.8 ± 21.7 unit/min/105 cells. Scramble treated cells are not different in O−2 when compared with control.

Conclusions

Ang II induces O−2 production in MMDD1 cells mediated via AT1 receptors. NOX2 is the primary source of in Ang II induced O−2.
Renal vasoconstriction elicited by a cocktail of potassium channel blockers
Authors: Sorensen Charlotte Mehlin , Magnusson Linda , Holstein‐Rathlou Niels‐Henrik , Salomonsson Max
Published: June 2021

Inhibition of K+ channels might mediate agonist‐induced or myogenic renal vasoconstriction by depolarization of VSMC. As inhibition of a single type of K+ channel caused only minor or no renal vasoconstriction in vivo in rats, we hypothesized that several classes of K+ channels must be blocked to achieve sufficient depolarization to elicit renal vasoconstriction. We measured renal blood flow (RBF) in vivo in anesthetized Sprague Dawley rats using an ultrasonic flow probe. Test agents were infused directly into the renal artery to avoid systemic effects. Inhibition of BKCa and Kir channels (with TEA and Ba2+, respectively) caused small and transient reductions of RBF to 93 ± 2 % and 95 ± 1 % of baseline, respectively. KATP, SKCa or Kv channel blockade (with glibenclamide, apamin and 4‐aminopyridine, respectively) was without effect. However, a cocktail of all blockers caused a massive reduction of RBF (down to 15 ± 10 % of baseline after 4 min P < 0.05). Nifedipine abolished this reduction (RBF = 94 ± 3 % of baseline after 4 min; NS vs. baseline). We conclude that inhibition of a single type of K+ channels is not sufficient to elicit renal vasoconstriction. On the other hand it is possible that a diverging mechanism, which affects several K+ channels, plays a role in the regulation of renal hemodynamics. Our results also suggest that the renal vasoconstriction elicited by K+ channel blockade is mediated by nifedipine sensitive Ca2+ channels.
Molecular mechanism effect of taxotere and ukrain in cell cycle regulating genes in positive and negative breast cancer cell lines
Authors: Alokail Majed Saleh , Al‐Mansouri Layla J , Bin Amer Suad S
Published: June 2021

Taxotere and ukrain have attracted some attention in the treatment of breast cancer due to its cytotoxicity induction by stabilizing microtubules and arrest in G2/M phase. We investigated the molecular mechanism of taxotere and ukrain, and their influence to certain cell cycle genes in breast cancer. We have used three different breast cell lines, MCF‐7 (ERá‐ve) cells, MDA‐MB231 (ERá ‐ve) cells and normal breast MCF‐12A cells. The cell cycle regulating genes were down regulated in MDA‐MB231 treated with taxotere or ukrain compared with MCF‐7. Cyclins (B1 and D1), CDKs (CDK4 and CDK5) were repressed in MCF‐7 treated with taxotere, indicating cell cycle arrest. Microarray showed down regulation of some cell proliferation and cell cycle genes like cyclins A1, B, D1, D3, and E2F5, TFDp‐1, TPp73 and inhibitor of DNA binding 1 in taxotere treated cells. Most of these genes were affected in taxotere treated MDA‐MB231, but in a lower number was affected in MCF‐7 and almost unaffected in case of MCF‐12A. Taxotere have shown to increase some genes related to apoptosis induction and tumor suppression in both cell lines. ukrain have shown to altered the expression of the most of cell cycle progression genes in case of MDA‐MB231, but unaffected in case of MCF‐7 and MCF‐12A cells. Our results conclude that taxotere and ukrain as breast cancer chemotherapy have shown to be useful predictive for gene analysis associated with breast cancer.
Copy number variation of testis‐specific protein Y‐encoded (TSPY) among different breeds of cattle (Bos taurus) and related individuals
Authors: Hamilton Christine Karin , Favetta Laura , Di Meo Giulia Pia , Floriot Sandrine , Perucatti Angela , Peippo Jaana , Kantanen Juha , Eggen Andre , Iannuzzi Leopoldo , King William Allan
Published: June 2021

Multi‐copied gene families are prevalent in mammalian genomes especially within the Y chromosome. Gene copy number variation can impact phenotype and is becoming more appreciated as a source of global variation. Testis specific protein Y‐encoded (TSPY) is present in variable copy number in many mammalian species. Cattle, for example, have copies numbers ranging from 50‐200. The purpose of this study was to investigate the extent to which TSPY copy number varies among bulls, between different breeds of cattle and between related (step‐brother) bulls. To investigate TSPY copy number we used relative real time polymerase chain reaction (PCR) to analyze the DNA of fourteen different cattle breeds and four sons of a single sire. The results showed variation both between and within breeds. Brown Swiss (161 copies, CI = 133‐195) had significantly higher levels of TSPY and Western Fjord (65 copies, CI = 45‐86) had significantly lower levels than some breeds, although most breeds had similar average TSPY copy numbers. All bulls showed within‐breed variation. The TSPY copy numbers of the sons ranged from 55‐75 copies and were found to differ significantly. These results show that copy number variation of TSPY can be seen within a single generation. This study demonstrates that copy number variation of TSPY is extensive in the bovine population; however, the purpose of this variation still remains a mystery. (Funded by CRC & NSERC)
Identification of Methylated Loci in the Trypanosoma brucei Genome
Authors: Jayakar Sangeeta K , Jensen Tina K , Hennick Stacy M , Militello Kevin T
Published: June 2021

Previous mass spectrometry and blotting experiments in our laboratory have shown that Trypanosoma brucei, the causative agent of African Sleeping Sickness, contains low levels of 5‐methylcytosine in its genomic DNA. In order to determine the location of 5‐methylcytosine in the genome, an immunoprecipitation strategy was utilized. T. brucei DNA was cut with DpnII, modified by linker addition, and immunoprecipitated with an antibody against 5‐methylcytosine. Immunoprecipitated DNAs were amplified by PCR, inserted into the pGEM‐T Easy plasmid, and analyzed by DNA sequencing. In total, greater than 100 clones have been analyzed representing DNA from the insect stage and bloodstream stage of the parasite. To date, all methylated loci are in the nuclear genome. Several loci were found in the immunoprecipitate multiple times, including variant surface glycoprotein genes and retrotransposon genes. Thus, DNA methylation may regulate expression of these genes. However, housekeeping genes were also found in the immunoprecipitate indicating that DNA methylation is not restricted to a single locus. To pinpoint the position of 5‐methylcytosine within specific genes, sodium bisulfite sequencing of retrotransposon genes was initiated. In total, our data demonstrate that 5‐methylcytosine is present in the nuclear genome and may be overrepresented in multi‐gene families and repeated sequences. This work is supported by National Institutes of Health award AI074035‐01 to K.T.M.
A rapid and efficient method for room temperature handling, storage and transport of RNA samples
Authors: Muller‐Cohn Judy , Ohgi Sharron , de Rozieres Sohela , Faix Peggy Ho , Muller Rolf
Published: June 2021

We have developed a novel stabilization technology designed to protect RNA samples from degradation during dry storage at room temperature. The storage medium is based on the natural principles of anhydrobiosis (meaning "life without water"), a mechanism employed by some organisms that enables their survival while dry for >100 years. The objective of this study is to evaluate and develop an alternative handling, storage and shipping strategy to optimize RNA stabilization to facilitate biological research. Results demonstrate protection of total purified RNA samples for up to 14 months at room temperature and for an equivalent of over 7 years under accelerated aging conditions. Data will be presented demonstrating inhibition of RNA degradation even at extremely elevated temperatures, indicating that dried samples can be protected during fluctuating conditions typically experienced during shipment. Samples rehydrated from storage were used directly without further purification and did not interfere or inhibit downstream applications including bioanalyzer and microarray analysis, cDNA amplification, quantitative RT‐PCR and electrophoresis. Results will also be presented using the stabilization technology for the development of a reagent that permits convenient and efficient concentration of dilute RNA samples with minimal sample loss as compared to conventional methods, such as ethanol precipitation or vacuum concentrating. The development of novel RNA stabilization methods and reagents will have a significant impact on life science and biomedical research by eliminating some of the detrimental variables associated with the handling, storage and transport of labile RNA specimens.
Nurses Promoting Inclusive, Safe, Resilient, and Sustainable Cities and Communities: Taking Action on COVID-19, Systemic Racism, and Climate Change
Authors: Schenk Elizabeth C. , Potter Teddie M. , Cook Cara , Huffling Katie , Rosa William E.
Published: June 2021

This article is one in a series in which contributing authors discuss how the United Nations (UN) Sustainable Development Goals (SDGs) are linked to everyday clinical issues; national public health emergencies; and other nursing issues, such as leadership, shared governance, and advocacy. The 2030 Agenda for Sustainable Development, a 15-year plan of action to achieve the goals, was unanimously adopted by all UN member states in September 2015 and took effect on January 1, 2016. The Agenda consists of 17 SDGs addressing social, economic, and environmental determinants of health and 169 associated targets focused on five themes: people, planet, peace, prosperity, and partnership. The SDGs build on the work of the UN Millennium Development Goals, which were in effect from 2000 to 2015. The current article highlights SDG 11—making “cities and human settlements inclusive, safe, resilient and sustainable.”
Comparison of the Analgesic Effects of Intravenous Infusion of Dexmedetomidine Versus Bilateral Superficial Cervical Plexus Block After Thyroidectomy
Authors: Xing Jibin , Wu Ranliang , Liang Ling , Fang Hongyi , Chen Liubing , Luo Chenfang
Published: June 2021

Objectives:

Dexmedetomidine (DEX) is widely used in clinical practice because of its safety and effectiveness. Superficial cervical plexus block (SCPB) can reduce pain in thyroid surgery. The objective of this study was to investigated whether intravenous DEX has an equivalent analgesic effect and patients’ satisfaction to SCPB for thyroid surgery.

Materials and Methods:

Ninety patients who had been scheduled for thyroidectomy under general anesthesia with endotracheal intubation were randomly divided into 3 groups. Group D: DEX was administered intravenously at an initial dose of 1 µg/kg over 10 minutes; then induction and endotracheal intubation performed, and then a continuous intravenous infusion of DEX was administered at a rate of 0.4 μg/kg/h until 30 minutes before the end of surgery. Group B: ultrasound-guided bilateral SCPB was performed, with 10 mL of 0.375% ropivacaine injected on each side. Group C: intravenous saline was administered at the same rate and dose as in group D. Patients’ perioperative status, visual analog scale scores, complications and patients’ satisfaction were recorded.

Results:

The pain at rest at 1 hour after extubation and the movement-evoked pain within 24 hours after extubation were significantly lower in groups D and B than in group C. Patients’ satisfaction was significantly higher in groups D and B than in group C. There was no difference in pain at rest, movement-evoked pain and patients’ satisfaction between group D and B.

Conclusions:

Perioperative intravenous infusion of DEX can effectively reduce wound pain after thyroidectomy, and the analgesic effect is equivalent to that of bilateral SCPB.
Minimally invasive approach to the management of tubo-ovarian abscesses
Authors: Hattiangadi Rohan , McEntee Kelli , Dahlman Marisa
Published: June 2021

Purpose of review

The purpose of this publication is to review the most up-to-date literature regarding the pathogenesis, diagnosis and management of tubo-ovarian abscesses.

Recent findings

Prior to the advent of broad-spectrum antibiotics, tubo-ovarian abscesses necessitated total abdominal hysterectomy and bilateral salpingo-oophorectomy. Although it carries a risk of treatment failure, antibiotic therapy enabled fertility-sparing treatment for many women. Recent studies have identified key predictors for antibiotic treatment failure, including age, BMI and abscess diameter. C-reactive protein was also found to be a strong predictor of antibiotic treatment response. Given the growing evidence of treatment failure with antibiotic therapy alone, along with increased availability and access to interventional radiology, image-guided drainage with or without catheter placement, combined with broad-spectrum antibiotics, is now considered first-line therapy.

Tubo-ovarian abscess is a diagnostic challenge, as presentation can vary. Inadequate treatment is associated with severe morbidity and mortality. Despite adequate conservative treatment, recurrence risk is high and clinical sequelae can have devastating effects on reproductive health. Recent evidence-based developments, including a risk score system to predict antibiotic failure, serve to provide appropriately directed risk-based care. However, large-scale randomized controlled trials are needed to clarify the most appropriate treatment modalities.
Bone Morphogenetic Protein-2 and Demineralized Bone Matrix in Difficult Bony Reconstructions in Cleft Patients
Authors: Makar Katelyn G. , Buchman Steven R. , Vercler Christian J.
Published: June 2021

Reconstruction of alveolar clefts includes fistula repair and bone grafting. However, bone is often harvested from the iliac crest or the skull, which can be associated with considerable donor site morbidity, and the failure rate may be as high as 20%. As such, some centers utilize bone morphogenetic protein (BMP)-2 to reconstruct the bony cleft. However, this remains an off-label use, and therefore we propose using BMP-2 only in patients with tenuous soft tissues, when the likelihood of graft failure is high. In four patients, we used BMP-2 with demineralized bone matrix (DBM) to reconstruct defects related to clefts—three patients had alveolar clefts, and the fourth patient was referred to us, with resorption of a necrotic premaxilla after premaxillary setback. In all cases, the decision was made to forego bone grafting intraoperatively given the poor quality of soft tissue and the increased risk of bone graft exposure. BMP-2 was infused onto a carrier and placed in the fistula, and Grafton DBM was then packed into the defect. In three cases, small amounts of bone from the piriform aperture were mixed with the BMP-2/DBM. After 3–7 months, all patients had generated bone in the clefts and did not require bone grafting. While we continue to prefer a “like with like” reconstruction, bone grafting has a high likelihood of failure in patients with suboptimal soft tissues or tight closures. We suggest that combining BMP-2 and DBM in higher risk patients is an excellent option to avoid bone graft loss and reoperation.
Training the Trainers in Microsurgery: A Success Story from Vietnam’s Hanoi National Hospital of Odonto-stomatology
Authors: Nguyen Hong Nhung , Chen Jill , Nguyen Tan Van , Le Duc Thanh , Nguyen Tai Son , Jeng Seng-Feng
Published: June 2021

Background:

Microsurgery is a highly specialized skill that requires advanced training. This is a recount of the 12-year development of Hanoi National Hospital of Odonto-Stomatology (NHOS) from a basic plastic surgery unit to a high-volume, subspecialized reconstructive center.

Methods:

We present a 12-year retrospective account of the development of NHOS with a brief summary of microsurgical reconstructive outcomes.

Results:

From 2008 to 2020, NHOS has performed 665 microsurgical flaps for reconstruction of various maxillomandibular defects. In the pioneering stage (2008-2011), without surgical microscopes, all five free flaps failed. After acquiring a microscope and mentoring from Hanoi's 108 Military Hospital, mandibular bone defect reconstruction with free fibula flaps had 85% success rate. In the growth stage (2012-2015), reconstruction advanced toward more complex defects requiring soft tissue, with a 98.7% success rate. The maturation stage (2016-2020) focused on refinement of reconstructive service to provide subspecialized care for malignant head and neck cancer patients with help from Taiwan's E-Da Hospital and Operation Smile's charity program. The charity mission trips were structured to facilitate good quality teaching rather than hit a quantitative goal of the number of surgeries done. And with a success rate of 99.4%, we have begun further education of the plastic surgery community in Vietnam.

Conclusions:

Our rapid 12-year maturation into a high-volume, subspecialized microsurgical center is the embodiment of the generous efforts of many international friends who invested their time and expertise. And we highly recommend charity mission trips to adopt the “training the trainers” concept to maximize lasting, local impact.
The Use of Peripheral Nerve Stimulation in Conjunction with TMR for Neuropathic Pain
Authors: Agrawal Nikhil A. , Gfrerer Lisa , Heng Marilyn , Valerio Ian L. , Eberlin Kyle R.
Published: June 2021

Targeted muscle reinnervation and regenerative peripheral nerve interfaces are increasingly utilized strategies to mitigate phantom and residual limb pain in amputees. These interventions are successful, yet often imperfect in completely ameliorating neuropathic pain following amputation. Implantable peripheral nerve stimulators are another tool in the armamentarium for management of neuropathic pain. These devices have been utilized adjacent to the spinal cord and more recently in the extremities with good results, and there has been additional interest in their utility for nerve regeneration. In this case report, we present the first reported case in the readily available literature of combining contemporary peripheral nerve strategies with an implantable peripheral nerve stimulator for postamputation neuropathic pain. The patient is a 72-year-old man who presented with severe neuropathic pain following prior below knee amputation with an osseointegrated implant and regenerative peripheral nerve interfaces. The authors performed targeted muscle reinnervation with intra-operative placement of a peripheral nerve stimulator. He did well after the procedure, and his pain improved with activation of the device. The most symptomatic nerve is targeted with the nerve stimulator, and it is placed adjacent to the nerve transfer(s). Combining these contemporary techniques may lead to improved prosthetic use and quality of life for these patients.
Effectiveness and Predictors of Discontinuation of Aripiprazole Long-acting Injection
Authors: Aftab Romaisa , Pereira Marco , Hewitt Jed , Whale Richard
Published: June 2021

Purpose/Background

This study aimed to explore the discontinuation rate of aripiprazole long-acting injection (LAI) in a naturalistic clinical setting.

Methods/Procedures

A retrospective cohort study of 1 year duration was conducted on the first 200 patients registered to receive aripiprazole LAI in Sussex, UK. Rate of discontinuation and the association of robustly recorded clinical variables with discontinuation or a new acute care episode were explored.

Findings/Results

Of 200 registered, 173 patients initiated aripiprazole LAI and 40% discontinued this by 1 year. Mean discontinuation time was 18 weeks. The commonest discontinuation reason was “patient choice,” independent of efficacy or adverse effects. Not having a diagnosis of schizophrenia spectrum was the only variable significantly associated with treatment continuation after 1 year. No single diagnostic group accounted for this, although a greater continuation rate was observed in those with bipolar disorder. Illness severity factors at baseline, including apparent treatment resistance, had no impact on later aripiprazole LAI discontinuation or on acute service use over the year. Medication-related variables had no identified impact on acute service use.

Implications/Conclusions

This study supports the clinical utility of aripiprazole LAI for its licensed indications. The 1-year discontinuation rate is equivalent to that in reports of similarly designed studies of paliperidone LAI. Further exploration of nonmedication factors influencing LAI discontinuation is required. Preferential use of aripiprazole LAI over other medications may be supported due to fewer associated metabolic adverse effects.
Preoperative nutrition care in Enhanced Recovery After Surgery programs: are we missing an opportunity?
Authors: Martin Lisa , Gillis Chelsia , Ljungqvist Olle
Published: June 2021

Purpose of review

A key component of Enhanced Recovery After Surgery (ERAS) is the integration of nutrition care elements into the surgical pathway, recognizing that preoperative nutrition status affects outcomes of surgery and must be optimized for recovery. We reviewed the preoperative nutrition care recommendations included in ERAS Society guidelines for adults undergoing major surgery and their implementation.

Recent findings

All ERAS Society guidelines reviewed recommend preoperative patient education to describe the procedures and expectations of surgery; however, only one guideline specifies inclusion of routine nutrition education before surgery. All guidelines included a recommendation for at least one of the following nutrition care elements: nutrition risk screening, nutrition assessment, and nutrition intervention. However, the impact of preoperative nutrition care could not be evaluated because it was rarely reported in recent literature for most surgical disciplines. A small number of studies reported on the preoperative nutrition care elements within their ERAS programs and found a positive impact of ERAS implementation on nutrition care practices, including increased rates of nutrition risk screening.

There is an opportunity to improve the reporting of preoperative nutrition care elements within ERAS programs, which will enhance our understanding of how nutrition care elements influence patient outcomes and experiences.
Status Triphasicus Versus Status Epilepticus?
Authors: Bicchi Manuel M. , Alkhachroum Ayham , Kanner Andres M.
Published: June 2021

Generalized periodic patterns with triphasic wave morphology, long referred to as triphasic waves [TWs], had been associated with metabolic encephalopathies, although other neurologic and systemic causes have since been identified. In a recent classification of periodic patterns, TWs were formally grouped with the generalized periodic discharges, which are often associated with ictal activity. The interpretation of generalized periodic patterns with TWs as nonictal can have significant implications in the management of comatose patients in nonconvulsive status epilepticus. Electrographic characteristics that help distinguish nonictal periodic patterns with TWs from generalized periodic discharge ictal patterns include (1) TWs in long runs of periodic bilaterally synchronous and symmetric discharges, maximal in frontocentral or posterior head regions with and without a frontal-to-occipital lag or posterior-to-anterior lag, respectively; (2) recurrent spontaneous and/or low-dose benzodiazepine-induced attenuation and/or suppression of the periodic pattern and replacement with a diffuse slow wave activity throughout a prolonged EEG recording; and (3) stimulation-induced activation and/or increase in frequency and/or organization of TWs. We coined the term of status triphasicus to describe the electrographic periodic pattern of TWs with these three distinct characteristics. In this article, we discuss the advantages and limitations of keeping the status triphasicus pattern as a distinct electrographic entity different from periodic ictal generalized periodic discharge patterns. We discuss the circumstances in which a status triphasicus pattern can be associated with ictal activity and propose a simple pragmatic classification of status triphasicus that encompasses the different clinical scenarios it can be associated with.
James Philip Elliott. 27 July 1929—21 October 2008
Authors: Van Isacker Piet , Gelletly William
Published: June 2021

James Philip Elliott made important contributions to improve our understanding of the structure of atomic nuclei in the second half of the twentieth century. In 1958 he proposed the SU(3) model, explaining rotational behaviour of nuclei in the context of the shell model. His idea, based on elegant and seminal group-theoretical concepts, reconciled the independent-particle with the liquid-drop model, which until then existed as disconnected views of the nucleus. In the 1960s and 1970s he developed methods to extract properties of the nuclear interaction from the phase shifts of nucleon–nucleon scattering. From 1980 until his death he contributed to the development of the interacting boson model of Arima and Iachello, and its microscopic understanding in terms of symmetries of the shell model. For his outstanding achievements in theoretical physics, in 2002 he and Francesco Iachello were awarded the Lise Meitner prize of the European Physical Society for ‘their innovative applications of group-theoretical methods to the understanding of atomic nuclei’. His achievements were also recognized by the award of the Rutherford Medal and Prize of the Institute of Physics in 1994.
Evidence-based pandemic preparedness: an infrastructure for population-scale genome-based based testing for COVID-19
Authors: Lehrach Hans , Curtis Jon , Lange Bodo , Ogilvie Lesley A , Gauss Richard , Steininger Christoph , Scholz Erhard , Kreck Matthias
Published: June 2021

Our lives (and deaths) have been dominated for more than a year by COVID-19, a pandemic that has caused hundreds of millions of disease cases, millions of deaths, trillions in economic costs, and major restrictions on our freedom. We argue that much of this could have been avoided by repeated and systematic population-scale PCR-based testing and targeted quarantine. We describe key elements of the current implementations of such a system and demonstrate (with Germany as an example), that this strategy could have suppressed the pandemic within weeks, eliminating the vast majority of its overall impact in terms of deaths, economic costs and restrictions. It can, however, still play a major role in further reducing the worldwide impact of the current phase of the pandemic, and remain as a key protection against similar dangers in the future.
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Che Xiaoyu , Brydges Christopher R. , Yu Yuanzhi , Price Adam , Joshi Shreyas , Roy Ayan , Lee Bohyun , Barupal Dinesh K. , Cheng Aaron , Palmer Dana March , Levine Susan , Peterson Daniel L. , Vernon Suzanne D. , Bateman Lucinda , Hornig Mady , Montoya Jose G. , Komaroff Anthony L. , Fiehn Oliver , Lipkin W. Ian
Published: June 2021

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods

Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results

In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion

Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

One Sentence Summary

Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.
Interferon Gamma Release Assays for Latent Mycobacterium tuberculosis Detection in Elderly Hispanics
Authors: Scordo Julia M. , Aguillón-Durán Génesis P. , Ayala Doris , Quirino-Cerrillo Ana Paulina , Rodríguez-Reyna Eminé , Joya-Ayala Mateo , Mora-Guzmán Francisco , Ledezma-Campos Eder , Villafañez Alejandro , Schlesinger Larry S. , Torrelles Jordi B. , Turner Joanne , Restrepo Blanca I.
Published: June 2021

Background

Aging is a tuberculosis co-morbidity. Interferon Gamma Release Assays (IGRAs) are used to detect latent Mycobacterium tuberculosis (M.tb) infection (LTBI) in adults, but their performance in the elderly is not well-established. We aim to evaluate the performance of IGRAs for LTBI detection in healthy elderly Hispanics with recent, remote or no history of M.tb exposure.

Study Design and Methods

Cross-sectional study in Hispanic elderly (60+y) and adult (18-50y) recent TB contacts (ReC) or community controls (CoC). LTBI was based on a positive T-SPOT.TB and/or QuantiFERON-Gold in-tube or –Plus assay.

Results

We enrolled 193 CoC (119 adults/74 elderly) and 459 ReC (361 adults/98 elderly). LTBI positivity increased with age in CoC (range 19-59%; trend p <0.001), but was similar in ReC (range 59-69%; trend p=0.329). The elderly had lower concordance between IGRAs (kappa 0.465 vs. 0.688 in adults) and more inconclusive results (indeterminate/borderline; 11.6% vs. 5.8% in adults; p=0.012). Exclusion of inconclusive results improved concordance between assays, notably in elderly ReC, who have the highest TB risk (from kappa 0.532 to 0.800). When both IGRAs were done simultaneously, inconclusive results were resolved in all cases as positive or negative with the other IGRA. The magnitude of the response to M.tb peptides used in the assays was similar between age groups, but responsiveness to mitogens was lower in the elderly.

Conclusions

IGRAs are suitable for LTBI detection in the elderly. Discordant and inconclusive findings are more prevalent in the elderly, but results were resolved when performing different IGRAs simultaneously in the same participant.
Testing & Opening in Augustusburg A Success Story?
Authors: Diederichs Marc , Mitze Timo , Schulz Felix , Wälde Klaus
Published: June 2021

The city of Augustusburg allowed for opening of, inter alia, restaurants and hotels joint with large-scale testing. We evaluate this testing & opening (T&O) experiment by comparing the evolution of case rates in Augustusburg with the evolution in other communities of Saxony. We have access to small-scale SARS-CoV-2 infection data at the community level (” Gemeinde”) instead of the county level (” Landkreis”) usually used for disease surveillance. Despite data challenges, we conclude that T&O did not lead to any increase in case rates in Augustusburg compared to its control county. When we measure the effect of T&O on cumulative cases, we find a small increase in Augustusburg. This difference almost completely disappears when we control for the effect of higher case rates due to more testing. Generally speaking, T&O worked much better than in comparable projects elsewhere.
Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury
Authors: Cross AR , de Andrea CE , María Villalba-Esparza , Landecho Acha MF , Cerundolo L , Weeratunga P , Etherington R , Denney L , Ogg G , Ho LP , Roberts ISD , Hester J , Klenerman P , Melero I , Sansom SN , Issa F
Published: June 2021

Severe lung damage in COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways and genes present across the spectrum of histopathological damage in COVID-19 lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from areas of interest within well preserved post-mortem lung samples from three patients. Despite substantial inter-patient heterogeneity we discovered evidence for a common immune cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines including CXCL9, CXCL10 and CXCL11 which are known to promote the recruitment of CXCR3+ immune cells. The tumour necrosis factor (TNF) superfamily members BAFF (TNFSF13B) and TRAIL (TNFSF10) were found to be consistently upregulated in the areas with severe tissue damage. We used published spatial and single cell SARS-CoV-2 datasets to confirm our findings in the lung tissue from additional cohorts of COVID-19 patients. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies.

One Sentence Summary

Spatial analysis identifies IFNγ response signatures as focal to severe alveolar damage in COVID-19 pneumonitis.