Incidence and risk factors for revision and contralateral anterior cruciate ligament reconstruction: A population-based retrospective cohort study.
There is a limited data on epidemiology of primary and recurrent anterior cruciate ligament reconstruction (ACLR) in Canada. The objectives of this study were to examine the incidence and factors associated with recurrent ACLR (revision and contralateral ACLR) in a western Canadian province of Alberta. We conducted a retrospective cohort study with an average follow up of 5.7 years. Albertans aged 10 to 60 years with a history of primary ACLR between 2010/11 to 2015/16 were included in the study. Participants were followed up until March 2019 to observe outcomes: Ipsilateral revision ACLR and contralateral ACLR. Kaplan Meir approach was used to estimate event free survival and Cox proportional hazard regression analysis was conducted to identify associated factors. Of the total participants with a history of primary ACLR on a single knee (n = 9292), n = 359, 3.9% (95% confidence interval: 3.5-4.3) underwent a revision ACLR. A similar proportion among those having primary ACLR on either knee (n = 9676), n = 344, 3.6% (95% confidence interval: 3.2-3.9) underwent a contralateral primary ACLR. Young age (<30 years) was associated with increased risk of contralateral ACLR. Similarly, young age (<30 years), having initial primary ACLR in winter and having allograft were associated with a risk of revision ACLR. Clinicians can use these findings in their clinical practice and designing rehabilitation plans as well as to educate patients about their risk for recurrent anterior cruciate ligament tear and graft failure.


Value of prophylactic oophorectomy in advanced breast cancer with parasternal lymph nodes metastasis.
In order to improve the poor prognosis of advanced breast cancer cases with positive parasternal lymph nodes metastasis, prophylactic oophorectomy was performed in 25 unselected cases. In a retrospective study on the breast cancer cases operated on from 1958 to 1969, comparison of eight advanced breast cancer cases with positive parasternal lymph nodes metastasis after radical mastectomy of Halsted type and parasternal lymph nodes dissection with, and 17 cases without prophylactic bilateral oophorectomy was made with respect to the survival rate, the survival time pattern by Mantel-Haenszel's procedure in their entirety and the recurrence rate. These results suggest the effectiveness of prophylactic oophorectomy for the advanced breast cancer.


Structures of hepatitis C virus nonstructural proteins required for replicase assembly and function.
Approximately 3% of the world population is infected with hepatitis C virus (HCV), causing a serious public health burden. Like other positive-strand RNA viruses, HCV assembles replicase complexes in association with cellular membranes and produces progeny RNA genomes through negative-strand intermediates. The viral proteins required for RNA replication are nonstructural (NS) proteins NS3 to NS5B. Owing to many obstacles and limitations in structural characterization of proteins and complexes with multiple transmembrane segments, attempts to understand the assembly and action of the HCV replicase complex have been challenging. Nevertheless, great progress has been made in obtaining structural information for several replicase components, providing insights into some aspects of the viral genome replication machinery.


Pharmacological management of nasal polyposis.
Nasal polyposis affects nearly 4% of the total population in Western countries, and presents a real challenge to the physician because of its severity, chronicity and recurrence rate. Characteristic histomorphological features of polyps are an eosinophilic inflammation and the destruction of connective tissue; recent research has focused on cytokines, chemokines, growth factors and metalloproteinases to explain these features, as the aetiology of nasal polyposis remains largely unclear. Currently, topical and systemic corticosteroids are first-choice drug therapy approaches, and good evidence from controlled trials is available for topical, but not for systemic, corticosteroid therapy. Surgery is indicated if adequate drug treatment fails, which often needs to be maintained after surgery. There is limited experience for other drugs, such as antihistamines, leukotriene antagonists and frusemide (furosemide), which may be added to corticosteroid therapy in selected patients. Aspirin (acetylsalicylic acid) desensitisation may be a therapeutic option for patients who do not respond to corticosteroids or surgery. Recently, antibiotics such as macrolides have been suggested to have therapeutic activity based on their anti-inflammatory properties but large-scale controlled trials are lacking. New approaches are currently evolving, specifically targeting eosinophilic recruitment (chemokine receptor 3, eotaxin) and inflammation (interleukin-4, -5, -13), immunoglobulin-E, or tissue remodeling by reducing the activity of metalloproteinases. This review summarises current knowledge on pathogenesis as well as established and future approaches in the pharmacological management of bilateral eosinophilic nasal polyposis.


Proteinuria and Albuminuria During and After Paricalcitol Treatment in Chronic Kidney Disease Patients.
Data on paricalcitol lowering albuminuria and proteinuria already exist; however, it is unclear how paricalcitol withdrawal affects both. Forty-two nondialysis chronic kidney disease (CKD) patients (29 men) aged 62.3 ± 12 years completed the study. CKD patients with proteinuria and intact parathyroid hormone ≥65 pg/mL received paricalcitol (1 μg/day po) for 6 months. After paricalcitol withdrawal we followed them for 6 more months. Paricalcitol treatment significantly reduced urinary albumin/creatinine ratio (UACR), 24-hour albuminuria (24hA), and 24-hour proteinuria (24hP). Six months after drug withdrawal UACR increased significantly, 24hA and 24hP did not change significantly. Serum creatinine and cystatin C significantly increased during treatment, and estimated glomerular filtration rate (eGFR) decreased. After drug withdrawal serum creatinine, cystatin C, and eGFR did not change significantly. In conclusion, 6-month paricalcitol treatment (1 μg/day) in nondialysis CKD patients significantly reduced albuminuria and proteinuria. Six months after paricalcitol withdrawal 24hA and 24hP did not change significantly. Kidney function decreased during paricalcitol treatment; after paricalcitol withdrawal it remained stable. The unaltered values of 24hA, 24hP, and kidney function after paricalcitol withdrawal could be a delayed effect of paricalcitol treatment.


The Importance of Thiopurine S-Methyltransferase Gene Analysis Before Azathioprine Therapy.
Neuromyelitis optica is an inflammatory central nervous system syndrome associated with serum aquaporin-4 IgG antibody. Optic nerve and spinal cord involvement is typical. We report a 9-year-old girl with a diagnosis of neuromyelitis optica, who developed azathioprine-induced pancytopenia that was subsequently found to be caused by thiopurine-methyltransferase mutation.


71% of the Danish municipal alcohol treatment centres use NADA acupuncture. This status report based on recent reviews of the effect and risks of using auricular acupuncture in alcohol treatment shows that the available studies do not have sufficient strength and methodological quality to draw conclusions about effectiveness on craving, alcohol-related outcome measures or withdrawal symptoms. The results warrant a reassessment of the use of NADA in publicly funded alcohol treatment.


Juvenile Paget's disease, familial expansile osteolysis and other genetic osteolytic disorders.
Several rare inherited osteolytic disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB). Familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia are related disorders caused by mutations affecting the TNFRSF11A gene, which encodes the receptor activator of NFkappaB (RANK). The mutations result in failure of normal processing of RANK and osteoclast activation. Inactivating mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause idiopathic hyperphosphatasia which is a severe disorder that shares phenotypic similarities with PDB. The syndrome of hereditary inclusion body myopathy, PDB and frontotemporal dementia is caused by mutations in the gene encoding for valosin-containing protein which is involved in regulating degradation of ubiquitinated proteins. Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear.


Emergency endovascular treatment of cavernous internal carotid artery acute bleeding with flow diverter stent: a single-center experience.
To describe our single-center experience in the treatment of cavernous internal carotid artery (ICA) acute bleeding with flow diverter stent (FDS), as a single endovascular procedure or combined with an endoscopic endonasal approach. We analyze a case series of 5 patients with cavernous ICA acute bleeding, i.e., 3 iatrogenic, 1 post-traumatic, and 1 erosive neoplastic. After an immediate nasal packing to temporarily bleeding control, patients underwent digital subtraction angiography (DSA) to identify the site of the ICA injury. A concomitant balloon occlusion test (BOT) was performed, to exclude post-occlusive ischemic neurological damage. An FDS was placed with parallel intravenous infusion of abciximab in 3 cases and tirofiban in 2 cases. In two patients, an innovative "sandwich technique" combining the endovascular reconstruction with an extracranial intrasphenoidal cavernous ICA resurfacing with autologous flaps or grafts by endoscopic endonasal approach was performed. No patient had periprocedural ischemic-hemorrhagic complications. All patients had a regular clinical evolution, without general complications or new onset of focal neurological deficits. No further bleeding occurred in 3 patients, while 2 cases experienced a mild rebleeding in a period ranging from 5 to 15 days after the endovascular procedure. In these two cases, we proceeded with an endoscopic endonasal procedure to resurface the exposed ICA wall in the sphenoid sinus. Although the treatment of choice for cavernous ICA acute bleeding remains the occlusion of the injured vessel, in cases of poor hemodynamic compensation at the BTO, the endovascular FDS emergency placement can be effective. A combined endoscopic endonasal technique to support the extracranial side of the vessel using autologous flaps or grafts can be performed to prevent the risk of rebleeding.


Postload glucose spike but not fasting glucose determines prognosis after myocardial infarction in patients without known or newly diagnosed diabetes.
The effect of postload glucose spikes (PGS), the difference between 2 hour post-load plasma glucose (2hPLPG) and fasting plasma glucose (FPG), on post-myocardial infarction (post-MI) prognosis in nondiabetic patients is unexplored. This is a retrospective cohort analysis of 847 nondiabetic post-MI survivors who underwent a predischarge oral glucose tolerance test (median PGS: 2.4 mmol/L). Patients were divided into the unmatched groups 1 and 2 (PGS ≤ and > 2.4 mmol/L) and the propensity score-matched groups 1M and 2M (355 pairs assembled from the overall cohort), and these groups were compared. Major adverse cardiac events (MACE: death and nonfatal reinfarction) were recorded during follow-up (median: 3.4 years). Event-free survival was compared by the Kaplan-Meier method. Multivariate Cox proportional hazards regression determined the predictors of MACE. C-statistics (change in area under the curve, δAUC), continuous net reclassification improvement (NRI>0 ), and integrated discrimination improvement (IDI) were used to compare models. The number of MACE was higher in groups 2 (27.3% vs 14.2%, P < .001) and 2M (24.5% vs 15.5%, P < .001). Event-free survival was worse in groups 2 (hazard ratio [HR] 2.01; 95% CI, 1.49-2.71; P < .001) and 2M (HR 1.63; 95% CI, 1.17-2.27; P = .004). PGS independently predicted MACE-free survival in the whole (HR 1.16; 95% CI, 1.06-1.26; P = .002) and matched cohort (HR 1.12; 95% CI, 1.02-1.24; P = .021). PGS, but not FPG or 2hPPG, improved the predictive performance of the base model (δAUC 0.013, P = .046), with greater improvement seen when PGS was added and compared to 2hPPG (δAUC 0.005, P = .034; NRI>0 0.2107, P = .013; IDI 0.0042, P = .046). PGS is a better predictor of post-MI prognosis than 2hPPG in nondiabetic patients.


Understanding engagement with Brown Buttabean Motivation, an Auckland grassroots, Pacific-led holistic health programme: a qualitative study.
The aim was to understand how participants engage with Brown Buttabean Motivation (BBM) a grassroots, Pacific-led holistic health programme and the meaning it has in their lives. The objectives were to explore the impact BBM had on all aspects of their health and well-being, what attracted them, why they stayed, identify possible enablers and barriers to engagement, and understand impact of COVID-19 restrictions. Qualitative study with thematic analysis of semi-structured interviews of BBM participants, followed by theoretical deductive analysis of coded data guided by Pacific Fonofale and Māori Te Whare Tapa Whā health models. In this meeting-house metaphor, floor is family, roof is culture, house-posts represent physical, mental, spiritual and sociodemographic health and well-being, with surroundings of environment, time and context. Interviews of BBM members conducted in South Auckland, New Zealand, 2020. 22 interviewees (50% female) aged 24-60 years of mixed Pacific and Māori ethnicities with a mixture of regular members, attendees of the programme for those morbidly obese and trainers. Two researchers independently coded data with adjudication and kappa=0.61 between coders. Participants identified the interactive holistic nature of health and well-being. As well as physical, mental and spiritual benefits, BBM helped many reconnect with both their family and their culture. BBM's primary aim is weight-loss motivation. Many weight loss studies provide programmes to improve physical exercise and nutrition, but seldom address sustainability and other core factors such as mental health. Programmes are often designed by researchers or authorities. BBM is a community-embedded intervention, with no reliance external authorities for its ongoing implementation. It addresses many factors impacting participants' lives and social determinants of health as well as its core business of exercise and diet change. Our results indicate that BBM's holistic approach and responsiveness to perceived community needs may contribute to its sustained success.


Genetic diversity and clonal relationships of Acinetobacter baumannii strains isolated in a neonatal ward: epidemiological investigations by allozyme, whole-cell protein and antibiotic resistance analysis.
Sixty-five strains of Acinetobacter baumannii which had been isolated from patients and the indoor environment of a neonatal intensive care unit and, for comparative purposes, isolates from three other wards, were examined by means of electrotyping and analysis of whole-cell protein and antibiotic resistance patterns. Fourteen different electrotypes were determined. The predominant type, a multiply resistant acinetobacter clone, persisted in the neonatal ward over several months. The results underline the usefulness of electrophoretic subtyping, in particular by means of allozyme pattern and as a supplement to whole-cell protein pattern analysis, in epidemiological investigations into the routes of transmission of nosocomial A. baumannii infections.


Chemically and biologically synthesized CPP-modified gelonin for enhanced anti-tumor activity.
The ineffectiveness of small molecule drugs against cancer has generated significant interest in more potent macromolecular agents. Gelonin, a plant-derived toxin that inhibits protein translation, has attracted much attention in this regard. Due to its inability to internalize into cells, however, gelonin exerts only limited tumoricidal effect. To overcome this cell membrane barrier, we modified gelonin, via both chemical conjugation and genetic recombination methods, with low molecular weight protamine (LMWP), a cell-penetrating peptide (CPP) which was shown to efficiently ferry various cargoes into cells. Results confirmed that gelonin-LMWP chemical conjugate (cG-L) and recombinant gelonin-LMWP chimera (rG-L) possessed N-glycosidase activity equivalent to that of unmodified recombinant gelonin (rGel); however, unlike rGel, both gelonin-LMWPs were able to internalize into cells. Cytotoxicity studies further demonstrated that cG-L and rG-L exhibited significantly improved tumoricidal effects, with IC50 values being 120-fold lower than that of rGel. Moreover, when tested against a CT26 s.c. xenograft tumor mouse model, significant inhibition of tumor growth was observed with rG-L doses as low as 2 μg/tumor, while no detectable therapeutic effects were seen with rGel at 10-fold higher doses. Overall, this study demonstrated the potential of utilizing CPP-modified gelonin as a highly potent anticancer drug to overcome limitations of current chemotherapeutic agents.


Effects of camptothecin, an inhibitor of DNA topoisomerase I on ribosomal gene structure and function in TG cells.
The effects of camptothecin treatment and topoisomerase I inhibition on ribosomal gene structure and function were investigated in TG cells, a human tumour cell line. 90- and 180-min treatments with 25 microM camptothecin resulted in an increased DNA fragmentation and decreased activity of topoisomerase I in cell extracts. After 180-min treatment, the incorporation of labelled uridine into total cell RNA was reduced to 39% and the ribosomal RNA synthesis to 10%, as compared to values of control cells. At the ultrastructural level, the nucleolar components appeared to be segregated; after selective DNA staining, with osmium-amine complex, a part of the nucleolar chromatin of treated cells showed the presence of thin, extended DNA filaments, superimposable to those present in control cells.


[Hyperspectral imaging for postoperative flap monitoring of pedicled flaps].
Since pedicle flaps were first described by the Indian physician Sushruta Samhita in the 6th century B. C., they have become an integral part of reconstructive surgery. As more and more research has been conducted into the underlying physical principles, flap monitoring has developed steadily in the last few decades. Hyperspectral Imaging (HSI) is a new quantitative measuring method for assessing the perfusion of the underlying tissue. This study aims to evaluate HSI as a monitoring method for pedicle flaps. In 16 patients who had undergone reconstructive surgery, oxygen saturation, haemoglobin and water concentration of the locoregional flap, necrotic flap areas as well as intact skin were measured on postoperative days 1 to 7. Subsequently, the data were statistically described and graphically illustrated. HSI revealed increased haemoglobin concentration and decreased oxygen and water concentration in necrotic flap areas compared with the monitor island and healthy skin. The distribution of the values collected from the vital skin areas and the monitor island was almost identical. HSI allows for safe, immediate, non-contact measurement of tissue perfusion of transferred tissue areas in patients after pedicle flap surgery. The use of HSI may improve postoperative flap monitoring.


Synchronous mediastinal ganglioneuroma and retroperitoneal pheochromocytoma.
We herein report the case of a 52-year-old woman who has mediastinal ganglioneuroma and retroperitoneal pheochromocytoma with different histologic entity. The patient first visited our hospital for surgical treatment of superior-posterior mediastinal tumor, which was successfully removed by thoracoscopic approach to reveal a benign ganglioneuroma. A retroperitoneal tumor was incidentally found postoperatively that was removed using a laparoscopic procedure. The retroperitoneal tumor was a nonfunctioning pheochromocytoma, which was different from the mediastinal neurogenic tumor. This association, although rare, should be recognized for management of neurogenic tumors in the thorax.


Absence of Lugol staining indicates initiation of esophageal squamous cell carcinoma: A combined genomic and epidemiologic study.
The genomic characteristics during the carcinogenic process of esophageal squamous cell carcinoma (ESCC) remain largely unknown. We report here the genomic characteristics of 106 esophageal tissues of various stages from a population-based screening cohort in China ("Endoscopic Screening for Esophageal Cancer in China" trial) and 57 ESCC tissues from a local hospital. A significant increase in somatic mutation and copy number alterations is observed in the non-dysplastic Lugol unstaining lesions (ND-LULs). Extensive clonal expansion has emerged in the ND-LULs to an extent similar to that in higher-stage lesions. The burden of genomic alterations correlates with the size of LULs in the ND-LULs. 8-year follow-up shows that ND-LULs harbor an increased risk of progression to ESCC (adjusted IRR6-10 mm vs. none = 4.66, adjusted IRR>10 mm vs. none = 40.70), and the risk is correlated with LUL size for both non-dysplastic and dysplastic lesions. Lugol unstaining can be the initial stage in the carcinogenic process of ESCC.


Effect of dilazep dihydrochloride on serum cardiac troponin T levels in hemodialysis patients.
Cardiac troponin T is a highly sensitive marker for the detection of myocardial injury. We studied whether dilazep dihydrochloride affects cardiac troponin T levels in hemodialysis patients. Our study included 60 hemodialysis patients without symptoms of acute myocardial ischemia. We measured serum cardiac troponin T levels by the Elecsys troponin T assay and randomized 40 hemodialysis patients with left ventricular hypertrophy (LVH) into two treatment groups: a dilazep dihydrochloride group (300 mg/day, n = 20) and a placebo group (n = 20). Treatment was continued for 12 months. There were no significant differences between pre- and postdialysis cardiac troponin T levels before treatment. LVH was noted in 40 patients out of 60 hemodialysis patients (67%). Cardiac troponin T levels were significantly higher in these patients (0.23 +/- 0.08 microg/l) than in hemodialysis patients without LVH (0.09 +/- 0.03 microg/l). Cardiac troponin T levels were reduced from 0.24 +/- 0.08 to 0.12 +/- 0.06 microg/l (p < 0.01) in patients treated with dilazep dihydrochloride. There were no change in cardiac troponin T levels in patients receiving placebo (from 0.21 +/- 0.08 at baseline to 0.20 +/- 0.07 microg/l). Dilazep dihydrochloride may be effective in ameliorating myocardial damage in hemodialysis patients.


[Evaluation of bubble oxygen inhalators' performances and an investigation on their solutions for improvement].
This paper analyses the defects of bubble oxygen inhalators currently used, and investigates into their solutions for improvement.


Obesity and leptin resistance: distinguishing cause from effect.
Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of 'leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as 'cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation.


S-Linked sialyloligosaccharides bearing liposomes and micelles as influenza virus inhibitors.
An efficient, homogeneous synthesis of phospholipid conjugation of S-Neu5Acα2-6Galβ1-4GluNAcβ1-3 (3) and its 6-sulphate analogue 4 has been developed. The self-assembled micelles and liposomes of these trisaccharides formed in solution were found to be inhibitors interfering with the entry of the H1N1 influenza virus into MDCK cells. Compound 3 bearing a liposome and a micelle displayed superior inhibitory activity than its 6-sulfate congener 4 in both the virus neutralization assay and the hemagglutination inhibition assay.


Levator lengthening technique using cartilage or fascia graft for paralytic lagophthalmos in facial paralysis.
Lid loading using gold weights has been commonly used to treat paralytic lagophthalmos (PL); however, the procedure has a relatively high complication rate and the availability of these plates varies among social circumstances. We used a levator lengthening (LL) technique, which originally elongated the levator aponeurosis by inserting a fascia graft between the edge of the levator aponeurosis and the tarsal plate. However, because this procedure tends to result in a wide residual lagophthalmos, we changed the graft material from fascia to conchal cartilage. In this study, we describe in detail our experience with LL using the cartilage graft. LL was performed in 18 patients with PL. Fascia grafts were used in seven patients and cartilage grafts in 11. Static reconstructions of the lower eyelid and eyebrow were also performed in most patients. Efficacy was evaluated from patient reports of ocular symptoms and by measuring the palpebral fissure width at opening and closing for both eyes. All patients experienced improved ophthalmological symptoms, which were more apparent in cartilage cases. The average palpebral fissure at eyelid closure was 1.8 mm in cartilage cases and 4.0 mm in fascia cases. In cases where an eyebrow lift was concurrently performed, the residual lagophthalmos became wider in fascia grafting but remained acceptable in cartilage grafting. LL is a simple and useful procedure for treating PL with higher efficacy when a cartilage graft is used. However, the level of the upper eyelid can be easily adjusted by changing the fixation position of the cartilage. Additional experience is required to obtain more consistent outcomes.


Aldehyde dehydrogenase-2 acts as a potential genetic target for renal fibrosis.
Obstructive renal injury and drug-induced nephrotoxicity are the two most common causes of renal fibrosis diseases. However, whether these two different pathogeny induced same pathological outcomes contain common genetic targets or signaling pathway, the current research has not paid great attention. GSE121190 and GSE35257 were downloaded from the Gene Expression Omnibus (GEO) database. While GSE121190 represents a differential expression profile in kidney of mice with unilateral ureteral obstruction (UUO) model, GSE35257 represents cisplatin nephrotoxicity model. By using GEO2R, 965 differential expression genes (DEGs) in GSE121190 and 930 DEGs in GSE35257 were identified. 43 co-DEGs were shared and were extracted for protein-protein interaction (PPI) analysis. Subsequently, three shared pathways including glycolysis/gluconeogenesis, fatty acid degradation and pathways in cancer were involved in two models with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We reconfirmed that these three pathways have relatively high scores by using Gene Set Enrichment Analysis (GSEA) software. Additionally, further bioinformatic analysis showed that Aldehyde dehydrogenase-2 (Aldh2) involved in the progression of renal fibrosis by mediating glycolysis pathway. Then real-time PCR and western blotting were performed to validate the expression of Aldh2 in kidney tissue after three different etiologies that caused renal fibrosis. Basically consistent with our bioinformatics results, our experiment showed that the expression of Aldh2 is the most significantly decreased in the UUO model, followed by ischemia-reperfusion injury (IRI) model and finally the cisplatin-induced model. Thus, Aldh2 can act as a common potential genetic target for different renal fibrosis diseases.


Thromboelastography Changes of Whole Blood Compared to Blood Component Transfusion in Infant Craniosynostosis Surgery.
Surgical treatment of craniosynostosis with cranial vault reconstruction in infants is associated with significant blood loss. The optimal blood management approach is an area of active investigation. Thromboelastography (TEG) was used to examine changes in coagulation after surgical blood loss that was managed by transfusion with either whole blood or blood components. Transfusion type was determined by availability of whole blood from the blood bank.This retrospective study examined differences in posttransfusion TEG maximum amplitude (MA), a measure of the maximum clot strength, for patients transfused with whole blood or blood components. We included all patients less than 24 months old who underwent cranial vault remodeling, received intraoperative transfusions with whole blood or blood components, and had baseline and posttransfusion TEG measured. Whole blood was requested for all patients and was preferentially used when it was available from the American Red Cross.Of 48 eligible patients, 30 received whole blood and 18 received blood components. All patients received an intraoperative antifibrinolytic agent. The posttransfusion MA in the whole blood group was 61.8 mm (IQR 59.1, 64.1) compared to 57.9 mm (IQR 50.5, 60.9) in the blood components group (P = 0.010). There was a greater posttransfusion decrease in MA for patients transfused with blood components (median decrease of 7.7 mm [IQR -3.4, 6.3]) compared with whole blood (median decrease of 2.1 mm [IQR -9.6, 7.5] P < 0.001).Transfusion with blood components was associated with a greater decrease in MA that was likely related to decreased postoperative fibrinogen in this group. Patients who received whole blood had higher postoperative fibrinogen levels.


Utilizing full-thickness skin grafts for vaginal reconstruction.
Full-thickness skin grafts are superior for certain types of vaginal reconstruction. The advantages of this procedure are decreased contraction, reduced time for postoperative stenting, correction at an earlier age, a lower risk of vaginal stenosis, and improved donor site cosmesis. In addition, the patient has the psychological assurance that she is externally normal as she develops through puberty and adulthood.


Evaluation of protein 3-D structure prediction: comparison of modelled and X-ray structure of an alkaline serine protease.
We describe the modelling of the structure of the highly alkaline subtilisin protease OPTICLEAN from Bacillus alcalophilus. The model was developed through modelling by homology. We used the structure of subtilisin Carlsberg from the Brookhaven protein databank (entry 1CSE) as start structure. Amino acid changes and deletions were performed with the graphic protein design program BRAGI. Force field calculations and molecular dynamic simulations were made with AMBER 3.0 on a Multiflow TRACE 14/300. The comparison of the model and the later solved X-ray structure of OPTICLEAN shows a high similarity between the two structures, but there were also remarkable deviations between the two structures in some loop regions. The comparison shows that the deviations are due to difficulties in the prediction of correct main chain torsion angles of the prolines and the selection of correct loops in deletion or insertion regions. Strategies to avoid these mistakes are discussed.


Coronary computed tomography angiography during arrhythmia: Radiation dose reduction with prospectively ECG-triggered axial and retrospectively ECG-gated helical 128-slice dual-source CT.
Arrhythmia during coronary computed tomography angiography (coronary CTA) acquisition increases the risk of nondiagnostic segments and high radiation exposure. An advanced arrhythmia rejection algorithm for prospectively electrocardiogram (ECG)-triggered axial scans using dual-source CT (DSCT) examinations has recently been reported. We compared image quality and effective dose at DSCT examinations using prospectively ECG-triggered axial scanning with advanced arrhythmia rejection software (PT-AAR) versus retrospectively ECG-gated helical scanning with tube-current modulation (RG-TCM) during arrhythmia. This was a retrospective case-control study of 90 patients (43 PT-AAR, 47 RG-TCM) with arrhythmia (defined as heart rate variability [HRV] > 10 beats/min during data acquisition) referred for physician-supervised coronary CTA between April 2010 and September 2011. A subset of 22 cases matched for body mass index, HR, HRV, and other scan parameters was identified. Subjective image quality (4-point scale) and effective dose (dose length product method) were compared. PT-AAR was associated with lower effective dose than RG-TCM (4.1 vs 12.6 mSv entire cohort and 4.3 vs 9.1 mSv matched controls; both P < 0.01). Image quality scores were excellent in both groups (3.9 PT-AAR vs 3.6 RG-TCM) and nondiagnostic segment rates were low (0.1% vs 0.6%). Significantly higher image quality scores were found with PT-AAR in the entire cohort (P < 0.05), and in matched controls with high HRV > 28 beats/min (P < 0.05). In patients with variable heart rates, prospectively ECG-triggered axial DSCT with arrhythmia rejection algorithm is feasible and can decrease radiation exposure by ∼50% versus retrospectively ECG-gated helical DSCT, with preserved image quality.


Therapeutic Hypothesis Testing With Rodent Brain Tumor Models.
The development and application of rodent models for preclinical testing of novel therapeutics and approaches for treating brain tumors has been a mainstay of neuro-oncology preclinical research for decades, and is likely to remain so into the foreseeable future. These models serve as an important point of entry for analyzing the potential efficacy of experimental therapies that are being considered for clinical trial evaluation. Although rodent brain tumor models have seen substantial change, particularly since the introduction of genetically engineered mouse models, certain principles associated with the use of these models for therapeutic testing are enduring, and form the basis for this review. Here we discuss the most common rodent brain tumor models while directing specific attention to their usefulness in preclinical evaluation of experimental therapies. These models include genetically engineered mice that spontaneously or inducibly develop brain tumors; syngeneic rodent models in which cultured tumor cells are engrafted into the same strain of rodent from which they were derived; and patient-derived xenograft models in which human tumor cells are engrafted in immunocompromised rodents. The emphasis of this review is directed to the latter.


The TNF-like weak inducer of the apoptosis/fibroblast growth factor-inducible molecule 14 axis mediates histamine and platelet-activating factor-induced subcutaneous vascular leakage and anaphylactic shock.
Anaphylaxis includes mast cell (MC) activation, but less is known about downstream mechanisms (ie, vascular permeability controlled by endothelial cells [ECs]). The TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor, fibroblast growth factor-inducible molecule 14 (Fn14), belong to the TNF superfamily and are involved in proinflammatory responses. We sought to investigate the role of TWEAK/Fn14 axis in anaphylaxis. In vivo vascular permeability and mouse models of passive systemic anaphylaxis (PSA) and active systemic anaphylaxis were applied to wild-type (WT), TWEAK- and Fn14-deficient mice (TWEAK-/- and Fn14-/-, respectively). Primary bone marrow-derived mast cells (BMMCs) and ECs from WT and Fn14-/- or TWEAK-/- mice were studied. The TWEAK/Fn14 axis was also investigated in human samples. Mice with PSA and active systemic anaphylaxis had increased Fn14 and TWEAK expression in lung tissues and increased serum soluble TWEAK concentrations. TWEAK and Fn14 deficiencies prevent PSA-related symptoms, resulting in resistance to decreased body temperature, less severe reactions, and maintained physical activity. Numbers of MCs after PSA are similar between genotypes in different tissue regions, such as ear skin and the trachea, tongue, peritoneum, lungs, and bone marrow. Moreover, in vitro studies revealed no differences in degranulation or mediator release between WT and Fn14-/- BMMCs after IgE-FcεRI stimulation. In vivo and in vitro histamine and platelet-activating factor administration increases Fn14 receptor expression in lungs and ECs. Moreover, Fn14 deficiency in ECs maintained in vitro impermeability when stimulated by mediators or activated BMMCs but not by TWEAK-/- BMMCs, indicating that Fn14 is crucial for endothelial barrier function. TWEAK/Fn14 deletion or TWEAK-blocking antibody prevented histamine/platelet-activating factor-induced vascular subcutaneous permeability. Circulating soluble TWEAK levels were increased in patients with anaphylaxis, and plasma from those patients increased Fn14 expression in ECs. The TWEAK/Fn14 axis participates in anaphylactic reactions. Inhibition of TWEAK/Fn14 interaction could be efficacious in anaphylaxis therapy.


Fluorescence staining of nuclear deoxyribonucleic acid allows for accurate assessment of the hamster egg penetration assay.
To improve the assessment of sperm penetration during the hamster penetration assay, we compared the Hoechst 33342 and 33258 DNA-specific fluorescent stains with the standard acetolacmoid stain. The fluorescence stains produced distinct staining of the DNA within the egg cytoplasm and nucleus, and this allowed for accurate and fast assessment of sperm penetration.


Impact of the biopsy forceps size on histological analysis and performances of the histological scoring systems.
To improve the reliability of the quantitative scorings of the synovial biopsies, we evaluate whether diameter of arthroscopic forceps influences histological quality of synovial tissue and/or histological scores and we compare the intra- and inter-observer performances of the main histological scoring systems. Synovial biopsies were retrieved in the same part of the joint using 1, 2 and 4 mm diameters grasping forceps. After standard staining and immunohistochemistry with anti-CD68 antibody, slides were scored blindly by 2 independent experienced operators for tissue quality and with Krenn score, de Bois-Tak score and CD68 semi-quantitative score. Four samples did not pass quality control. No difference other than a higher number of vessels in the 4 mm versus 2 mm forceps (p = 0.01) was found among the 3 groups. CD68 score was significantly higher in the 2 versus 4 mm forceps (p = 0.009). So we concluded that only vessels quantification and CD68 semi-quantitative score seemed affected by the forceps size. The intra-reader agreement was variable across observers and features: 0.78 (0.66-0.87) for the Krenn scoring system, 0.89 (0.78-0.97) for the de Bois-Tak score and 0.93 (0.81-1.00) for the CD68 score. Interobserver reliabilities of Krenn score, de Bois-Tak score and CD68 scores were satisfactory: 0.95 (0.92-0.99) for Krenn, 0.98 (0.96-0.99) for de Bois-Tak and 0.80 (0.71-0.89) for CD68.


20th Annual Feigenbaum Lecture: Echocardiography for Precision Medicine-Digital Biopsy to Deconstruct Biology.
Heart failure with preserved ejection fraction (HFpEF) is a complex, heterogeneous syndrome in need of improved classification given its high morbidity and mortality and few effective treatment options. HFpEF represents an ideal setting to examine the utility and feasibility of a precision medicine approach. This article (based on the 20th annual Feigenbaum Lecture, presented at the 2019 American Society of Echocardiography Scientific Sessions) describes the utility of echocardiography as a "digital biopsy" and how deep quantitative echocardiographic phenotyping, coupled with machine learning, can be used to identify novel HFpEF phenotypes. The cellular and ultrastructural basis of abnormal speckle-tracking echocardiography- (STE-) based measurements of cardiac mechanics can provide a window into cardiomyocyte calcium homeostasis. STE-based measurements of longitudinal strain can thus inform the extent of myocardial involvement in patients with HFpEF, which may help to determine responsiveness to cardiac-specific HF medications. However, classifying the complex, systemic, multiorgan nature of HFpEF appropriately likely requires more advanced methods. Using unsupervised machine learning, HFpEF can be classified into three distinct phenogroups with differing clinical and echocardiographic characteristics and outcomes: (1) natriuretic peptide deficiency syndrome; (2) extreme cardiometabolic syndrome; and (3) right ventricle-cardio-abdomino-renal syndrome. Each can be probed to determine their biological basis. The goal of improved classification of HFpEF is to match the right patient with the right treatment, with the hope of improving the track record of HFpEF clinical trials. This article emphasizes the central role of echocardiography in advancing precision medicine and illustrates the integration of basic, translational, clinical, and population research in echocardiography with the goal of better understanding the pathobiology of a complex cardiovascular syndrome.


HgCl2-induced changes in cytosolic Ca2+ of cultured rabbit renal tubular cells.
Fura 2 was used to measure changes in cytosolic [Ca2+] ([Ca2+]i) in cultured rabbit kidney proximal tubule cells exposed to HgCl2. Treatment with 2.5-10 microM HgCl2 resulted in an extracellular [Ca2+] ([Ca2+]e)-independent 2- to 12-fold increase in [Ca2+]i above resting levels of about 100 nM. Treatment with 25-100 microM HgCl2 caused a rapid [Ca2+]e-independent 10- to 12-fold increase in [Ca2+]i within 1 min followed by a recovery to about 2-fold steady state by 3 min. With 25-100 microM HgCl2, both magnitude and rate of Ca2+ increase were similar, but recovery was greater with increasing doses. A slower, secondary increase in [Ca2+]i followed which varied with HgCl2 concentration and required [Ca2+]e. The first increase in [Ca2+]i represents release from intracellular pools. Calcium channel blockers, calmodulin inhibitors, and mitochondrial inhibitors do not alter the patterns of [Ca2+]i changes due to HgCl2. The recovery response with higher HgCl2 concentrations appears to be triggered by Hg2+ and not by the increased [Ca2+]i. Sulfhydryl modifiers N-ethylmaleimide, PCMB and PCMBS produced [Ca2+]e-independent [Ca2+]i increases similar to those induced by low HgCl2 concentrations. Cell killing with HgCl2 was about 50% greater with normal [Ca2+]e than with low [Ca2+]e, suggesting that [Ca2+]e influx is important in accelerating injury leading to cell death.


Efficacy and safety of antibiotic agents in children with COVID-19: a rapid review.
The aim of this review was to evaluate the efficacy and safety of antibiotic agents in children with COVID-19, as well as to introduce the present situation of antibiotics use and bacterial coinfections in COVID-19 patients. We searched Cochrane library, Medline, Embase, Web of Science, CBM, Wanfang Data and CNKI from their inception to March 31, 2020. In addition, we searched related studies on COVID-19 published before March 31, 2020 through Google Scholar. We evaluated the risk of bias of included studies, and synthesized the results using a qualitative synthesis. Six studies met our inclusion criteria. Five studies on SARS showed an overall risk of death of 7.2% to 20.0%. One study of SARS patients who used macrolides, quinolones or beta lactamases showed that the mean duration of hospital stay was 14.2, 13.8 and 16.2 days, respectively, and their average duration of fever was 14.3, 14.0 and 16.2 days, respectively. One cohort study on MERS indicated that macrolide therapy was not associated with a significant reduction in 90-day mortality (adjusted OR 0.84, 95% CI: 0.47-1.51, P=0.56) and improvement in MERS-CoV RNA clearance (adjusted HR 0.88, 95% CI: 0.47-1.64, P=0.68). According to the findings of 33 studies, the proportion of antibiotics use ranged from 19.4% to 100.0% in children and 13.2% to 100.0% in adults, despite the lack of etiological evidence. The most commonly used antibiotics in adults were quinolones, cephalosporins and macrolides and in children meropenem and linezolid. The benefits of antibiotic agents for adults with SARS or MERS were questionable in the absence of bacterial coinfections. There is no evidence to support the use of antibiotic agents for children with COVID-19 in the absence of bacterial coinfection.


Aquaponics using a fish farm effluent shifts bacterial communities profile in halophytes rhizosphere and endosphere.
The intensification of marine aquaculture raises multiple sustainability issues, namely the handling of nutrient-rich effluents that can adversely impact ecosystems. As integrated multi-trophic aquaculture (IMTA) gains momentum, the use of halophyte plants to phytoremediate aquaculture effluents has received growing attention, particularly in aquaponics. It is, therefore, important to obtain a more in-depth knowledge of the microbial communities present in the root systems of these plants, both in their natural environment (sediment) and in aquaponics, in order to understand their nutrient removal potential. The present study used denaturing gradient gel electrophoresis (DGGE) and barcoded pyrosequencing to assess the bacterial community present in the endosphere and rhizosphere of three halophyte plants: Halimione portulacoides, Salicornia ramosissima and Sarcocornia perennis. Species-specific effects were recorded in the profile and diversity of the bacterial communities present in halophyte roots, with significant differences also recorded for the same halophyte species grown in contrasting environments (sediment vs. aquaponics). In aquaponics the most abundant groups belonged to the orders Rhodocyclales, Campylobacterales, Rhodobacterales and Desulfobacterales, while in the natural environment (sediment) the most abundant groups belonged to the orders Rhizobiales, Sphingomonadales and Alteromonadales. An overall enrichment in bacterial taxa involved in nutrient cycling was recorded in the roots of halophytes grown in aquaponics (such as Denitromonas, Mesorhizobium, Colwellia, Dokdonella and Arcobacter), thereby highlighting their potential to reduce the nutrient loads from aquaculture effluents.


Primary healthcare provider's lost opportunity to help abused women.
To determine how often primary care providers have the opportunity to assess and intervene for intimate partner violence (IPV) in a population of women who are known to be experiencing IPV. A convenience sample of 149 abused women presenting to the justice system for protection orders or to file assault charges against in intimate partner were interviewed about the date and reason for her last healthcare visit, whether she had been screened for IPV, and the presence of selected conditions, medication use, and hospitalizations. Although 86% (n = 128) of the women had sought healthcare services within the previous year, only 24% (n = 36) had been assessed for IPV. Abused women use healthcare services at higher rates and have more health conditions than non-abused women. Despite recommendations of professional organizations, health providers have low rates of screening for IPV. Universal screening for IPV by nurse practitioners could substantially interrupt ongoing abuse.


Can placental pathology explain second-trimester pregnancy loss and subsequent pregnancy outcomes?
This study sought to determine whether specific placental pathology may provide further insight into the mechanisms of second-trimester pregnancy loss, particularly in cases without inflammation. A blinded pathologist examined placentas from 90 patients with spontaneous second-trimester pregnancy loss and 17 controls who presented for induction of labor for fetal indications. Inflammation was staged and evidence of other vascular pathology recorded. Significant associations were determined by chi(2) analysis and Fisher's exact test. A secondary analysis examined losses without inflammation. Twelve patients with a subsequent pregnancy were also evaluated. Acute inflammation was more prevalent in cases than controls (P < .001). Sixty-seven percent of all cases and none of the controls showed a stage 2-3 inflammatory response. Histologic abruption was also more prevalent in cases than controls (P = .05). Second-trimester pregnancy loss is strongly associated with placental inflammation. Histologic abruption is likely another etiology. Future research should focus on subsequent pregnancy outcomes in these women based on initial placental pathology to help determine etiology and recurrence risk.


Buserelin-mediated osteoporosis: effects of restoring estrogen on bone resorption and whole body calcium content in the rat.
In the rat, prolonged administration of the luteinizing, hormone-releasing hormone agonist buserelin (25 micrograms/kg body wt/day s.c.) lowers blood estradiol, raises bone resorption, and induces osteopenia. The present study was undertaken to determine whether withdrawal of buserelin normalizes blood estradiol, slows bone resorption, and corrects buserelin-mediated osteopenia. Four groups of female rats with 45Ca-labeled bones were studied: group 1A received 0.2 ml saline s.c. daily for 4 weeks; group 2A received 0.2 ml buserelin s.c. daily for 4 weeks; group 1B received 0.2 ml saline s.c. daily for 8 weeks; group 2B received 0.2 ml buserelin s.c. daily for 4 weeks followed by 0.2 ml saline s.c. daily for 4 weeks. Bone resorption was monitored by measuring urinary 45Ca and hydroxyproline. The rats in groups 1A and 2A were killed after 4 weeks and those in groups 1B and 2B after 8 weeks. The mineral contents of the femoral bones and the whole skeletons were measured. Buserelin lowered blood estradiol, elevated urinary 45Ca and urinary hydroxyproline, and lowered femur and total body calcium and 45Ca in group 2A vs. 1A (P less than 0.05). By contrast all these measurements became similar in groups 2B and 1B. Thus, osteopenia generated by a 4-week period of buserelin-mediated hypo-estrogenism is reversible by withdrawing buserelin for 4 weeks. Consequently, buserelin administration and withdrawal may be used to study effects of inducing and reversing estrogen-deficiency bone loss in the rat.


Micro-CT analysis and mechanical properties of low dimensional CFR-PEEK specimens additively manufactured by material extrusion.
Material extrusion of thermoplastic polymers enables the realization of complex specific designs with high performance composites. The present study aims at evaluating the mechanical properties of carbon fiber-reinforced semi-crystalline thermoplastic polymer polyether ether ketone (CFR-PEEK) manufactured by material extrusion and correlating them with results obtained by micro-CT. Samples in the shape of small bars were provided by Kumovis (Munich, Germany). The determination of surface roughness and density was followed by three-point bending tests. To reveal the pore distribution as well as the fusion quality of CFR PEEK when applied with external forces, micro-CT scans were performed with an X-ray microscope before and after the mechanical test to localize the sites where the fracture is generated. The density of CFR-PEEK bars indicated that they had superior mechanical properties compared with our previous study on unfilled 3D printed PEEK (bending modulus: (5.4 ± 0.5) GPa vs. (1.05 ± 0.05) GPa to (1.48 ± 0.10) GPa; bending strength: (167 ± 11) MPa vs. (51 ± 15) to (193 ± 7) MPa). Micro-CT analyses revealed the local 3D-distribution of voids. Voids of 30 μm diameter are nearly spherical and make up the main part of the total porosity. The larger the voids, the more they deviate from a spherical shape. Significant lack-of-fusion voids are located between the deposited filaments. By growing and merging, they act as seeds for the forming fracture line in the region of the flexural specimens where the maximum local tensile stresses occurred under bending load. Our work provides a detailed analysis of printed PEEK with fiber additive and relates this with mechanical properties.


Posterior wall gastric leiomyoma: endoscopic tattooing facilitates laparoscopic resection.
To demonstrate the application of tattooing for the intraoperative localization of posterior wall gastric leiomyoma during laparoscopic resection. The preoperative injection of Indian ink in the tumor-bearing area of the posterior gastric wall eliminates the need to perform anterior wall gastrostomy or intraoperative upper endoscopic tumor localization. A patient with posterior wall gastric leiomyoma was marked with Indian ink during preoperative upper endoscopy. The dye was visualized intraoperatively facilitating wedge resection of the tumor-bearing area with the Endo GIA. The patient had an uneventful surgery and recovery. Complete excision of the tumor was accomplished. The preoperative endoscopic marking of gastric lesions, facilitates the intraoperative localization and resection of these lesions.


Pharmacokinetics of ganciclovir in renal transplant children.
Three cytomegalovirus (CMV)-seronegative children received renal transplants from CMV-seropositive donors and developed clinical symptoms of CMV infection between days 20 and 34 post transplantation. Ganciclovir (DHPG) was administered in a 1-h infusion, and the doses and dose intervals were adapted to the degree of renal insufficiency, according to the manufacturer's recommendations for adults. Individual pharmacokinetic parameters of DHPG were determined and were markedly altered. Plasma clearances were 0.4, 1.1 and 2.2 ml/min per kg and were related to individual creatinine clearances (20, 45 and 60 ml/min per 1.73 m2); the corresponding elimination half-lives were 23.7, 9.9 and 3.9 h. In two patients, the doses had to be further reduced in order to maintain plasma levels within the recommended values for peak and trough plasma concentrations. Therefore, monitoring of DHPG appears essential in adjusting dosage for optimal efficacy and minimal toxicity.


tRF-3013b inhibits gallbladder cancer proliferation by targeting TPRG1L.
tRNA-derived fragments (tRFs) are newly discovered noncoding RNAs and regulate tumor progression via diverse molecular mechanisms. However, the expression and biofunction of tRFs in gallbladder cancer (GBC) have not been reported yet. The expression of tRFs in GBC was detected by tRF and tiRNA sequencing in GBC tissues and adjacent tissues. The biological function of tRFs was investigated by cell proliferation assay, clonal formation assay, cell cycle assay, and xenotransplantation model in GBC cell lines. The molecular mechanism was discovered and verified by transcriptome sequencing, fluorescence in situ hybridization (FISH), target gene site prediction, and RNA binding protein immunoprecipitation (RIP). tRF-3013b was significantly downregulated in GBC compared with para-cancer tissues. Decreased expression of tRF-3013b in GBC patients was correlated with poor overall survival. Dicer regulated the production of tRF-3013b, and its expression was positively correlated with tRF-3013b in GBC tissues. Functional experiments demonstrated that tRF-3013b inhibited GBC cell proliferation and induced cell-cycle arrest. Mechanically, tRF-3013b exerted RNA silencing effect on TPRG1L by binding to AGO3, and then inhibited NF-κB. TPRG1L overexpression could rescue the effects of tRF-3013b on GBC cell proliferation. This study indicated that Dicer-induced tRF-3013b inhibited GBC proliferation by targeting TPRG1L and repressed NF-κB, pointing to tRF-3013b as a novel potential therapeutic target of GBC.


In vitro and in silico analysis of signal peptides from the human blood fluke, Schistosoma mansoni.
Proteins secreted by and anchored on the surfaces of parasites are in intimate contact with host tissues. The transcriptome of infective cercariae of the blood fluke, Schistosoma mansoni, was screened using signal sequence trap to isolate cDNAs encoding predicted proteins with an N-terminal signal peptide. Twenty cDNA fragments were identified, most of which contained predicted signal peptides or transmembrane regions, including a novel putative seven-transmembrane receptor and a membrane-associated mitogen-activated protein kinase. The developmental expression pattern within different life-cycle stages ranged from ubiquitous to a transcript that was highly upregulated in the cercaria. A bioinformatics-based comparison of 100 signal peptides from each of schistosomes, humans, a parasitic nematode and Escherichia coli showed that differences in the sequence composition of signal peptides, notably the residues flanking the predicted cleavage site, might account for the negative bias exhibited in the processing of schistosome signal peptides in mammalian cells.


Surgery for scleroderma of the hand.
The role of hand surgery in systemic sclerosis (scleroderma) has been documented infrequently. Out of a series of 813 consecutive patients with scleroderma, 31 have had one or more surgical procedures on their involved hands--a total of 52 operations. Raynaud's phenomenon and digital tip ulcerations have been controlled medically by vasodilators and meticulous local wound care. Most digital ulcerations progressing to frank gangrene have been allowed to autoamputate to maximize the length of the salvaged finger, but 23 digital amputations have been performed when conservative measures failed. Digital sympathectomy and microsurgical revascularization have produced relief of symptoms in several patients. Severe flexion contractures of the proximal interphalangeal (PIP) joints, with secondary hyperextension of the metacarpophalangeal (MP) joints, have been effectively treated by arthrodesis of the PIP joints in 44 to 55 degrees of flexion. This has allowed both improved hand function and primary healing of dorsal ulcers in 53 PIP joints in 12 patients.


Lymphedema as first clinical presentation of Cantu Syndrome: reversed phenotyping after identification of gain-of-function variant in ABCC9.
Cantu Syndrome (CS), [OMIM #239850] is characterized by hypertrichosis, osteochondrodysplasia, and cardiomegaly. CS is caused by gain-of-function (GOF) variants in the KCNJ8 or ABCC9 genes that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. Many subjects with CS also present with the complication of lymphedema. A previously uncharacterized, heterozygous ABCC9 variant, p.(Leu1055_Glu1058delinsPro), termed indel1055, was identified in an individual diagnosed with idiopathic lymphedema. The variant was introduced into the equivalent position of rat SUR2A, and inside-out patches were used to characterize the KATP channels formed by Kir6.2 and WT or mutant SUR2A subunits coexpressed in Cosm6 cells. The indel1055 variant causes gain-of-function of the channel, with an increase of the IC50 for ATP inhibition compared to WT. Retrospective consideration of this individual reveals clear features of Cantu Syndrome. An additional heterozygous ABCC9 variant, p.(Ile419Thr), was identified in a second individual diagnosed with lymphedema. In this case, there were no additional features consistent with CS, and the properties of p.(Ile416Thr) (the corresponding mutation in rat SUR2A)--containing channels were not different from WT. This proof-of-principle study shows that idiopathic lymphedema may actually be a first presentation of otherwise unrecognized Cantu Syndrome, but molecular phenotyping of identified variants is necessary to confirm relevance.


Changes in brachytherapy-based APBI patient selection immediately before and after publication of the ASTRO consensus statement.
In July 2009, American Society of Radiation Oncology (ASTRO) released a consensus statement (CS) to guide patient selection for accelerated partial breast irradiation (APBI). The goal of this study was to examine how practice patterns changed following the guideline's release. The Surveillance, Epidemiology, and End Results database was queried from 2008 to 2010 for females aged ≥20 years receiving breast conservation via brachytherapy. Among the APBI cohort, characteristics and CS grouping ("suitable," "cautionary," or "unsuitable") of patients receiving APBI in the 18 months before (January 2008 to June 2009) and after (July 2009 to December 2010) guideline publication were analyzed. A total of 87,528 patients undergoing breast conservation therapy were identified. Of this, 4,253 patients (4.9%) received brachytherapy-based APBI. Limiting the analysis to patients not missing data that would affect their CS classification rendered 3,828 patients. The proportion of breast conservation patients receiving brachytherapy-based APBI before and after CS release remained the same (4.9% vs. 4.8%, p = 0.36). Among patients receiving brachytherapy-based APBI, the unsuitable category decreased (15.8 vs. 11.1%, p < 0.01), whereas the suitable category increased (37.7% vs. 42.1%, p = 0.03), and the cautionary category was stable (46.5% vs. 46.7% p = 0.90) after guideline publication. Joinpoint regression analysis failed to reveal that the changes in practice patterns corresponded with the CS publication date. The period before and after publication of the ASTRO CS was associated with a decrease in "unsuitable" patients and an increase in "suitable" patients being treated with brachytherapy-based APBI. This trend began before guideline release and thus cannot be definitively attributed to the ASTRO CS.


Angiotensin-converting enzyme: an indicator of bleomycin-induced pulmonary toxicity in humans?
In order to evaluate bleomycin-associated lung damage in humans, lung function parameters and serum levels of the endothelial-bound angiotensin-converting enzyme (ACE) were determined by serial measurements in 11 patients who were treated for testicular cancer. None developed clinical or radiological evidence of pulmonary damage. While the static and dynamic lung function parameters were unchanged, carbon monoxide diffusion capacity (DLCO) decreased significantly (P less than 0.01) during a total of 126 days of pulsed regimen, indicating damage to the alveolar-endothelial membrane. S-ACE was unchanged within each treatment course but increased significantly (P less than 0.05) from the initial value to the last treatment course. Two months after cessation of treatment S-ACE returned to pretreatment values. Although the changes were modest they might mirror treatment-associated endothelial damage.


[Differential diagnosis between toxoplasmosis and leptospirosis of 26 Mexican cases with posterior uveitis].
26 patients with active posterior uveitis were studied by methodologies for the confirmation of leptospirosis. ELISA-IgG was positive in 10 patients and MAT in 21. Leptospiras were observed in blood and urine. The results suggest that posterior uveitis may be caused by pathogenic leptospiras.


Clinicopathological study of gastric carcinoma in high- and low-mortality countries: Comparison between Japan and the United States.
BACKGROUND: Gastric carcinoma is a tumor that shows marked differences in geographic distributions. The incidence of the gastric carcinoma has been falling dramatically in Western countries. In sharp contrast, the incidence in Japan is still quite high.METHODS: A comparative clinicopathological study was performed, examining gastric carcinomas in 978 Japanese patients (Tokyo) and 157 United States patients (San Diego), that had been surgically resected over the 11-year period 1980-1991.RESULTS: The median age of US the patients (64.1 years) was higher than that of the Japanese patients (59.0 years). There was no difference in the sex ratios. Forty-five of the Japanese patients had early gastric cancer, while this occurred in 10% of the US patients. In terms of tumor location, 47% were in the upper portion of the stomach in the US patients, while, in contrast, this proportion in Japanese patients was 23%. In association with the marked difference in tumor location, 36.5% of the US patients underwent operations with the thoraco-abdominal approach, while this approach was used in 7.5% of the Japanese patients. The distribution of histological types was similar in the two countries' samples. There was also no significant difference in the distribution of the histological types in the same age groups in the two countries' samples. The rate of the well differentiated type increased with age while the rate of poorly differentiated type decreased. In US patients, 35.8% had marked neural invasion, while this occurred in 8.5% of Japanese patients.CONCLUSION: This study revealed marked differences in the features of gastric cancer between the US and Japan in terms of tumor location and surgical procedures.


Generation of osteoblasts and chondrocytes from embryonic stem cells.
The efficient generation of mesenchymal cells such as adipocytes, osteoblasts, and chondrocytes from embryonic stem cells is achieved by following sequential steps: embryoid body formation, retinoic acid (RA) treatment, and exposure to specific reagents for differentiation. RA treatment of embryoid bodies is critical for subsequent mesengenesis. Adipogenesis, osteogenesis, and chondrogenesis occur by culturing outgrowths for 2-3 wk with insulin/triiodothyronine, bone morphogenetic protein/dexamethasone-beta/glycerophosphate/ascorbic acid, and transforming growth factor-beta3/parathyroid hormone/1% fetal bovine serum, respectively. Emergence of these mesenchymal cells using a common initial procedure suggests that embryoid body formation and subsequent RA treatment results in the generation of a common progenitor for osteoblasts and chondrocytes.


Optic nerve infarction.
In three cases infarction in the inferotemporal prelaminar portion of the optic disk resulted in shallow cupping and arcuate visual field defects. Such changes occurred acutely, were not progressive, and required no treatment.


Sequence and analysis of a plasmid-encoded mercury resistance operon from Mycobacterium marinum identifies MerH, a new mercuric ion transporter.
In this study, we report the DNA sequence and biological analysis of a mycobacterial mercury resistance operon encoding a novel Hg(2+) transporter. MerH was found to transport mercuric ions in Escherichia coli via a pair of essential cysteine residues but only when coexpressed with the mercuric reductase.


Timing of cholecystectomy after percutaneous transhepatic gallbladder drainage for acute cholecystitis: a nationwide inpatient database study.
Optimal interval from percutaneous transhepatic gallbladder drainage (PTGBD) to cholecystectomy for acute cholecystitis remains unclear. We analyzed patients undergoing cholecystectomy following PTGBD for acute cholecystitis, using a national database. We performed restricted cubic spline (RCS) analyses to investigate the association of interval from PTGBD to cholecystectomy with outcomes (mortality/morbidity, blood transfusion, duration of anesthesia, and postoperative hospital stay). Among 9,256 patients, RCS analyses showed reverse J-shaped associations of the interval with mortality/morbidity and blood transfusion, and J-shaped associations of the interval with both duration of anesthesia and postoperative hospital stay. Each interval was compared with the bottom of the spline curve. Patients with intervals ≤6 days or ≥27 days had higher mortality/morbidity than those with a 10-day interval. Patients with intervals ≤8 days had higher proportions of blood transfusion than those with a 10-day interval. Patients with intervals ≥17 days had longer duration of anesthesia than those with a 5-day interval. Postoperative hospital stay was longer among those with intervals ≤10 days or ≥19 days than those with a 15-day interval. Based on the mortality/morbidity data, the optimum time to perform cholecystectomy is between 7 and 26 days after PTGBD.


Dose-rate effect on induction and repair rate of radiation-induced DNA double-strand breaks in a normal and an ataxia telangiectasia human fibroblast cell line.
Using pulsed-field gel electrophoresis (PGFE), we measured DNA double-strand breaks (DSB) in a normal human fibroblast and in a cell line derived from a patient suffering from ataxia telangiectasia (AT), a syndrome associated with a hypersensitivity to ionizing radiation. Initial DSB levels assessed after irradiation at 4 degrees C are similar in both cell lines. The DSB repair rate was measured after 30 Gy delivered at 4 degrees C and followed by an incubation at 37 degrees C for 24 h. In AT cells, the DSB repair rate is faster between 0.5 and 9 h and slower between 9 and 24 h. In addition, the DSB levels were measured after irradiation at 37 degrees C at 0.01 Gy min-1 (5-40 Gy). The shape of the curves was curvilinear and a plateau was reached at 10 Gy in the control. After an irradiation at 37 degrees C, DSB levels were significantly higher in AT cells than in the normal fibroblast cells. A model was developed assuming that DSB induction is independent of temperature and that DSB repair rate is independent of dose-rate and dose. This model was used to predict the 37 degrees C DSB data on the basis of the 4 degrees C data. Experimental data and predictions are in agreement, thus validating the above assumptions. It is suggested that, even for extreme situations such as 30 Gy delivered at 4 degrees C or 30 Gy delivered at 37 degrees C at 0.01 Gy min-1, DSB induction and repair are identical. Our results could be interpreted assuming an heterogeneity of DSB. A small fraction of DSB is slowly repaired. This fraction is lower in control than in AT cells. By protracting repair time, the 37 degrees C low-dose rate experiments permit a cleaner distinction between AT and control cells.


NMR spectroscopy with force-gradient detection on a GaAs epitaxial layer.
We demonstrate nuclear magnetic resonance spectroscopy on 35 μm(3) of (69)Ga in a GaAs epitaxial layer in vacuum at 5K, and 5T yielding a linewidth on the order of 10 kHz. This was achieved by a force-gradient magnetic resonance detection scheme, using the interaction between the force-gradient of a Ni sphere-tipped single crystal Si cantilever and the nuclear spins to register changes in the spin state as a change in the driven cantilever's natural resonant frequency. The dichotomy between the background magnetic field (B0) homogeneity requirements imposed by NMR spectroscopy and the magnetic particle's large magnetic field gradient is resolved via sample shuttling during the NMR pulse encoding. A GaAs sample is polarized in a B0 of 5T for 3 T1. The sample is shuttled away from the magnetic particle to a region of negligible magnetic field inhomogeneity. A (π/2)x pulse rotates the polarization to the xy-plane, the magnetization is allowed to precess for 2-200 μs before a (π/2)x or (π/2)y pulse stores the remaining spin along the z-axis that represents a single point of the free induction decay (FID). The sample is shuttled back to the established tip-sample distance. An adiabatic rapid passage (ARP) sweep inverts the spins in a volume of interest, causing the cantilever's natural resonance frequency to shift an amount proportional to the spin polarization in the volume. By varying the delay between the first and second (π/2) pulses the entire FID is measured.


gamma Aminobutyric acid uptake, release, and effect on 36Cl--influx in bovine pineal gland.
Two apparent affinities for Na+-dependent, 3H-GABA uptake were found in bovine pineal fragments in vitro i.e., a high affinity uptake (Km = 37 +/- 5 microM) and a low affinity uptake (Km = 435 +/- 50 microM). GABA or the neuronal and glial GABA uptake inhibitor nipecotic acid was significantly more effective than the inhibitor of the GABA glial uptake beta-alanine to decrease pineal 3H-GABA uptake. High K+ concentration release 3H-GABA in superfused bovine pineals, no differences in 3H-GABA release among fragments taken from medial, proximal or distal pineal regions being apparent. Superfusion of pineal fragments in the absence of Ca2+ but in the presence of EGTA, Mg2+ or verapamil decreased significantly 3H-GABA release induced by K+. In every case a Ca2+-independent pineal GABA release was found. Preincubation with GABA or nipecotic acid, but not with beta-alanine, blunted subsequent 3H-GABA release. GABA increased 36Cl--influx in pineal homogenates, an effect blocked by picrotoxin. Incubation of pineal homogenates in the presence of aminooxyacetic acid decreased Vmax of glutamic acid decarboxylase, without modifying its Km. These results are compatible with a transmitter or modulator role of GABA in bovine pineal gland.


An AIE luminogen self-assembled nanoprobe for efficient monitoring of the concentration and structural transition of human serum albumin.
Monitoring the content and structural transition of human serum albumin (HSA) is valuable for diagnosing hypoalbuminemia and albuminuria and elucidating its transport function, respectively. Herein, we developed a multifunctional and efficient nanoprobe based on the self-assembly of an amphiphilic aggregation-induced emission luminogen, TPNN, for HSA detection and structure monitoring. TPNN molecules formed loose self-assembly in aqueous media and emitted faint fluorescence due to vigorous intramolecular motion. In the presence of HSA, a remarkable fluorescence enhancement accompanied by dissociation of TPNN assembly was observed due to the site-specific binding of TPNN to the middle long-narrow pocket of HSA. This binding blocked the intramolecular motion while producing a sensitive, selective, fast and stable fluorescence turn-on response to HSA, making TPNN assembly suitable for the HSA assay. TPNN assemblies also showed superior selectivity to HSA than bovine serum albumin (BSA) due to the distinct binding modes, and enabled us to distinguish the two homologous proteins. Furthermore, the generated TPNN-HSA complex underwent stepwise fluorescence quenching in the presence of protein denaturants and proteases, which revealed the process and kinetics of HSA unfolding and cleavage. TPNN assembly provides a powerful tool for accurate quantification of HSA in serum and urine and real-time monitoring of HSA structural transition.


Synergistic benefits of Nicotine and Thymol in alleviating experimental rheumatoid arthritis.
Given to the anti-inflammatory effect of Nicotine and Thymol, this study was done to evaluate the effects of co-administration of Nicotine and Thymol on the clinical aspects, and immunity responses in Freund's complete adjuvant (FCA)-induced RA in Wistar rat. The study population contained a total of 50 male Wistar rats with a weight range 150 ± 7 g, which RA was induced through FCA at them. These animals were randomly allocated into five groups (n = 10): RA rats treated with PBS (100 mg/kg orally), RA rats treated with Thymol (100 mg/kg orally), RA rats treated with Nicotine (2.5mg/kg-orally), and RA rats treated with combined Nicotine and Thymol (half doses with each one-orally). All treatments were initiated at day seven p.i. when all rats showed a clinical score of ≥1. Clinical symptoms of the disease were recorded every other day until the day 23 p.i. Obtained data revealed the combination therapy reduced the severity of the disease and improved weight-gaining more profound than each medication alone. Furthermore, combination therapy caused a reduction in some hematological and biochemical RA parameters, such as Rheumatoid factor, C-Reactive Protein, Nitric oxide, Myeloperoxidase, IL-1, and IL-17 more impressive than each treatment alone. Interestingly, the combination therapy with half doses of Nicotine and Thymol did not have any synergistic advantage in anti-proliferation effect, and therefore immunosuppression side effect compared with using each of agents alone. Collectively, it is possible that combination therapy can be applied as a beneficial strategy to control RA.


Efficacy of pioglitazone on type 2 diabetic patients with hemodialysis.
Unfortunately, growing number of type 2 diabetic hemodialysis (HD) patients with insulin resistance are now being diagnosed in Japan. Worse still, PPARgammaagonists such as pioglitazone are now contraindicated in diabetic HD patients in Japan. In this study we evaluated the efficacy of pioglitazone in diabetics on HD. Following a 12-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean hemoglobin A1c (HbA1c) levels greater than 6.5% at baseline and who were not receiving insulin injection therapy. The patients were administered pioglitazone 15mg daily with their morning meal for the first 4 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose and HbA1c), and insulin resistance (plasma immunoreactive insulin (IRI) and homeostasis model assessment for insulin resistance (HOMA-R)). Safety and tolerance were determined by monitoring clinical and laboratory parameters. Pioglitazone was effective in reducing plasma glucose and HbA1c from the baseline levels from week 4 after the commencement of treatment. The agent was also effective in reducing triglycerides. Plasma IRI and HOMA-R, two parameters of insulin resistance, decreased significantly at 4 weeks, and the decreases continued for 24 weeks. Systolic and diastolic blood pressures were statistically lower at 8 weeks. No serious adverse effects such as hypoglycemia, liver impairment, or rhabdomyolysis were observed in any of the patients. Pioglitazone was effective in the treatment of diabetics on dialysis therapy. Pioglitazone might have the potential to reduce the number of type 2 diabetics on HD who ultimately require insulin injection therapy.


Sequencing the intersections of printed strokes with writing instrument strokes using DocuCentre expert (PIA 6000-EDF).
Introduction of the digital techniques in document examination has encouraged the Forensic Document Examiners to work with better accuracy in non-destructive ways. In this study, the examination of sequence of intersecting strokes of printers (inkjet printer, laser printer, dot-matrix printer) and typewriters with writing instruments (gel ink pen, ballpoint pen and fountain pen) of different colors was carried out by using Docucenter Expert via PIA-6000 software utilizing extended depth of focus. The continuity of the stroke is the only characteristic which has been observed at the point of intersection.


Global Patterns and Drivers of Bee Distribution.
Insects are the focus of many recent studies suggesting population declines, but even invaluable pollination service providers such as bees lack a modern distributional synthesis. Here, we combine a uniquely comprehensive checklist of bee species distributions and >5,800,000 public bee occurrence records to describe global patterns of bee biodiversity. Publicly accessible records are sparse, especially from developing countries, and are frequently inaccurate throughout much of the world, consequently suggesting different biodiversity patterns from checklist data. Global analyses reveal hotspots of species richness, together generating a rare bimodal latitudinal richness gradient, and further analyses suggest that xeric areas, solar radiation, and non-forest plant productivity are among the most important global drivers of bee biodiversity. Together, our results provide a new baseline and best practices for studies on bees and other understudied invertebrates.


A cephalometric study of incisor angulations in a Nigerian population.
This paper has the objective of establishing a standard norm for incisor angulations in a Nigerian population. The upper incisor angle to the Frankfort plane has a biological norm of between 119 degrees and 127 degrees, while the lower incisor angle (to the mandibular plane) is between 96 degrees and 104 degrees. The value for the interincisal angle is between 108 degrees and 116 degrees.


Effect of Continuing Nursing Education on the Quality of Nursing Management of Cancer Pain in China.
Limited knowledge and poor attitudes toward pain are major barriers to nursing management of cancer pain. This study investigated the effect of continuing nursing education (CNE) on the management of cancer pain. Annual CNE was provided from 2016 to 2019, and evaluation of nursing management of cancer pain was conducted every 2 years. The effect of CNE was determined based on the evaluation results. After annual CNE, the participating hospitals showed significant improvement in nursing management of cancer pain. Annual CNE significantly increased subscores in all domains except the domain of initial pain assessment. In terms of hospital levels, nursing management of cancer pain was significantly improved only for tertiary A hospitals. Annual CNE significantly improved nursing management of cancer pain. [J Contin Educ Nurs. 2021;52(11):535-540.].


Magnetic resonance elastography of the liver: everything you need to know to get started.
Magnetic resonance elastography (MRE) of the liver has emerged as the non-invasive standard for the evaluation of liver fibrosis in chronic liver diseases (CLDs). The utility of MRE in the evaluation of different CLD in both adults and children has been demonstrated in several studies, and MRE has been recommended by several clinical societies. Consequently, the clinical indications for evaluation of CLD with MRE have increased, and MRE is currently used as an add-on test during routine liver MRI studies or as a standalone test. To meet the increasing clinical demand, MRE is being installed in many academic and private practice imaging centers. There is a need for a comprehensive practical guide to help these practices to deliver high-quality liver MRE studies as well as troubleshoot the common issues with MRE to ensure smooth running of the service. This comprehensive clinical practice review summarizes the indications and provides an overview on why to use MRE, technical requirements, system set-up, patient preparation, acquiring the data, and interpretation.


Simultaneous determination of capsid proteins in nine-valent human papilloma virus vaccines by liquid chromatography tandem mass spectrometry.
A liquid chromatography-tandem mass spectrometry method was developed to determine nine types of capsid proteins simultaneously in nine-valent human papillomavirus vaccines. Signature peptides were optimized in terms of specificity, repeatability, determination accuracy and sensitivity. As a result, three signature peptides per capsid protein were obtained. The linear calibration curves were achieved in the range of 11.6-373.6 nmol/L (R2 > 0.998). Compared to our previous liquid chromatography-tandem mass spectrometry method, the current method was more sensitive (3.18-fold) and it can be used for quality evaluation of nine-valent human papillomavirus vaccines, unlike the previous method, which could only be used for bivalent human papillomavirus vaccines. Then, they were utilized to determine nine types of capsid proteins in nine-valent human papillomavirus vaccines from four different manufactures. Intraday and interday precision values for the determination of capsid proteins in nine-valent human papillomavirus vaccines were less than 6.8 and 9.1%, respectively. Recovery rates of all capsid proteins investigated were in the range of 80-120%. In addition, the current assay was used for determination of free capsid protein in nine-valent human papilloma virus vaccines, and the results were used to evaluate the adsorption rate of the adjuvant.


Tobacco Use at the Intersection of Sex and Sexual Identity in the U.S., 2007-2020: A Meta-Analysis.
A 2009 systematic review synthesized data between 1987 and 2007 and revealed a higher prevalence of smoking among sexual minority populations than among heterosexuals. Subsequently, growing attention to tobacco use among sexual minority populations has spurred more literature on this issue because higher tobacco use prevalence has been found in certain sexual minority subgroups relative to others. However, a population-level synthesis of tobacco use prevalence by sexual minority subgroup has not been done for the past decade. Investigators conducted a meta-analysis by searching MEDLINE, Web of Science, EMBASE, and PsycINFO for U.S.-based studies published between 2007 and 2020 that specifically reported tobacco use prevalence among adults and separated the sexes and gays/lesbians versus bisexuals. Using random-effects models, meta-prevalence estimates, 95% CIs, and heterogeneity (I2) were calculated for each sexual minority subgroup. A total of 30 studies were included in the meta-analysis. The highest current cigarette use prevalence estimates were found among bisexual women (37.7%), followed by lesbians (31.7%), gay men (30.5%), and bisexual men (30.1%). Heterosexual men (21.0%) and women (16.6%) had the lowest prevalence. Tobacco use prevalence among sexual minorities during 2007-2020 remained at similarly high levels as those during 1987-2007, and tobacco use disparity between sexual minorities and heterosexuals persisted in the past decade. Significant heterogeneity existed in tobacco use across sexual minority subgroups, with bisexual women having the highest prevalence. These findings are critical for increasing decision maker's awareness and action to address sexual minorities' persistent high prevalence of tobacco use, particularly among bisexual women.


A comparison of conditional and unconditional randomization tests for highly stratified designs.
An unconditional randomization procedure is proposed for use in highly stratified randomized experiments where the sample size assigned to each treatment cannot be fixed in advance. This procedure is contrasted to the usual conditional randomization procedure in which sample sizes assigned within randomization units are treated as fixed and randomization units without both treatments assigned are deleted. The unconditional procedure is shown to have superior power for the populations studied.


Breast tumor detection using piezoelectric fingers: first clinical report.
Mammography is key to detection of breast cancer in high-risk populations. Currently, aside from palpation and risk-assessment questionnaires, there is no prescreening test that can improve the accuracy, safety, and cost effectiveness of screening low-risk populations. The piezoelectric finger (PEF) is a radiation-free, portable, and low-cost breast tumor detector we developed to be used as a prescreening tool. Patients presenting with breast abnormalities detected by palpation or imaging were enrolled in this IRB-approved study. The PEF testing was performed with the patient in supine position before undergoing biopsy or surgical excision. The locations of the lesions detected by PEF were compared with those confirmed on imaging or pathology. A total of 40 patients were enrolled and 46 lesions were confirmed by imaging or pathology. The PEF reported 55 lesions, with 9 false positives and 2 true positives not originally found on imaging or palpation. The overall sensitivity of the PEF test was 87% (40 of 46). In women 40 years old or younger, overall sensitivity was or 100% (19 of 19). In women who had a lesion visible on mammography, PEF had a sensitivity of 83% (24 of 29). Of these, in women aged 40 years or younger, PEF identified all 7 mammographically visible lesions, including 2 malignant lesions. When compared with ultrasound, PEF correctly identified 87% (34 of 39) in this group. Of these, in women aged 40 years or younger, PEF identified 100% (19 of 19) of all ultrasound-visible lesions. The PEF identified abnormalities in all 39 patients who presented with breast abnormalities and did not demonstrate any false negatives that would prevent the patients from additional evaluation, which makes it a good prescreening tool. In addition, PEF demonstrated 100% sensitivity in women aged 40 years or younger, a traditionally low-risk population.


Retinoic acid-induced downmodulation of telomerase activity in human cancer cells.
Most human cancers express telomerase but its activity is highly variable and regulated by complex mechanisms. Recently, several studies have suggested that retinoic acid (RA) downregulates telomerase activity and that this effect could be a major determinant of its therapeutic activity. To elucidate possible mechanisms of RA-mediated downmodulation of telomerase activity, we measured the kinetics of concentration changes of several transcription regulators by using standard biochemical techniques at low (10 muM) and high (100 muM) RA concentrations. We further evaluated the global impact of the RA treatment on gene expression profiles using microarray. It was found that the kinetics of c-Myc correlates most closely with the telomerase activity suggesting in agreement with previous studies that this protein is a major intermediate of the RA-induced downregulation of telomerase activity. Other telomerase regulators as Sp1 and Mad1 did not exhibit significant correlation. The dominant role of c-Myc in RA-induced telomerase downmodulation is confirmed by microarray data. Additionally, a number of proteins were found as possible correlates of telomerase activity by microarray analysis. These data suggest a complex interplay between c-Myc and other proteins that may be important determinants of the RA effects on telomerase activity in human cancer cells. The complex mechanism through which telomerase activity is controlled during differentiation and cancer transformation is also reflected.


The Predictive Value of the G8 Questionnaire in Older Patients with Lung Cancer or Mesothelioma before Systemic Treatment.
The standard evaluation of older lung cancer or mesothelioma patients for systemic anti-cancer treatment, based on performance status, is inaccurate. We used the G8 questionnaire to assess a patient's fitness for chemotherapy and explored the correlations between G8 scores, treatment decisions and clinical outcomes. In total, 201 older patients (≥70 years) with advanced lung cancer or mesothelioma were prospectively assessed by standard clinical methods and a G8 questionnaire. Treatment decisions before and after reviewing the G8 score were documented. Patients were divided into low (<11), intermediate (11-14) and high (>14) G8 score groups. Patients' characteristics, treatment plans and clinical outcomes among each G8 score group were compared. Similar analyses were compared between good (<2) and poor (≥2) performance status. 10.1% of patients' treatment plans changed after oncologists reviewed G8 scores. The G8 score correlated inversely with performance status. More patients with low G8 scores (22.5%) were offered the best supportive care compared with 4.5% in intermediate and 1.9% in high G8 score groups. More patients (30.1%) with low G8 scores had treatment changed from chemotherapy to best supportive care on the planned day of their treatment, compared with intermediate (7.5%) and high (6.1%) G8 score groups. High G8 score patients received higher chemotherapy intensity and survived longer than patients with intermediate or low G8 scores. The G8 score with two cut-off values can predict functional status, chemotherapy tolerability and prognosis in older patients with lung cancer or mesothelioma, thus supporting oncologists on treatment decisions for this population.


Letting go: Dishevelled phase separation recruits Axin to stabilize β-catenin.
Dishevelled exerts a molecular force that guides cell fate, but how it does so remains enigmatic. In this issue, Kang et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202205069) show Dvl2 undergoes liquid-liquid phase separation to stabilize β-catenin by pulling Axin into its biomolecular condensate at the plasma membrane.


[Comparative characteristics of chromatin endonuclease fragments].
Soluble fragments of chromatin obtained by Ca, Mg-dependent endonuclease digest of rat liver nuclei, have been separated by gel chromatography on Sepharose 4B into three zones, containing oligomers, tetramers--dimers and monomers, respectively. The content of nonhistone proteins and particularly lysine-rich histones is decreased with a transition from theoligomers to monomers. The average protein/DNA ratio of the monomers is equal to 1.36 and that of histone/DNA ratio--to 0.82. The dependence of the degree of chromatin digest by endonuclease on its protein content and conditions of isolation and incubation of nuclei is discussed. The chromatin monomer formed appears to be made up of a nucleosome and short portions of spacer DNA bound to some part of histone HI and nonhistone proteins.


A nomogram to predict the risk of postoperative intracranial rebleeding in patients with spontaneous intracranial hematoma.
The 30-day mortality rate of spontaneous cerebral hemorrhage (ICH) is approximately 30-50%. Surgery may improve the prognosis of patients with severe ICH. However, ICH survivors after surgery still face the risks of postoperative intracranial rebleeding (PIB), and clinical tools that accurately predict the risk of PIB occurrence are not available. Therefore, a retrospective study was performed. The population was divided into two groups according to the occurrence of PIB. Univariate and multivariate logistic regression analyses were performed to screen risk factors for PIB. Next, an early PIB risk nomogram prediction model was constructed. In addition, the impact of PIB on the prognosis of ICH was evaluated. In total, 150 ICH patients were continuously enrolled in this study; 21 patients suffered from PIB, and the overall incidence of PIB was 14.0% (21/150). Coronary heart disease history, a lower GCS score, and subarachnoid hemorrhage absence were screened as risk factors for early PIB. The early PIB risk nomogram showed good calibration and discrimination with a concordance index of 0.807 (95% confidence interval (CI), 0.715-0.899), which was confirmed to be 0.788 through bootstrapping validation. In addition, a significant difference in discharged GOS scores (P = 0.043) was observed between the PIB group and the n-PIB group. These results showed that a history of coronary heart disease, a lower GCS score, and absence of subarachnoid hemorrhage were risk factors for early PIB. In addition, the early PIB risk nomogram prediction model exhibits good discrimination and calibration. The occurrence of PIB could reduce the prognosis of ICH patients.


Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants.
Caenorhabditis elegans homologues of the retinoblastoma (Rb) tumour suppressor complex specify cell lineage during development. Here we show that mutations in Rb pathway components enhance RNA interference (RNAi) and cause somatic cells to express genes and elaborate perinuclear structures normally limited to germline-specific P granules. Furthermore, particular gene inactivations that disrupt RNAi reverse the cell lineage transformations of Rb pathway mutants. These findings suggest that mutations in Rb pathway components cause cells to revert to patterns of gene expression normally restricted to germ cells. Rb may act by a similar mechanism to transform mammalian cells.


Problems in Audiovisual Filtering for Children with Special Educational Needs.
There is pervasive evidence that problems in sensory processing occur across a range of developmental disorders, but their aetiology and clinical significance remain unclear. The present study investigated the relation between sensory processing and literacy skills in children with and without a background of special educational needs (SEN). Twenty-six children aged between 7 and 12 years old, from both regular classes and SEN programmes, participated. Following baseline tests of literacy, fine motor skills and naming speed, two sets of instruments were administered: the carer-assessed Child Sensory Profile-2 and a novel Audiovisual Animal Stroop (AVAS) test. The SEN group showed significantly higher ratings on three Child Sensory Profile-2 quadrants, together with body position ratings. The SEN participants also showed a specific deficit when required to ignore an accompanying incongruent auditory stimulus on the AVAS. Interestingly, AVAS performance correlated significantly with literacy scores and with the sensory profile scores. It is proposed that the children with SEN showed a specific deficit in "filtering out" irrelevant auditory input. The results highlight the importance of including analysis of sensory processes within theoretical and applied approaches to developmental differences and suggest promising new approaches to the understanding, assessment, and support of children with SEN.


Use of a whole-cell biosensor and flow cytometry to detect AHL production by an indigenous soil community during decomposition of litter.
Quorum sensing, mediated by acylated homoserine lactones (AHLs), is well described for pure culture bacteria, but few studies report detection of AHL compounds in natural bacterial habitats. In this study, we detect AHL production during a degradation process in soil by use of whole-cell biosensor technology and flow cytometry analysis. An indigenous soil bacterium, belonging to the family of Enterobacteriaceae, was isolated and transformed with a low-copy plasmid harboring a gene encoding an unstable variant of the green fluorescent protein (gfpASV) fused to the AHL-regulated P(luxI) promoter originating from Vibrio fischeri. This resulted in a whole-cell biosensor, responding to the presence of AHL compounds. The biosensor was introduced to compost soil microcosms amended with nettle leaves. After 3 days of incubation, cells were extracted and analyzed by flow cytometry. All microcosms contained induced biosensors. From these microcosms, AHL producers were isolated and further identified as species previously shown to produce AHLs. The results demonstrate that AHL compounds are produced during degradation of litter in soil, indicating the presence of AHL-mediated quorum sensing in this environment.