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The improvement of enzyme thermostability often accompanies the decreased activity due to the loss of the key regions' flexibility. As a representative structure, unlocking the potential of loop dynamics will not only provide new ideas for stabilization strategies, but also help to deepen the understanding of the relationship between enzyme structural dynamics and function. In this study, a creative "hook loop dynamics engineering" (HLoD) strategy was successfully proposed for simultaneously improving the thermostability and maintaining activity of the model enzyme, Candida Antarctica lipase B. A small and smart mutant library involving five key residues located at the "hook loop" was meticulously identified and systematically investigated and thus yielded a five-point multiple mutant M1 (L147S/T244P/S250P/T256D/N292D), demonstrating a remarkable 7.0-fold increase in thermostability at 60 °C compared to the wild-type (WT). Furthermore, the activity of M1 remained comparable to that of WT, effectively transcending the barrier of activity-stability trade-off. Molecular dynamics simulations revealed that the precise regulation of hook loop dynamics via intermolecular interactions, such as salt bridges and hydrogen bonding, curbed the excessive flexibility of the pivotal regions α5 and α10 at high temperatures, thus driving the substantial enhancement of the thermostability of M1. Refining the dynamics of the flexible region via HLoD, which transcended the barrier of activity-stability trade-off, exhibited to be a robust and potentially universal strategy for designing enzymes with outstanding thermostability and activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The Woven EndoBridge (WEB) is a device used for intrasaccular flow diversion, designed for the elimination of wide-necked bifurcation aneurysms from the circulation. In this study, we aim to assess the safety and efficacy of the WEB and its uses in treating aneurysms of different morphologies and locations., Methods: In a retrospective analysis, we compiled a comprehensive dataset from patients treated with the WEB device across three major Australian neurovascular centers from May 2017 to September 2023. The case series encompassed a spectrum of aneurysm types, including wide-necked bifurcation, sidewall, and irregularly shaped aneurysms, as well as cases previously managed with alternative therapeutic strategies. This study additionally encompasses cases where aneurysms were managed using the WEB device in combination with supplementary endovascular devices., Results: The study included 169 aneurysms in 161 patients. The rate of satisfactory aneurysm occlusion was 85.6%, with 86.7% of patients maintaining good functional status at their most recent follow-up. The procedure exhibited a low mortality rate of 0.6% and a thromboembolic complication rate of 7.1% (n = 12/161). There were no instances of postoperative re-rupture and the procedure-related hemorrhage rate was low (1.2%, n = 2/169), aligning with the literature regarding the safety and efficacy of the WEB device., Conclusions: Our multicenter trial reinforces the WEB device's role as an effective and safe modality for intracranial aneurysm management, supporting its expanded application beyond wide-necked bifurcation aneurysms. Further prospective studies are required to delineate its evolving role fully., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Serum albumin reflects nutritional status and is associated with postoperative complications and mortality. Delta albumin (ΔAlb), defined as the difference between preoperative and lowest postoperative levels, could predict complications and mortality, even with postoperative levels above 30 g/L prompting albumin infusions. This study aimed to assess how ΔAlb relates to outcomes in craniotomy patients with brain tumors., Methods: This retrospective study screened patients diagnosed with a brain tumor who underwent cerebral surgery from a single Chinese hospital between December 2010 and April 2021. Patients were divided into 4 groups based on their ΔAlb levels: <5 g/L (normal), 5-9.9 g/L (mild ΔAlb), 10-14.9 g/L (moderate ΔAlb), and ≥15 g/L (severe ΔAlb). The primary outcome was postoperative 30-day mortality., Results: Among the 9660 patients undergoing craniotomy for brain tumors, the median ΔAlb level after craniotomy was 7.3 g/L. ΔAlb was associated with increased postoperative 30-day mortality; odds ratios for mild, moderate, and severe ΔAlb were 1.93 (95% confidence interval [CI], 1.17-3.18, P = 0.01), 2.21 (95% CI, 1.28-3.79, P = 0.004), and 7.26 (95% CI, 4.19-12.58, P < 0.01), respectively. Significantly, ΔAlb >5 g/L was found to have a strong association with a higher risk of mortality, even when the nadir Alb remained greater than 30 g/L (odds ratio, 1.84; 95% CI, 1.13-3.00, P = 0.014)., Conclusions: Among patients undergoing craniotomy for brain tumor resection, a mild degree of ΔAlb was associated with increased 30-day mortality, even if the nadir Alb remained greater than 30 g/L. Moreover, ΔAlb was associated with postoperative complications and longer lengths of stay., (Copyright © 2024. Published by Elsevier Inc.)

Objective: An elevated preoperative red cell distribution width (RDW) is associated with adverse prognostic outcomes in various diseases. However, the correlation between changes in RDW (ΔRDW) and the prognosis following brain tumor craniotomy remains unclear. Accordingly, this study aimed to investigate the prognostic significance of perioperative changes in RDW in patients undergoing brain tumor craniotomy., Methods: This retrospective cohort study included patients undergoing craniotomy for brain tumors at West China Hospital, Sichuan University, from January 2011 to March 2021. We defined perioperative changes in RDW: group A (non-significant RDW changes, ΔRDW ≤0.4%), group B (drop in RDW, ΔRDW < -0.4%), and group C (rise in RDW, ΔRDW >0.4%). The relationship between the changes in RDW and all-cause mortality was analyzed by categorizing the patients according to perioperative ΔRDW (RDW at postoperative one week - RDW at admission)., Results: The present study included a total of 9589 patients who underwent craniotomy for the treatment of brain tumors. A rise in RDW was significantly associated with increased mortality, with an adjusted OR of 3.56 (95% CI: 2.56-4.95) for 30-day mortality and 1.57 (95% CI: 1.33-1.85) for one-year mortality compared to those with non-significant RDW changes (ΔRDW ≤0.4%). Conversely, a decrease in RDW showed no significant association with 30-day mortality (adjusted OR: 1.04, 95% CI: 0.53-2.04) and one-year mortality (adjusted OR: 1.18, 95% CI: 0.92-1.53). These findings were also supported by restricted cubic spline, which shows that increases in RDW were significantly associated with lower survival rates compared to stable RDW levels during the follow-up period., Conclusions: Among patients undergoing craniotomy for a brain tumor, a rise in RDW was associated with 30-day mortality and higher long-term mortality risks, even if patients' admissions for RDW values were within the normal range. It was worth noting that maintaining stable RDW levels during this period was associated with better survival., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.ZCX., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Computed tomography angiography (CTA) is a well-established diagnostic modality for carotid stenosis. However, false-positive CTA results may expose patients to unnecessary procedural complications in cases where surgical intervention is not warranted. We aim to assess the correlation of CTA to digital subtraction angiography (DSA) in carotid stenosis and characterize patients who were referred for intervention based on CTA and did not require it based on DSA., Methods: We retrospectively reviewed 186 patients who underwent carotid angioplasty and stenting following preprocedural CTA at our institution from April 2017 to December 2022., Results: Twenty-one of 186 patients (11.2%) were found to have <50% carotid stenosis on DSA (discordant group). Severe plaque calcification on CTA was associated with a discordant degree of stenosis on DSA (LR+=7.4). Among 186 patients, agreement between the percentage of stenosis from CTA and DSA was weak-moderate (r 2 =0.27, P<0.01). Among concordant pairs, we found moderate-strong agreement between CTA and DSA (adj r 2 =0.37) (P < 0.0001). Of 186 patients, 127 patients had CTA stenosis of ≥70%, and 59 had CTA of 50%-69%. Correlation between CTA and DSA in severe CTA stenosis was weak (r 2 =0.11, P<0.01)., Conclusions: In patients with stenosis found on CTA, over 88% also had stenosis on DSA, with this positive predictive value in line with previous studies. The percent-stenosis value from CTA and DSA was weakly correlated but does not affect the overall clinical judgement of stenosis. Severe calcification found on CTA may potentially indicate nonstenosis on DSA., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: Hypernatremia is a treatable biochemical disorder associated with significant morbidity and mortality in patients undergoing surgery. However, its impact on patients who undergo elective craniotomy is not well understood. This study aimed to investigate the prognostic implications of postoperative hypernatremia on the 30-day mortality of patients undergoing elective craniotomy., Design: Retrospective cohort study., Setting: The Department of Neurosurgery of a high-volume center., Patients: Adult patients undergoing elective craniotomy except those with pituitary tumors, intracerebral hemorrhage, subarachnoid hemorrhage, or traumatic brain injury., Interventions: None., Measurements: Perioperative laboratory data were collected for all study participants, including sodium levels, neutrophil count, serum albumin, lymphocyte count, and blood glucose. These measurements were obtained as part of routine clinical care and provided valuable information for data analysis., Main Results: Of the 10,223 identified elective craniotomy patients who met our inclusion and exclusion criteria, 14.9% (1519) developed postoperative hypernatremia. This population's overall postoperative 30-day mortality rate was 1.7% (175). After performing an adjusted logistic regression analysis, we found that the odds of 30-day mortality increased gradually with increasing severity of hypernatremia: 2.9 deaths (OR, 3.79; 95% CI, 2.46-5.85) in patients with mild hypernatremia, 13.9 deaths (OR, 17.73; 95% CI, 11.17-28.12) in those with moderate hypernatremia, and 38.3 deaths (OR, 67.00; 95% CI, 40.44-111.00) in those with severe hypernatremia., Conclusions: Hypernatremia is common after elective craniotomy, and its presence is associated with increased mortality and complications, particularly in cases of severe hypernatremia. These results emphasize the significance of risk evaluation in neurosurgical patients and propose the advantages of closely monitoring serum sodium levels in high-risk individuals. Future randomized controlled trials could provide more insight into the effect of treating postoperative hypernatremia in these patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to this work. This research was not funded by any external agency, institution, or corporation. The authors have full control of all primary data, and they agree to allow the journal to review such data if required. All authors have read and approved the final version of the manuscript and are responsible for its content., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, PD-L1-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented., Patients and Methods: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1:1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary end point was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population., Results: Between May 5, 2016, and May 28, 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cutoff (November 30, 2020) was 45.1 months (interquartile range, 39.0-48.8). Median OS was 17.2 months (95% confidence interval [CI], 11.7-22.9) with pembrolizumab and 15.3 months (95% CI, 10.9-18.1) with chemotherapy (hazard ratio, 0.90 [95% CI, 0.67-1.19; P = 0.2262]). Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage)., Conclusion: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events., Clinical Trial Registry: ClinicalTrials.gov, NCT02611960., (Copyright © 2022. Published by Elsevier Ltd.)

A 61-year-old man presented to the ED with fever, chills, cough, purulent sputum, and progressive shortness of breath for 7 days. The patient was an active smoker with at least 80 pack-year smoking history. He had no other medical or surgical history and was not on any medication at home., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Using the data on 110 listed high-polluting enterprises in China, this study investigates the impact of environmental information disclosure (EID) on the innovation of high-polluting enterprises. The results indicate that EID has a positive and significant impact the innovation of high-polluting enterprises but that political connections weaken the impact of EID on enterprises' innovation. The results of the grouping tests indicate that EID can promote innovation in both state-owned and non-state owned high-polluting enterprises, and political connections have weakened the impact of EID on enterprises' innovation in SOEs. Results of findings in different regions show that EID significantly promotes innovation in those high-polluting enterprises in coastal areas but has no significant impact on the innovation by high-polluting enterprises in inland regions. In the further mechanism testing, this paper finds that EID stimulates innovation by enterprises through increases in business income., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for the coronavirus disease -19 (COVID-19). Since December 2019, SARS-CoV-2 has infected millions of people worldwide, leaving hundreds of thousands dead. Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial medications that have been found to have in vitro efficacy against SARS-CoV-2. Several small prospective studies have shown positive outcomes. However, this result has not been universal, and concerns have been raised regarding the indiscriminate use and potential side effects. The clinicians are conflicted regarding the usage of these medications. Appropriate dose and duration of therapy are unknown. Here, we will discuss the pharmacokinetic and pharmacodynamic properties of CQ and HCQ, as well as review the antiviral properties. The manuscript will also examine the available data from recent clinical and preclinical trials in order to shed light on the apparent inconsistencies., Competing Interests: Conflict of Interest The authors have no conflict of interest., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to explore the relationship between glycosylated hemoglobin (HbA1c) and the risk of anti-tuberculosis (TB) drug resistance for TB-type 2 diabetes mellitus (T2DM) patients., Methods: From March 2014 to June 2019, medical records from multiple centers were searched. Logistic regression analyses were performed. A predictive model for multidrug-resistance (MDR) was developed and validated. Calibration and discrimination of the model were assessed., Results: Inconsistent results were found in the systemic review. A multicenter chart review with 657 records was thus conducted. The HbA1c <7% group and HbA1c ≥7% group had 390 and 267 patients, respectively. The HbA1c<7% group had a lower risk of developing rifampicin resistance, isoniazid resistance and MDR, with odd ratios (ORs) of 1.904 (p=0.001), 2.896 (p<0.001) and 3.228 (p<0.001), respectively. The between-group differences in the risk of anti-TB drug resistance were analyzed based on data from three provinces in China. After adding HbA1c grading, the predictive model for MDR (https://mengyuan.shinyapps.io/Shinyapp/) showed excellent capacity with an AUC of 75.4% in the training set (Sichuan and Gansu) and 73.9% in the internal validation set (Henan). The performances in calibration, prediction probabilities and net clinical benefit were significantly improved by HbA1c grading., Conclusions: HbA1c grading was an independent risk factor for isoniazid resistance and MDR in TB-T2DM patients., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Venous thromboembolism events, including deep venous thrombosis and pulmonary embolism are the most common cause of preventable deaths in hospitalized patients in the United States. Although the risk of venous thromboembolism events in benign gynecologic surgery is generally low, the potential for venous thromboembolism events in urogynecologic population is significant because most patients undergoing the pelvic organ prolapse surgery have increased surgical risk factors., Objective: This study aimed to investigate the incidence and risk factors for venous thromboembolism events within 30 days after different routes of the pelvic organ prolapse surgery in a large cohort population using the American College of Surgeons-National Surgical Quality Improvement Program., Study Design: This retrospective cohort study used Current Procedural Terminology codes to identify pelvic organ prolapse repairs with and without concurrent hysterectomy performed during 2011-2017 in the American College of Surgeons-National Surgical Quality Improvement Program database. Demographics, preoperative length of hospital stay, operative time, preoperative comorbidities, smoking status, American Society of Anesthesiologists classification system scores, along with other variables were collected. Postoperative 30-day complications, including readmission, reoperation, and mortality, were collected. The incidence rates of venous thromboembolism, as defined by American College of Surgeons-National Surgical Quality Improvement Program, were compared among different surgical routes. Descriptive statistics were used, and logistic regression was performed to identify associations., Results: Among 91,480 pelvic organ prolapse surgeries identified, 63,108 were analyzed: 43,279 (68.6%) were performed vaginally, 16,518 (26.2%) laparoscopically, and 3311 (5.2%) abdominally. A total of 34,698 (55.0%) underwent a concurrent hysterectomy. Of 63,108 subjects, 133 developed venous thromboembolism within 30 days after surgery (0.21%; 95% confidence interval, 0.18-0.25; P<.0001). More than half (60%) of venous thromboembolism events occurred within 10 days after surgery. For all surgical routes, older age (P<.041), higher body mass index (P=.002), race or ethnicity (P=.04), longer operating time (P<.0001), inpatient status (P<.0001), American Society of Anesthesiologists 3 or 4 (P<.0001), having preoperative renal failure (P=.001), and chronic steroid use (P=.02) were significantly associated with venous thromboembolism. In addition, in the vaginal pelvic organ prolapse repair group, concurrent hysterectomy (P=.03) and preoperative dyspnea (P=.01) were associated with development of venous thromboembolism. In the abdominal pelvic organ prolapse repair, concurrent hysterectomy (P=.005) and hypertension requiring medication (P=.04) were also independently associated with venous thromboembolism development (Table 1). The incidence of venous thromboembolism was highest in abdominal repairs (0.72%), followed by laparoscopic repairs (0.25%) and vaginal repairs (0.16%). After adjusting for confounders, abdominal compared with vaginal approach (adjusted odds ratio, 3.27; 95% confidence interval, 1.93-5.41; P<.0001), longer operative time (adjusted odds ratio, 1.005; 95% confidence interval, 1.003-1.006; P<.0001), older age (adjusted odds ratio, 1.020; 95% confidence interval, 1.00-1.037; P=.015), greater body mass index (adjusted odds ratio, 1.04; 95% confidence interval, 1.01-1.07; P=.0006), American Society of Anesthesiologists 3 or 4 (adjusted odds ratio, 1.55; 95% confidence interval, 1.03-2.31; P=.03), and preoperative renal failure (adjusted odds ratio, 8.87; 95% confidence interval, 1.16-44.15; P=.04) remained significantly associated with developing venous thromboembolism. Neither laparoscopic repair (compared with vaginal repair) nor concurrent procedures (hysterectomy, antiincontinence procedure, vaginal mesh insertion) were found to be significantly associated with the development of venous thromboembolism. The abdominal pelvic organ prolapse repairs were associated with an increased hazard of venous thromboembolism (hazard ratio, 3.27; 95% confidence interval, 1.96-5.45; P<.0001). Venous thromboembolism development was associated with 30-day mortality, readmission, and reoperation (all P<.0001)., Conclusion: The overall incidence of venous thromboembolism after pelvic organ prolapse repairs based on a recent, large cohort database was very low, confirming the finding in previous smaller cohort studies. The highest venous thromboembolism risk was associated with abdominal route, and more than 60% of venous thromboembolism events occurred within 10 days after surgery. Thus, focus should be placed on risk-reducing strategies in the immediate postoperative period, with greater emphasis on patients undergoing abdominal surgery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia with thrombocytopenia. In addition to the primary TMA syndromes, microangiopathic hemolytic anemia with thrombocytopenia can be seen in many systemic diseases. Transplant associated TMA (TA-TMA) affects patients following stem cell or solid organ transplant. A 48-year-old male who underwent autologous stem cell transplant for nonsecretory multiple myeloma was admitted to our hospital with worsening anemia, thrombocytopenia, renal dysfunction and hepatosplenomegaly. Initial blood work revealed rare schistocytes and normal lactate dehydrogenase and haptoglobin levels. He underwent an extensive workup looking for an infectious, inflammatory or malignant etiology but a definitive diagnosis could not be reached. Over his prolonged stay at the hospital, he suffered from multiorgan failure and eventually passed away. An autopsy revealed TMA involving all clinically affected organ systems and was deemed to be the cause of his demise. The absence of typical blood work suggestive of hemolysis does not rule out a diagnosis of TA-TMA. Knowledge of this rare disease entity will help physicians identify and treat this life-threatening condition early and effectively., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus., Methods: In this systematic review, we searched Medline, Embase, and Cochrane databases from their inception with no language restrictions until May 8, 2019 and updated on February 5, 2020, for randomized controlled trials comparing the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus. A Meta-analysis was conducted to calculate the risk ratio (RR) using random-effects models., Results: We identified 7 trials with a total of 1028 participants. Levetiracetam was not associated with an increased rate of clinical seizure cessation within 60 min compared with phenytoin (RR, 1.02; 95 %CI, 0.92-1.13; I 2  = 3%; 60.0 % [309/515] vs 59.3 % [275/463];12 more events [95 % CI, -48 to 77] per 1000 participants; moderate-quality evidence). Results were similar in the subgroup analysis of adults and children. The sample size met the optimum size in trial sequential analysis. There were also no statistically significant effects on good functional outcome (RR, 1.05; 95 % CI, 0.90-1.23), admission to critical care (RR, 1.09; 95 % CI, 0.95-1.24), or all-cause mortality (RR, 1.09; 95 % CI, 0.55-2.16)., Conclusions: Moderate-quality evidence suggested that levetiracetam was not significantly superior to phenytoin in seizure cessation in patients with established status epilepticus., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Acute sentinel hypoxia-ischaemia in neonates can target the hippocampus, mammillary bodies, thalamus, and the basal ganglia. Our previous work with paediatric patients with a history of hypoxia-ischaemia has revealed hippocampal and diencephalic damage that impacts cognitive memory. However, the structural and functional status of other brain regions vulnerable to hypoxia-ischaemia, such as the basal ganglia, has not been investigated in these patients. Furthermore, it is not known whether there are any behavioural sequelae of such damage, especially in patients with no diagnosis of neurological disorder. Based on the established role of the basal ganglia and the thalamus in movement coordination, we studied manual motor function in 20 participants exposed to neonatal hypoxia-ischaemia, and a group of 17 healthy controls of comparable age. The patients' handwriting speed and accuracy was within the normal range (Detailed Assessment of Speed of Handwriting), and their movement adaptation learning (Rotary Pursuit task) was comparable to the control group's performance. However, as a group, patients showed an impairment in the Grooved Pegboard task and a trend for impairment in speed of movement while performing the Rotary Pursuit task, suggesting that some patients have subtle deficits in fine, complex hand movements. Voxel-based morphometry and volumetry showed bilateral reduction in grey matter volume of the thalamus and caudate nucleus. Reduced volumes in the caudate nucleus correlated across patients with performance on the Grooved Pegboard task. In summary, the fine movement coordination deficit affecting the hand and the wrist in patients exposed to early hypoxic-ischaemic brain injury may be related to reduced volumes of the caudate nucleus, and consistent with anecdotal parental reports of clumsiness and coordination difficulties in this cohort., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Pneumatosis of the gastrointestinal tract is defined as presence of air in the wall of the gastrointestinal tract and can occur in any part of the gastrointestinal tract. It is most commonly seen in the intestine and very rarely in the esophagus. The exact pathogenesis is still unknown. It is managed primarily by conservative and non-surgical therapy, unless there are findings to suggest an acute abdomen or other co-morbidities. On review of literature, very few case reports of esophageal pneumatosis have been published. We present a rare case of pneumatosis of the esophagus with cytomegalovirus (CMV) infection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The DinB (PolIV) protein of Escherichia coli participates in several cellular functions. We investigated a dinB mutation, Δ(dinB-yafN)883(::kan) [referred to as ΔdinB883], which strongly sensitized E. coli cells to both UV- and X-radiation killing. Earlier reports indicated dinB mutations had no obvious effect on UV radiation sensitivity which we confirmed by showing that normal UV radiation sensitivity is conferred by the ΔdinB749 allele. Compared to a wild-type strain, the ΔdinB883 mutant was most sensitive (160-fold) in early to mid-logarithmic growth phase and much less sensitive (twofold) in late log or stationary phases, thus showing a growth phase-dependence for UV radiation sensitivity. This sensitizing effect of ΔdinB883 is assumed to be completely dependent upon the presence of UmuDC protein; since the ΔdinB883 mutation did not sensitize the ΔumuDC strain to UV radiation killing throughout log phase and early stationary phase growth. The DNA damage checkpoint activity of UmuDC was clearly affected by ΔdinB883 as shown by testing a umuC104 ΔdinB883 double-mutant. The sensitivities of the ΔumuDC strain and the ΔdinB883 ΔumuDC double-mutant strain were significantly greater than for the ΔdinB883 strain, suggesting that the ΔdinB883 allele only partially suppresses UmuDC activity. The ΔdinB883 mutation partially sensitized (fivefold) uvrA and uvrB strains to UV radiation, but did not sensitize a ΔrecA strain. A comparison of the DNA sequences of the ΔdinB883 allele with the sequences of the Δ(dinB-yafN)882(::kan) and ΔdinB749 alleles, which do not sensitize cells to UV radiation, revealed ΔdinB883 is likely a "gain-of-function" mutation. The ΔdinB883 allele encodes the first 54 amino acids of wild-type DinB followed by 29 predicted residues resulting from the continuation of the dinB reading frame into an adjacent insertion fragment. The resulting polypeptide is proposed to interfere directly or indirectly with UmuDC function(s) involved in protecting cells against the lethal effects of radiation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children., Methods: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post-mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy., Findings: We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89·3%, 95% CI 85·8-91·9) cases: 175 (94·6%, 90·3-97·0) of 185 fetuses at 24 weeks' gestation or less, 88 (95·7%, 89·3-98·3) of 92 fetuses at more than 24 weeks' gestation, 34 (81·0%, 66·7-90·0) [corrected] of 42 newborns aged 1 month or younger, 45 (84·9%, 72·9-92·1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53·6%, 35·8-70·5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99·4% (96·6-99·9)., Interpretation: Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases., Funding: Policy research Programme, Department of Health, UK., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Migraine is a recognised cause of brain white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). However radiological characteristics of those in migraine are not well defined. We sought to study the radiological characteristics and factors associated with WMH in migraine., Methods: Migraine patients who were investigated with MRI of the brain in the outpatient clinic were studied retrospectively. Two groups were delineated based on the presence or absence of WMH in MRI scans. The clinical and demographic characteristics between the two groups were compared to delineate the associations of WMH., Results: Forty four patients were studied, out of which 19 demonstrated WMH on MRI. Frontal lobe was involved in all subjects with WMH. Infratentorial hyperintensities were not seen in any. Subcortical and deep white matter was the commonest distribution while callosal and subcallosal lesions were very rare. Family history of migraine, increasing age, and increasing headache frequency emerged as significant associations of WMH in multivariable analysis., Conclusions: There are characteristic radiological features and clinical associations of WMH in migraine., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

We review, for the first time, a 20-year Chinese story of research and development pertaining to tribendimidine, a promising anthelmintic agent that is safe and exhibits a broad spectrum of activity. Tribendimidine was first synthesized at the National Institute of Parasitic Diseases in Shanghai in the mid 1980s. In laboratory studies, tribendimidine showed high efficacy against Nippostrongylus braziliensis in rats, Necator americanus in hamsters, Ancylostoma caninum and Toxocara canis in dogs, and Syphacia mesocriceti in mice. Activity was also found against several species of cestodes in chicken. In clinical trials, a single oral dose of 400 mg tribendimidine, administered to patients infected only with N. americanus, or with N. americanus and Ancylostoma duodenalis, resulted in cure rates of 85.7% (132/154) and 89.8% (53/59), respectively. In comparison, a single oral dose of 400 mg albendazole resulted in significantly lower cure rates, namely 65.5% (91/139; chi(2) = 16.47, P < 0.001) and 71.7% (43/60; chi(2) = 6.29, P = 0.012), respectively. Single oral doses of tribendimidine (300 mg) and albendazole (400mg) were equally effective against Ascaris lumbricoides infections; cure rates were 96.0% (97/101) and 98.1% (101/103), respectively. In 5-14-year-old children with an Enterobius vermicularis infection, treated with a single oral dose of 200 mg tribendimidine, a cure rate of 81.6% (93/114) was observed. Tribendimidine was well-tolerated as only mild and transient side effects were observed. It would be of great public health significance if these findings are confirmed in other epidemiological settings, as more than one-quarter of the world population is currently affected by intestinal nematodes, with only very few drugs currently available on the market.

The alkyladenine DNA glycosylase (AAG) has been cloned from mouse and humans. AAG knock out mouse cells are sensitized to a variety of alkylating and cross-linking agents suggesting AAG is active on a variety of substrates. In humans, two isoforms have been characterized that are generated by alternative splicing and contain either exon 1a or 1b (hAAG1 or hAAG2). In this study, we examine the ability of the both known isoforms of human AAG (hAAG) to contribute to survival of Escherichia coli from treatments with simple alkylating agents and cross-linking alkylating agents. Our results show that hAAG is effective at repairing methyl lesions when expressed in E. coli, but is unable to afford increased resistance to alkylating agents producing larger alkyl lesions such as ethyl lesions or lesions produced by the cross-linking alkylating agents N,N'-bis-chloroethyl-N-nitrosourea (BCNU), N-(2-chloroethyl)-N-nitrosourea (CNU) or mitomycin C. In the case of CNU, expression of hAAG causes increased sensitivity rather than resistance, suggesting deleterious effects of hAAG activity. We also demonstrate that there are no apparent differences between the two isoforms of hAAG when recovery from damage produced by all alkylating agents is tested., (Copyright 2002 Elsevier Science B.V.)

Using a 4-echo spin-echo sequence, cerebral T2 was measured in specific anatomic regions in eleven healthy newborn infants, whose gestational plus postnatal ages (GPAs) lay between 37 and 42 weeks. For a region in the pons, T2 was 141+/-9 ms (mean +/- standard deviation), and no significant dependence upon GPA was seen. In the thalamus mean T2 was 136+/-13 ms, and T2 demonstrated a significant negative linear dependence upon age (r = 0.690; p < 0.02). In periventricular and frontal regions, mean T2 were 217+/-33, and 228+/-32 ms respectively, and more marked negative linear correlations with age were observed (r = 0.833; p < 0.001 and r = 0.722; p < 0.02). For these regions, the rate of T2 decrease with age appeared to be related to known patterns of myelination. For the parietal region studied, mean T2 was 204+/-34 ms, no significant dependence upon GPA being seen. T2 shows promise as an objective measure of cerebral development in the perinatal period.

Background: Children generally lie still enough for magnetic resonance imaging (MRI) only if they are asleep, either under sedation, which is deeper than conscious sedation, or under anaesthesia. Anaesthesia resources, however, are limited, and non-anaesthetists must use sedation frequently. Demand for MRI has increased and the failure of our sedation regimen led to an impractical demand for anaesthesia and unacceptable waiting times for scanning. We have therefore developed a nurse-led sedation service in a designated unit next to the scanner. This study assessed the safety and efficacy of this approach., Methods: Children who required MRI were sedated in the unit by designated sedationist nurses, who used an oral drug regimen (according to weight and age from conception: weight <5 kg, 50 mg/kg chloral hydrate; 5-10 kg, 100 mg/kg chloral hydrate; 10-20 kg, 1 mg/kg temazepam plus 0.25 mg/kg droperidol; >20 kg temazepam and droperidol as directed by radiologist, maximum doses 20 mg and 5 mg respectively). Nurses checked patients for their suitability, charted and administered the drugs according to a protocol, and monitored the children throughout the sedation. We prospectively audited failure and complications of sedation., Findings: During the 30 month study, there were 1155 sedations. 61 (5%) were unsuccessful, and there were no adverse events relating to the airway or breathing. After scanning had finished all children, in response to gently pinching the nose, could open their mouths to maintain their airway., Interpretation: This study suggests that it is possible to have a nurse-led sedation service for MRI of children that is both successful and safe.

A prospective, cross-sectional study was designed to determine the magnetic resonance relaxation times of cerebral white matter in human immunodeficiency virus (HIV) infected individuals. T1 and T2 were estimated at 1.5 T using four-point methods. Seventy-five HIV-1 seropositive subjects, 48 seronegative blood donors, and 17 seronegative homosexual men were studied. Associations between relaxometry and clinical classification, neurological status, immunological status, and qualitative MRI were investigated. Statistically significant differences in white matter T1 relaxation time were found comparing low-risk control and AIDS groups (p < .005), seropositive subjects with neurological signs and those without (p < .005), and subjects with low (CD4 < or = 200 x 10(6)/l) and high (CD4 > 200 x 10(6)/1) CD4 cell counts (p < .05). These findings add to the body of information that reveals no HIV-related change in the brain before the onset of symptomatic immunosuppression and go someway to validating the previous visually rated, qualitative findings. Statistically significant difference in white matter T2 relaxation time were also found comparing the two control groups (p < .005) highlighting the need for appropriate controls.

Short echo time proton spectra have been acquired from the brains of 30 male homosexual Acquired Immunodeficiency Syndrome (AIDS) patients and 12 age-matched control subjects on a 1.5 T MR system. The acquisition protocol used stimulated acquisition voxel localisation with a voxel size of 8 ml and repeat, echo, and mixing times of 5000, 20, and 30 ms, respectively. A single 25.6-ms Gaussian water suppression pulse was used with 128 spectral acquisitions and the data were eddy current corrected using a water reference. Baseline-corrected spectra were nonlinearly least squares fitted to a model function consisting of Gaussian functions representing the major metabolites reported in short echo proton spectra. Results indicate that the N-acetyl/creatine (NA/Cr) ratio is significantly reduced by 20% in AIDS patients [NA/Cr = 1.91 (0.51)] compared to control subjects [NA/Cr = 2.37 (0.25)] at short echo times.

In vivo proton spectroscopy has demonstrated abnormalities in the cerebral metabolite ratios from subjects with acquired immunodeficiency syndrome (AIDS). Some of the sequences employed are subject to T1 or T2 weighting, which may affect spectroscopic interpretation. The relaxation times of choline (Cho), creatine (Cr), and N-acetyl (NA) resonances have been estimated at 1.5 T in 21 patients infected with the human immunodeficiency virus (HIV) and 8 controls using gradient localised, spin-echo spectroscopic sequences of varying echo and repetition times. A statistically significant increase in the T2 of NA was found in the HIV seropositive patients who had diffuse abnormalities on MR imaging consistent with HIV encephalopathy (493 +/- 199 ms) when compared to controls (292 +/- 118 ms; p < .05). No other statistically significant differences were found in the relaxation times between patients and control subjects. These results demonstrate that signals from the NA resonance obtained using long echo time sequences in subjects who are HIV seropositive are not solely indicative of metabolite concentration.

Photorelaxation elicited by ultraviolet light (366 nm) was investigated on isolated rat thoracic aorta and trachealis. Rat tracheal smooth muscle but not aorta did not show UV-induced photorelaxation. Both streptozotocin, NO-carrying molecule and N omega-nitro-L-arginine, NO2-carrying molecule significantly enhanced photorelaxation, concentration-dependently, in rat trachealis and aorta. Methylene blue (10 microM) inhibited the potentiation action of streptozotocin and N omega-nitro-L-arginine in both tissues. Superoxide dismutase (300 U/ml) enhanced streptozotocin- and N omega-nitro-L-arginine-potentiated photorelaxation in rat trachealis, while pyrogallol (0.1 mM), a potent O2- generating agent, inhibited streptozotocin-potentiated photorelaxation in trachealis. Streptozotocin was much more effective than N omega-nitro-L-Arginine in potentiating of photorelaxation elicited by UV light in both tissues. From these findings, we conclude that streptozotocin and N omega-nitro-L-arginine produce EDRF like labile substance(s) by UV irradiation.

The role of the endothelium was evaluated in the relaxation of rat and guinea pig aortic rings induced by ascorbic acid. Ascorbic acid relaxed rat and guinea pig aortic rings that were previously contracted with submaximal dose of phenylephrine (PE), in a concentration dependent manner. Removal of the endothelium significantly reduced the sensitivity but not the magnitude of the response to ascorbic acid. Methylene blue, but not propranolol, blocked the endothelial augmentation of vascular relaxation to ascorbic acid. Vessels precontracted with potassium chloride (high K+) were also relaxed by ascorbic acid. Methylene blue also inhibited the response to ascorbic acid in the intact vessels precontracted with high K+. A23187 and acetylcholine, but not ADP, variably caused endothelium dependent component relaxation in guinea pigs, whereas all of these three probes constantly caused it. In Ca(2+)-free medium, Ca(2+)-induced contraction of high K(+)-depolarized rat aorta was inhibited by the presence of ascorbate, which was more pronounced in endothelium intact rings than in endothelium denuded ones. PE-induced contraction in the presence of different concentrations of ascorbate reduced both the sensitivity and the maximal contractile force in rat aorta. Ascorbic acid (0.125-32 mM) did not change the pH in the medium. From these findings, it is speculated that 1) receptor- and potential-operated Ca2+ channels may be modulated by ascorbate, 2) endothelium has a significant role in promoting relaxation induced by ascorbic acid.

The title compound, 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7 alpha-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17 alpha-alkyl substitution.