Acupuncture for Opioid Dependence Patients Receiving Methadone Maintenance Treatment: A Network Meta-Analysis.
Objectives: Opioid dependence has been a threat to public health for hundreds of years. With the increasing number of studies on acupuncture-related therapies for opioid dependence patients receiving methadone maintenance treatment (MMT), its effect of acupuncture therapy in treating MMT patients remains controversial. Therefore, we conducted a multiple-treatments meta-analysis, and incorporated both direct and indirect comparisons, in order to discover the most effective treatment for opioid dependence patients receiving MMT. Methods: Five English databases and three Chinese databases were searched from its inception to August 20, 2020, in order to compare the effects of acupuncture-related therapies and MMT, which was summarized as Western medicine (WM) in the following texts. The quality of studies was assessed according to Cochrane's risk of bias tool 5.1.0, and a pair-wise meta-analysis, cumulative meta-analysis, and the network meta-analysis was performed using the R software (Version 3.6.1) and STATA (Version 14.0). The primary outcome was the effective rate, which was calculated by the ratio of detoxifying patients to the total. The secondary outcome was the Modified Himmelsbach Opiate Withdrawal Scale (MHOWS). Results: A total of 20 trials were included, which consisted of comparisons among WM, traditional Chinese medicine (TCM), and the four types of acupuncture, namely, manual acupuncture (MA), electro-acupuncture (EA), auricular acupuncture (AA), and transcutaneous electrical acupoint stimulation (TEAS). Though none of the trials were at low risk of bias. In the pair-wise meta-analysis, no statistically significant differences were observed in terms of the effective rate. Furthermore, MA was more efficacious than WM, EA, and TEAS in MHOWS, with mean differences (MDs) of (-8.59, 95% CI: -15.96 to -1.23, P < 0.01), (-6.15, 95% CI: -9.45 to -2.85, P < 0.05), and (-10.44, 95% CI: -16.11 to -4.77, P < 0.05), respectively. In the network meta-analysis, MA was more effective than WM (RR: 1.40, 95% CI: 1.05 to 1.99) on the effective rate, and (MD: -5.74, 95% CI: -11.60 to -0.10) on MHOWS. TEAS was more effective than WM (MD: -15.34, 95% CI: -27.34 to -3.46) on MHOWS. Synthetically, MA had the highest probability to rank first in treating opioid dependence. Conclusions: The existing evidence shows that acupuncture related-therapies may effectively be used for treating patients receiving MMT, and that manual acupuncture may be the best choice for opioid dependence among all kinds of acupuncture-related therapies. Nevertheless, reducing the relapse and promoting the recovery of opioid dependence need more efforts from not only the medical industry but also government support, security system, and educational popularization. To strengthen the assurance of acupuncture-related therapies in the treatment of opioid dependence, we expected that clinical trials with high quality would be conducted, to provide more confident evidence.


Simultaneous determination of fluoxetine and norfluoxetine in dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.
Therapeutic drug monitoring (TDM) of the widely prescribed antidepressant fluoxetine (FLU) is recommended in certain situations, such as occurrence of toxicity, inadequate response or suspect of poor adherence. Dried blood spot (DBS) sampling is an increasingly studied alternative for TDM, particularly for outpatients, due to its ease of collection and inherent stability. The aim of this study was to develop and validate an LC-MS/MS assay for the simultaneous quantification of FLU and norfluoxetine (NFLU) in DBS. The assay is based on a liquid extraction of single DBS with 8mm of diameter, using FLU-D6 as the internal standard, followed by reversed phase separation in an Accucore® C18 column (100×2.1mm, 2.6μm). Mobile phase was composed of water and acetonitrile (gradient from 80:20 to 50:50, v/v), both containing formic acid 0.1%. The assay was validated and applied to 30 patients under FLU pharmacotherapy. The assay was linear in the range 10-750ngmL-1. Precision assays presented CV% of 3.13-9.61 and 3.54-7.99 for FLU and NFLU, respectively, and accuracy in the range of 97.98-110.44% and 100.25-105.8%. FLU and NFLU were stable at 25 and 45°C for 7days. The assay was evaluated in 30 patients under FLU treatment. Concentrations of both compounds were higher in DBS than in plasma, and the use of the multiplying factors 0.71 and 0.68 for FLU and NFLU, respectively, allowed acceptable estimation of plasma concentrations, with median prediction bias of -0.55 to 0.55% and mean differences of 0.4 to 2.2ngmL-1. The presented data support the clinical use of DBS for therapeutic drug monitoring of FLU.


Japanese quail (Coturnix japonica) as a laboratory animal model.
For the past 50 years, the Japanese quail (Coturnix japonica) has been a popular animal model in numerous fields of research. The quail's 16-d developmental period and its easily accessible embryo make C. japonica a convenient model for studies of developmental biology. Because its lifespan is relatively short and its physiology is comparable to that of humans, the adult quail is useful for studies of aging and disease. The authors describe the Japanese quail as an animal model and, drawing on their experience raising a quail colony at the California Institute of Technology, present detailed guidelines for the husbandry of the species.


Separation and Visualization of Glycans by Fluorophore-Assisted Carbohydrate Electrophoresis.
Fluorophore-assisted carbohydrate electrophoresis (FACE) is a method in which a fluorophore is covalently attached to the reducing end of carbohydrates, thereby allowing high-resolution separation by electrophoresis and visualization. This method can be used for carbohydrate profiling and sequencing, as well as for determining the specificity of carbohydrate-active enzymes. Here we describe and demonstrate the use of FACE to separate and visualize the glycans released following digestion of oligosaccharides by glycoside hydrolases (GHs) using two examples: (i) the digestion of chitobiose by the streptococcal β-hexosaminidase GH20C and (ii) the digestion of glycogen by the GH13 member SpuA.


Stiff upper lip: coping strategies of World War II veterans with phantom limb pain.
Study of coping with phantom pain in nonclinical war veteran amputees. Semistructured interview with amputees in their home setting. Residential home for war veteran amputees or respondents' own homes. Amputee veterans of World War II with phantom pain. Pain (McGill Pain Questionnaire) and pain history, coping (daily coping; Stone and Neale, J Pers Soc Psychol 1984;46:892-906), size of social network, and quality of war memories. No differences in pain or coping were associated with place of residence (and prevalence of cues) or social networks; war memories appeared not to be associated with availability of cues, whether media coverage or other amputees. There was some association between the emotional tone of war memories and pain intensity. Veteran amputees were in general accepting of high levels of pain and made little use of medical resources, relating that to past experience of their pain being dismissed. Coping with phantom pain in war veteran amputees is predominantly silent acceptance of the pain, with little use of social support however available, and rare recourse to medical help, based on past unhelpful experience. Pain and mood appeared to be unrelated to specific war cues, but higher pain scores were reported by those with unhappier war memories.


Correction: Viruses Utilize Cellular Cues in Distinct Combination to Undergo Systematic Priming and Uncoating.
[This corrects the article DOI: 10.1371/journal.ppat.1005467.].


Pharmacokinetic Drug Interactions of Apatinib With Rifampin and Itraconazole.
Apatinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced-stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug-drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers. Compared with the single administration of apatinib, its coadministration with rifampin resulted in a 5.6-fold plasma clearance (CL/F) and 83% decrease in plasma AUC0-t of apatinib. By contrast, coadministration with itraconazole reduced the CL/F of apatinib by 40% and increased its AUC0-t by 75%. In summary, a strong CYP3A4 inducer (rifampin) had a strong effect (>5-fold) on the clinical pharmacokinetics of apatinib, whereas a strong CYP3A inhibitor (itraconazole 100 mg once a day) had a weak effect (1.25- to 2-fold). Whether these effects are of clinical significance needs further research and information about the exposure-safety and exposure-efficacy relationship of apatinib.


Fatty acid binding proteins in multiple myeloma.
Fatty acid binding proteins (FABPs) transport fatty acids (FA) into cells as an energy source, and their inhibition suppressed tumor proliferation in solid tumors. Multiple myeloma (MM) is a hematologic malignancy, known for disrupted protein metabolism including high proteasome activity, where proteasome inhibitors made a dramatic improvement in its treatment. Recent discovery found FABPs as a novel metabolic pathway in MM, which will have an impact on understanding the biology and on therapeutic application in MM.


Modulation of elevated plus maze behavior after chronic exposure to the anabolic steroid 17alpha-methyltestosterone in adult mice.
Exposure to supraphysiological doses of androgens may disrupt affective components of behavior. In this study, behavior of adult C57Bl/6 male mice was studied after exposure to the anabolic androgenic steroid (AAS) 17alpha-methyltestosterone (17alpha-meT; 7.5 mg/kg) via a subcutaneous osmotic pump for 17 days. Controls received vehicle implants (0.9% NaCl + 30% cyclodextrine). On day 15, experimental animals were challenged with an ethanol (EtOH) injection (i.p.; 1 g/kg) while controls received saline injections. Five minutes after the injection, animals were tested in an automated elevated plus maze (EPM) or in automated activity chambers. In addition, injection-free animals were tested for ethanol consumption on day 16 after an overnight water deprivation period. Whereas chronic exposure to 17alpha-meT did not modulate open arm behavior, EtOH-exposed animals made more entries into the open arms than controls (P < 0.05). A significant reduction of risk assessment behaviors (rearing, flat approach behavior, and stretch attended posture) over the EPM was noted for EtOH-exposed animals whereas a reduction in stretch attended postures was observed among 17alpha-meT-exposed animals. Locomotor activity, and light-dark transitions in activity chambers remained unaltered. Exposure to AAS did not modulate EtOH consumption. Our data suggest that exposure to a supraphysiological dose of 17alpha-meT has minimal effects on exploratory-based anxiety.


Classification of calcium channels and calcium antagonists: progress report.
The molecular biology and electrophysiology of calcium channels is proceeding apace, partially driven by the clinical success of the drugs classed as "calcium antagonists." Indeed, there are now more than 70 drugs in development that have been claimed to be "calcium antagonists" of one type or another. In order to ensure that there is a logical nomenclature for the channels and the drugs acting at the channels, an international committee has met over the last 2 years to classify the channels and the drugs. This report consists of an overview of current thinking, which will be finalized in a document submitted to the IUPHAR (International Union of Pharmacologists) nomenclature committee.


Interstitial nephritis from mesalazine: case report and literature review.
We report a new case of biopsy-confirmed mesalazine-induced interstitial nephritis in an 18-year-old male with ulcerative colitis. His renal function improved with drug discontinuation and corticosteroid treatment. An English literature review revealed an additional 22 cases of this complication that, taken together, showed (1) a male predominance, (2) an absence of specific symptoms or findings on urinalysis, (3) a 61% frequency of residual chronic renal insufficiency with 13% of patients developing end-stage renal disease, and (4) an apparent favorable response to steroid therapy. We conclude that patients receiving 5-aminosalicylates should be routinely monitored with serum creatinine measurements to prevent this uncommon but potentially serious adverse drug reaction.


Neurochemical and morphological studies of bulk isolated rat brain cells. II. Preparation of viable cerebral neurons which retain synaptic complexes.
The bulk isolation from rat cerebral cortex of viable neurons retaining synaptic complexes is described. The basis of this procedure is to dissociate the neurons in situ from the surrounding glial cells. The glial structures that are normally adjacent to the neuronal cell body and to the proximal parts of the neuronal processes are largely destroyed by perfusion of the brain under special conditions. The most important of these conditions was found to be a hyperosmolar concentration of hexoses in the perfusion medium. In addition, the presence of collagenase and hyaluronidase in the perfusion medium and specific perfusate flow characteristics were required to produce the structural changes throughout the brain tissue. When the perfused brain was further dissociated into a cell suspension by mincing and sieving, isolated neurons were obtained, the majority of which retained the proximal parts of their processes. A novel feature of these neurons was the retention of synaptic boutons on the plasma membrane. Presynaptic terminals with mitochondria and vesicles as well as pre- and postsynaptic membranes and densities were observed on the isolated neurons. The neurons were fractionated to 90--95% purity using discontinuous Ficoll density gradient centrifugation with a liquid fluorocarbon as cushion. Highly purified, viable cerebral neurons retaining synaptic complexes are thus available in bulk for neurobiological studies.


Non-vascular drug eluting stents as localized controlled drug delivery platform: preclinical and clinical experience.
Stents occupy an important place in the medical field for their widespread application. They have been used in vascular as well as in non-vascular organs for various reasons. Among vascular stents, development of coronary drug eluting stents (DESs) has completely revolutionised the percutaneous coronary intervention. Similarly, attempts have been made to make use of this modality in non-vascular organs. This paper focuses on the preclinical and clinical experience with drug-eluting non-vascular stents with emphasis on drug delivery systems and regulatory requirements for their development.


The role of the orthodontist in the diagnosis of Gorlin's syndrome.
Gorlin's syndrome is a relatively rare generalized disorder. Its diagnosis in childhood is usually through oral abnormalities. Some of the most frequent clinical features of this syndrome are discovered through radiographs commonly used in orthodontia. Thus, the orthodontist may be able to contribute to its diagnosis. The article shows three clinical cases that illustrate the role that the orthodontist may play in diagnosis of this syndrome.


Pharmacist implementation of a transitions of care electronic referral process to provide hand-off between inpatient and outpatient settings.
To describe the implementation of an electronic transitions of care referral process within a large, academic medical center. To improve communication between the inpatient and ambulatory care pharmacists, the pharmacy department created an electronic referral (e-referral) order, which becomes part of the patient's electronic medical record. Data were collected to describe use of the electronic order and to discuss the role of the referrals in supporting a newly developed ambulatory care pharmacy service. The e-referral was built to enhance the efficiency of direct patient care and prioritize patient care activities. This electronic order was built to collect specific details focused on medication-related concerns and provide hand-off to ambulatory care pharmacists for outpatient follow-up. A retrospective, cohort analysis of patients was conducted from August 1, 2014, to July 31, 2015. Patients were included in the project if they were 18 years of age or older and received an e-referral order upon transition from the inpatient to the outpatient setting. Patients were excluded if the e-referral was sent from an outpatient setting or if they were younger than 18 years of age. Data were collected to describe the e-referral process and discuss how these referrals supported a new outpatient pulmonary clinic. A total of 268 inpatient referral orders were included for analysis. Common indications for the referrals included education (49%), follow-up from inpatient consult (46%), adherence (45%), and therapy optimization (42%). A total of 241 (90%) e-referrals were sent from an inpatient pharmacist to an ambulatory care pharmacist; the other 27 (10%) referrals were sent by a physician or mid-level provider. Of the 241 pharmacist referrals, 46 (19%) were placed by pharmacy residents. The majority of inpatient e-referrals (63.4%) were for chronic obstructive pulmonary disease and sent to the outpatient pulmonary clinical pharmacist for follow-up after discharge. The pulmonary clinic ambulatory care pharmacist completed 110 discharge calls (95.7%). An e-referral from inpatient to ambulatory care pharmacists provides pharmacist-to-pharmacist hand-off for medication-related needs after discharge.


Purification and properties of a new bacillus subtilis RNA processing enzyme. Cleavage of phage SP82 mRNA and Bacillus subtilis precursor rRNA.
An RNA processing activity capable of cleaving Bacillus subtilis phage SP82 early mRNA has been purified to apparent homogeneity from crude extracts of uninfected B. subtilis. The enzyme, a functional monomer of Mr approximately 27,000, cleaves only at the 5' side of adenosine residues at processing sites and is competitively inhibited by double-stranded synthetic RNA polymers. Processed SP82 mRNAs were translated in an Escherichia coli cell-free system and no qualitative or quantitative effects of processing on the synthesis of polypeptides was observed. The processing enzyme does not cleave T7 mRNA, E. coli precursor rRNA, or double-stranded poly(AU). A recombinant plasmid containing portions of two B. subtilis rRNA gene sets was transcribed in vitro and the resulting RNA was cleaved in the spacer region between the 16 S and 23 S rRNA genes. The ability of the B. subtilis processing enzyme to cleave SP82 mRNA and B. subtilis precursor rRNA and the fact that the enzyme has high affinity for double-stranded RNA suggest that it is the functional analog of E. coli RNase III.


Cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) gene V115F (G-->T) polymorphism is associated with phenotypes of metabolic syndrome in Japanese men.
Cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA) regulates energy expenditure in the adipose tissue and is implicated in the development of obesity. A single nucleotide polymorphism in the CIDEA gene that causes an amino acid substitution of valine 115 to c(V115F) has recently been shown to be associated with obesity in the Swedish population. Here, we determined the effects of this polymorphism on phenotypes of metabolic syndrome within the Japanese population. Two hundred seventy unrelated Japanese male workers (mean age, 44.5 years) were analyzed in a cross-sectional study. The clinical features regarding metabolic syndrome, as well as CIDEA V115F polymorphism, were determined for each individual. The V115F polymorphism associated with waist circumference and fasting plasma glucose. These parameters were at higher levels in the VF + FF group than in the VV group (P < .05). The VF + FF group compared with the VV group had a higher prevalence for abdominal obesity (odds ratio [OR] = 1.89; 95% confidence interval [CI], 1.03-3.44), high fasting plasma glucose (OR = 2.81; 95% CI, 1.03-7.67), and metabolic syndrome (OR = 3.15; 95% CI, 1.05-9.48). These results suggest that the F allele of the CIDEA gene may serve as a risk factor for phenotypes related to metabolic syndrome in Japanese men.


Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample.
Detection of somatic mutations using patients sequencing data has many clinical applications, including the identification of cancer driver genes, detection of mutational signatures, and estimation of tumor mutational burden (TMB). We have previously developed a tool for detection of somatic mutations using tumor RNA and a matched-normal DNA. Here, we further extend it to detect somatic mutations from RNA sequencing data without a matched-normal sample. This is accomplished via a machine-learning approach that classifies mutations as either somatic or germline based on various features. When applied to RNA-sequencing of >450 melanoma samples high precision and recall are achieved, and both mutational signatures and driver genes are correctly identified. Finally, we show that RNA-based TMB is significantly associated with patient survival, showing similar or higher significance level as compared to DNA-based TMB. Our pipeline can be utilized in many future applications, analyzing novel and existing datasets where only RNA is available.


Orgasmic Function after Radical Prostatectomy.
We examined postprostatectomy orgasmic function and assessed for potential predictors. Between 2005 and 2013, 499 men underwent radical prostatectomy and completed quality of life questionnaires prospectively before surgery and at regular postoperative intervals. We used mixed effects logistic regression models to evaluate average differences in followup measures and interactions with time. At a median followup of 36 months orgasmic function was worse, stable or improved in 300 (60.1%), 152 (30.5%) and 47 men (9.4%), respectively. Orgasmic function recovery plateaued at 15 to 21 months. High postoperative orgasmic function was positively associated with younger age (50 years or younger vs 51 to 60 OR 3.40, 95% CI 1.56-7.41), nerve sparing (bilateral OR 7.11, 95% CI 2.55-19.77, modified 4.34, 95% CI 1.38-13.58 and unilateral OR 3.93, 95% CI 1.17-13.16), erectile function (OR 4.67, 95% CI 3.32-6.57) and sexual desire (OR 5.51, 95% CI 3.95-7.68) but negatively associated with lower urinary tract symptoms (OR 0.58, 95% CI 0.41-0.82) and urinary incontinence (OR 0.38, 95% CI 0.25-0.56). Although robotic status did not influence orgasmic function in the overall cohort, it was associated with faster recovery on subgroup analysis of 356 patients with long followup. On another subgroup analysis of 235 men with long followup and poor erectile function the association of high preoperative orgasmic function and bilateral nerve sparing with high orgasmic function persisted, suggesting an independent effect on orgasmic function apart from that on erectile function. Orgasmic function recovery after radical prostatectomy is a lengthy process. Predictors of orgasmic function include preoperative orgasmic function, age, nerve sparing status, erectile function, sexual desire and urinary control and function.


Exercise training in high-risk ethnic populations with type 2 diabetes: a systematic review of clinical trials.
To review clinical trials that have prescribed exercise training in high-risk, ethnic populations with type 2 diabetes mellitus (T2DM) and delineate areas for future research. A systematic review using computerized databases was performed. The systematic review located nine trials, including four uncontrolled trials, and five randomized controlled trials (RCTs) that included 521 participants. Cohorts studied included African, Indian, Polynesian, Hispanic, Arabian, and Chinese peoples and interventions included aerobic training, resistance training or a combination thereof. Several trials documented improvements in HbA1c, insulin action, body composition, blood lipids and systolic and diastolic blood pressure. In general, a longer duration and greater frequency of training resulted in greater adaptation. Studies demonstrating no effect were generally limited by an inadequate intervention. There was evidence of differential training responses between Caucasians and non-Caucasians in two studies drawing such comparisons. Robust RCTs prescribing appropriate, targeted interventions and investigating relevant outcomes may be required to stimulate greater advocacy for exercise as a therapeutic adjunct for diabetes management in these populations. Investigations should be extended to other high-risk populations, particularly indigenous peoples who suffer an extreme burden of T2DM. Translation of research into clinical application should remain the overall objective.


Foliage phenols and nitrogen in relation to growth, insect damage, and ability to recover after defoliation, in the mountain birch Betula pubescens ssp tortuosa.
We studied growth of the mountain birch, and the role of foliage phenols, nitrogen, and variance in the timing of bud burst, as potential defensive characters, in Finnish Lapland in 1975-1979. Annual and local variation both in phenol and nitrogen concentration of foliage were significant. Individual trees retained their position in the foliage and nitrogen distribution of the population in successive years, as well as in the order of leaf flush in spring. Growth of twigs, mature leaf size, and ability of trees to recover in the year following artificial defoliation correlated positively with the sum of degree days in the previous growing season. Foliage nitrogen correlated negatively with foliage phenols in within-site comparisons. Twig growth correlated negatively with foliage phenols, particularly in growing seasons following cool summers, but did not correlate with foliage nitrogen. Birches flushing early did not grow more than birches flushing late. Between-site differences in foliage phenol content were mainly determined by abiotic conditions, like temperature and nutrient availability. In a between-site comparison insect chewing marks in leaves correlated positively with foliage phenols as well as with nitrogen; intensity of invertebrate predation presumably explained variable herbivory between the sites. In a within-site comparison trees with the highest foliage phenol content had few herbivores only at the site with the highest average phenol level.


A dynamical model for post-translational modifications of microtubules.
In many cases, post-translational modifications constitute indirect markers of non-dynamic microtubules. The correlation between stability of microtubular systems and post-translational modifications suggests that they may act as a signal in patterning mechanisms. However, a crucial question remains as to how the repertoire of distinctly modified microtubules is generated. We propose here an ubiquitous mechanism of spatial and temporal differentiation of microtubules. In this model, the diversity of post-translational modifications results from a dynamical pathway separation which is ensured by biochemical switches between self-regulated mechanisms of differentiation. Thus, it does not require any hypothetical subcellular compartmentalization of enzymatic activities responsible for the various post-translational modifications. These results are discussed in relation to experimental evidences for a temporal and spatial regulation of microtubule modifications.


Supramolecular pseudo-block gene carriers based on bioreducible star polycations.
A series of supramolecular pseudo-block polycations (CD-SS-pDM/Ad-pPEGs) were realized by assembling bioreducible β-cyclodextrin-cored star poly (2-dimethyl amino)ethyl methacrylate with different molecular weight and an adamantine-ended linear poly(poly(ethylene glycol)ethyl ether methacrylate) (pPEGEEMA) via the host-guest interaction. The pseudo-block CD-SS-pDM/Ad-pPEG carriers were investigated in terms of DNA binding capability, cytotoxicity, gene transfection in HepG2 and COS7 cell lines, and in vivo anti-tumor activity. The pseudo-block carriers exhibited undiminished pDNA-condensing abilities compared with the starting star carriers. Meanwhile, the pseudo-block carriers displayed lower cytotoxicity and higher gene transfection efficiencies at various N/P ratios. These results are consistent with the favorable properties of pPEGEEMA as expected. Furthermore, cellular internalization results and in vivo anti-tumor activity analysis demonstrated that assembled pPEGEEMA could enhance the stability of pseudo-block carriers, thus improving their cellular internalization and gene transfection efficiency. The present study demonstrated that supramolecular pseudo-block polycations via the host-guest interaction is an effective means to produce new gene carriers.


Molecular landscape of TP53 mutations in breast cancer and their utility for predicting the response to HER-targeted therapy in HER2 amplification-positive and HER2 mutation-positive amplification-negative patients.
We used targeted capture sequencing to analyze TP53-mutated circulating tumor DNA (ctDNA) in metastatic breast cancer patients and to determine whether TP53 mutation has predictive value for anti-human epidermal growth factor receptor 2 (HER2) treatment for in HER2 amplification-positive patients (HER2+) and HER2 mutation-positive, amplification-negative (HER2-/mut) patients. TP53 mutation features were analyzed in the Geneplus cohort (n = 1184). The MSK-BREAST cohort was used to explore the value of TP53 mutation in predicting anti-HER-2 antibody efficacy. Sequencing of ctDNA in phase Ib, phase Ic, phase II clinical trials of pyrotinib (HER2+ patients), and an investigator-initiated phase II study of pyrotinib (HER2-/mut patients) were performed to analyze the relationships between TP53 mutation and prognosis for HER2 TKIs. The MSK-BREAST cohort, MutHER, and SUMMIT cohort were used for verification. TP53 mutations were detected in 53.1% (629/1184) of patients in the Geneplus cohort. The TP53 mutation rate was higher in HR-negative (p < 0.001) and HER2 amplification-positive (p = 0.015) patients. Among patients receiving anti-HER2 antibody therapy, those whose tumors carried TP53 mutations had a shorter PFS (p = 0.004). However, the value of TP53 mutation in predicting HER2 TKI response was inconsistent. In HER2+ patients, no difference in PFS was observed among patients with different TP53 statuses in the combined analysis of the pyrotinib phase Ib, phase Ic, and phase II clinical trials (p = 1.00) or in the MSK-BREAST cohort (p = 0.62). In HER2-/mut patients, TP53 mutation-positive patients exhibited a trend toward worse prognosis with anti-HER2 TKI treatment than TP53-wild-type patients in our investigator-initiated phase II study (p = 0.15), and this trend was confirmed in the combined analysis of the MutHER and SUMMIT cohorts (p = 0.01). TP53 mutation can be used to identify biomarkers of anti-HER2 antibody drug resistance in HER2+ patients and HER2 TKI resistance in HER2-/mut patients.


Dissection-related carotid-cavernous fistula (CCF) following surgical revascularization of chronic internal carotid artery occlusion: a new subtype of CCF and proposed management.
The development of carotid-cavernous fistulas (CCFs) during surgical recanalization of chronic internal carotid artery occlusion (ICAO) may be secondary to severe ICA dissection rather than a focal tear of the cavernous ICA seen in typical traumatic CCFs. The purpose of this study is to investigate the causal relationship between the CCFs and severe ICA dissections and to characterize technical outcomes after treatment with stenting. Five patients underwent treatment with self-expanding stents due to intraprocedural CCF and ICA dissection following surgical removal of ICAO plaque. The stents were telescopically placed via true channel of the dissection. Safety of the procedure was evaluated with 30-day stroke and death rate. Procedural success was determined by the efficacy of CCF obliteration and ICAO recanalization with angiography. All CCFs were associated with spiral and long segmental dissection from the cervical to cavernous ICA. After stenting, successful dissection reconstruction with TICI 3 was achieved in all patients, with complete (n = 4) or partial CCF (n = 1) obliteration. No patient had CCF syndrome, stroke, or death during follow-up of 6 to 37 months; but one patient had pulsatile tinnitus, which resolved 1 year later. Angiography at 6 to 24 months demonstrated CCF obliteration in all 5 patients and durable ICA patency in 4 patients. Intraprocedural CCFs with spiral and cervical-to-cavernous ICA dissection during ICAO surgery are dissection-related because of successful obliteration after stenting for dissection reconstruction. Self-expanding stenting through true channel of the dissection, serving as implanting stent-autograft, may be an optimal therapy for the atypical CCF complication from ICAO surgery.


Feasibility of a novel system for intraductal balloon-anchored direct peroral cholangioscopy and endotherapy with an ultraslim endoscope (with videos).
Advantages of direct peroral cholangioscopy (DPOCS) by using an ultraslim endoscope include a single-operator platform, image quality equal to that of standard endoscopy, and separate water and air channels. However, DPOCS has significant limitations, including cumbersome biliary access, en-face position with the ampulla, and gastric looping of the endoscope. A newly designed anchoring balloon may overcome these challenges. To report the feasibility of DPOCS with the anchoring balloon. Pilot study, porcine model. Animal resources center. The anchoring balloon system developed by Cook Medical (Winston-Salem, NC) was used for DPOCS. Primary: Feasibility of biliary access maintenance and intraductal mobility. Secondary: Feasibility of intraductal therapeutic procedures. Four animal subjects underwent DPOCS with the anchoring balloon. Ductal access was achieved with sphincterotomy in 2 subjects and with a balloon sphincteroplasty in 2 subjects. Intraductal placement of the ultraslim endoscope was achieved in all biliary access attempts without balloon migration or deflation. Common bile duct, cystic duct, bifurcation, and main right and left duct direct visualization was achieved in all cases. Therapeutic interventions by DPOCS, including intraductal biopsy, balloon dilatation, and intraductal bilateral metal stent placement, were all completed successfully. Biliary perforation occurred in one case because of balloon overinflation and in a second case because of sphincterotomy. Prototype study in an animal model and small study size. Our results show that the novel anchoring balloon system successfully and safely enables DPOCS for both diagnostic and therapeutic interventions. If corroborated in human trials, it could offer a new platform for biliary interventions.


Flow dynamics in a stenosed carotid bifurcation model--Part I: Basic velocity measurements.
A model of the human carotid artery bifurcation has been constructed and tested under mean physiologic flow conditions (fluid viscosity = 0.035 poise; mean Re inlet = 400; unconstricted flow split = 70:30, internal carotid artery:external carotid artery). Smooth, axisymmetric constrictor plugs with 0, 20, 40, 60, and 80% diameter reduction are placed in the simulated proximal internal carotid artery to provide a range of flow conditions similar to those found clinically. Axial velocity measurements are made at sites +/- 0.625 radius within the lumen of the tube at distances of 0, 1, 3, 5 and 10 diameters downstream of the constrictor throat using H2 bubble markers and a 7.5 MHz ultrasound pulse Doppler. Measurement of mean, mode -3 dB down high and low and -9 dB down high and low velocities are made from selected fast-Fourier transform (FFT) spectra. The flow field downstream of the 0% diameter reduction is entirely laminar, exhibiting a peak skewed toward the flow divider along the entire 10 diameters downstream and having a consistently narrow bandwidth. Obstruction of the flow channel produces increased axial velocity at the constrictor (20%), an oscillatory jet extending approximately 5 diameters downstream (40%), a transitional jet extending approximately 5 diameters downstream (60%) and a turbulent jet extending approximately 3 diameters downstream (80%). Velocity bandwidth (both -3 dB and -9 dB) increases with degree of constriction and low velocity flow patterns exist between the center line and both tube walls. Presence of constriction produces characteristic downstream flow patterns which are distinctive for each degree of diameter reduction.


Lack of effect of cimetidine in chronic-idiopathic urticaria.
The effect of an H1 and an H2 receptor blocker singly and in combination was studied in 20 patients with chronic idiopathic urticaria. Both H1 receptor blockade alone and in combination with H2 receptor blockade produced a significant reduction in wealing and itch; there was no significant difference between these treatments. H2 blockade alone produced no significant reduction in wealing; there was a slight increase in itch, though not statistically significant.


Optimizing cadmium and mercury specificity of CadR-based E. coli biosensors by redesign of CadR.
The metalloprotein, CadR, was redesigned to optimize cadmium and mercury specificity of CadR-based E. coli biosensors. By truncating 10 and 21 amino acids from the C-terminal extension of CadR, CadR-TC10 and CadR-TC21 were obtained, respectively. The genes cadR, cadR-TC10 and cadR-TC21 were used as sensing elements to construct green fluorescent protein based E.coli biosensors. Induction at 30 °C for 4 h in supplemented M9 medium was the optimized condition for the biosensor. Compared with CadR-based biosensor, there was a clear decline in induction coefficient for CadR-TC21-based biosensor (decreased by 86 % in Zn(II), 44 % in Hg(II), and only 37 % in Cd(II)). While in CadR-TC10-based biosensor, the induction coefficient decreased by 95 % in Zn(II), 70 % in Hg(II), and 67 % in Cd(II). Improved performances of CadR mutants based E. coli biosensors indicated that truncating C-terminal extension of CadR could improve the specificity.


Relationship between colloid osmotic pressure and pulmonary artery wedge pressure in patients with acute cardiorespiratory failure.
Close relationships between progressive respiratory failure, roentgenographic signs of pulmonary opacification and decreases in the difference between colloid osmotic pressure of plasma and the pulmonary artery wedge pressure (colloid-hydrosatic pressure gradient) were demonstrated in 49 critically ill patients with multisystem failure, in patients in shock. The potential importance of this relationship is underscored by the observation that fatal progression of pulmonary edema was related to a critical reduction in the colloid-hydrostatic pressure gradient to levels of less than 0 mm Hg. More often, reduction in colloid osmotic pressure rather than increases in left ventricular filling pressure (pulmonary artery wedge pressure) accounted for the decline in colloid-hydrostatic pressure gradient. Routine measurement of colloid osmotic pressure, preferably in conjunction with pulmonary artery wedge pressure, is likely to improve understanding of the mechanisms of acute pulmonary edema.


Diacerein versus adipoRon as adiponectin modulators in experimentally-induced end-stage type 2 diabetes mellitus in rats.
The objective of the present study is to evaluate and compare the possible anti-diabetic effects of adipoRon and diacerein in type 2 diabetes mellitus (T2DM) rats. T2DM is marked by impaired oxidative, inflammatory and metabolic signaling. Indeed, T2DM progression is associated with elevated HbA1C%, low adiponectin and insulin concentration. Moreover, in this study epididymal adipose tissue and soleus muscle MDA contents significantly escalated, while serum TAC and epididymal adipose Nrf2 significantly declined. Nevertheless, serum TNF-α, epididymal NLRP3, NF-κB, PPARγ and CD68 expression rose significantly with a parallel significant reduction in serum IL-10 and soleus muscle expression of IRS1. Both adipoRon and diacerein significantly improved adiponectin and insulin secretion with augmentation of anti-oxidant defenses and diminution of oxidative burden, with obvious anti-inflammatory consequences (p < 0.05). Thus, adipoRon and diacerein positively modulated adiponectin expression with down-regulation of NF-κB/NLRP3/PPARγ expression with subsequent improvement in glycemic control, inflammatory and oxidative signaling.


Reproducibility of liver iron concentration estimates in MRI through R2* measurement determined by least-squares curve fitting.
Measuring transverse relaxation rate (R2* = 1/T2*) via MRI allows for noninvasive evaluation of multiple clinical parameters, including liver iron concentration (LIC) and fat fraction. Both fat and iron contribute to diffuse liver disease when stored in excess in the liver. This liver damage leads to fibrosis and cirrhosis with an increased risk of developing hepatocellular carcinoma. Liver iron concentration is linearly related to R2* measurements using MRI. A phantom was constructed to assess R2* quantification variability on 1.5 and 3 T MRI systems. Quantification was executed using least-squares curve fitting techniques. The phantom was created using readily available, low-cost materials. It contains four vials with R2* values that cover a clinically relevant range (100 to 420 Hz at 1.5 T). Iron content was achieved using ferric chloride solutions contained in glass vials, each affixed in a three-dimensional (3D)-printed polylactide (PLA) structure, surrounded by distilled water, all housed in a sealed acrylic cylinder. Multiple phantom stands were also 3D-printed using PLA for precise orientation of the phantom with respect to the direction of the static magnetic field. Acquisitions at different phantom angles, across multiple MRI systems, and with different pulse sequence parameters were evaluated. The variability between any two R2* measurements, taken in the same vial under these various acquisition conditions, on a 1.5 T MRI system, was <7% for each of the four vials. For 3 T MRI systems, variability was less than 14% in all cases. Variability was <6% for both 1.5 and 3 T acquisitions when unchanged pulse sequence parameters were used. The phantom can be used to mimic a range of clinically relevant levels of R2* relaxation rates, as measured using MRI. These measurements were found to be reproducible relative to the gold-standard method, liver biopsy, across several different image acquisition conditions.


Behaviorism, private events, and the molar view of behavior.
Viewing the science of behavior (behavior analysis) to be a natural science, radical behaviorism rejects any form of dualism, including subjective-objective or inner-outer dualism. Yet radical behaviorists often claim that treating private events as covert behavior and internal stimuli is necessary and important to behavior analysis. To the contrary, this paper argues that, compared with the rejection of dualism, private events constitute a trivial idea and are irrelevant to accounts of behavior. Viewed in the framework of evolutionary theory or for any practical purpose, behavior is commerce with the environment. By its very nature, behavior is extended in time. The temptation to posit private events arises when an activity is viewed in too small a time frame, obscuring what the activity does. When activities are viewed in an appropriately extended time frame, private events become irrelevant to the account. This insight provides the answer to many philosophical questions about thinking, sensing, and feeling. Confusion about private events arises in large part from failure to appreciate fully the radical implications of replacing mentalistic ideas about language with the concept of verbal behavior. Like other operant behavior, verbal behavior involves no agent and no hidden causes; like all natural events, it is caused by other natural events. In a science of behavior grounded in evolutionary theory, the same set of principles applies to verbal and nonverbal behavior and to human and nonhuman organisms.


The early-onset fearful panic attack as a predictor of severe psychopathology.
The objective of this study was to replicate previous findings indicating that early-onset panic attack (< or =20 years) with fear represents a possible prodrome of early-onset severe psychopathology. Data were drawn from the Epidemiologic Catchment Area Survey (ECA) (n=20 291), a household sample of adults aged 18 and older drawn from five cities in the United States. Multivariate logistic regression analyses were used to differentiate those with early-onset panic attacks with fear from those with other panic attacks (early-onset without fear, late-onset without fear, late-onset with fear) with regard to psychiatric comorbidity, age at onset of comorbid mental disorders, and suicidal ideation and suicide attempts. Results of statistical analyses revealed that early-onset fearful panic attack (n=368) was associated with increased likelihood of major affective and substance use disorders, significantly earlier onset of comorbid mental disorders, higher rates of suicidal ideation and suicide attempt, and higher rates of antisocial personality disorder compared with those with other subtypes of panic attacks. Multiple logistic regression analyses showed that early-onset fearful panic was independently associated with increased odds of major depression [OR=3.0 (2.6, 3.5)], bipolar disorder [OR=7.9 (5.7, 10.8)], antisocial personality disorder [OR=1.5 (1.3, 1.7)], agoraphobia [OR=1.2 (1.1, 1.4)], simple phobia [OR=1.6 (1.4, 1.8)], and alcohol dependence [OR=1.3 (1.2, 1.5)], compared with those with all other panic attacks. These findings are consistent with previous epidemiologic data and provide new evidence to suggest that early-onset fearful panic attack may be a marker of increased vulnerability to severe and persistent psychopathology and associated with high rates of suicidality.


Utilising mobile game based learning methods effectively to support education.
This paper is a response concerning the implications of scholarship of the article entitled "A critical review of 13 years of mobile game-based learning" by Giannakas et al. (in Educ Technol Res Dev 66:341-384, 2018). This response focuses on the key ideas presented in Giannakas et al. (2018) from a practical perspective, highlighting how practitioners, scholars and designers can use their findings to effectively utilise mobile Game Based Learning (mBGL) approaches to support and enhance learning. This response paper is discussing the value, impact and practical implications of Giannakas, et al. (2018) and possible future directions relevant to the use of smartphone enabled virtual reality to support mGBL.


Transgenerational consequences of adolescent morphine exposure in female rats: effects on anxiety-like behaviors and morphine sensitization in adult offspring.
Opiate abuse in adolescent girls has increased in the past decade; however, few animal studies have examined the potential consequences of opiate use occurring at this time. The purpose of the present study was to determine whether exposing female rats to morphine during the peripubertal period can alter the adult behavior of their offspring. Beginning at 30 days of age, female rats were injected subcutaneously (s.c.) twice daily with either morphine sulfate or saline. The initial morphine dose of 2.5 mg/kg was increased by 2.5 mg/kg daily for a total of 20 days. Ten days after the final drug treatment, all subjects were mated. Their subsequent offspring were then tested as adults on the elevated plus maze, in a novel environment or were examined in a morphine locomotor sensitization paradigm. Adult female offspring of dams exposed to morphine during puberty spent less time in the open arms of the elevated plus maze and displayed decreased exploration in a novel environment. Female offspring also demonstrated a more rapid induction of morphine sensitization. Finally, male offspring demonstrated a significant enhancement in the expression of morphine sensitization. Chronic morphine exposure during adolescence can have significant transgenerational effects on adult offspring. Future studies will be needed to determine how these changes are transferred to the offspring and whether these effects are specific to drug exposure that occurs during the peripubertal period.


Efficient separation of monobromotoluene isomers by nonporous adaptive perbromoethylated pillar[5]arene crystals.
Herein we report an efficient adsorptive separation approach for monobromotoluene isomers using nonporous adaptive crystals of perbromoethylated pillar[5]arene (BrP5). The purity of separated m-bromotoluene from an equal volume mixture of m-bromotoluene and o-bromotoluene reaches 96.6% in one cycle and the adsorbent BrP5 can be reused without losing separation performance.


The use of live models in the teaching of gross anatomy.
Live models were introduced into the first-year gross anatomy course to provide medical students with an opportunity to apply to the living person what they learned from cadaver dissection. After each major segment of the cadaver dissection, clinical correlation sessions were presented for the students by clinicians using live models for demonstration, examination and correlation. At the completion of the course, an evaluation questionnaire was given to students. Their response indicated that the new teaching technique made anatomy seem more relevant to clinical medicine than using cadavers alone. Live models were rated superior to using cadavers, especially in demonstrating superficial anatomical structures and landmarks. On the basis of student response it was concluded that this programme provided medical students with a unique introduction to living human anatomy.


Synthesis and biological properties of chemically modified siRNAs bearing 1-deoxy-D-ribofuranose in their 3'-overhang region.
To elucidate the role of the sugar moiety in the two natural nucleotides of the 3'-overhang region of small interfering RNA (siRNA), we synthesized siRNAs that incorporated two abasic nucleosides, 1-deoxy-D-ribofuranose (R(H)). We improved the method for preparing an O-protected abasic nucleoside, 1-deoxy-2,3,5-tri-O-benzoyl-β-D-ribofuranose, via the reductive cleavage of the anomeric position of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose. To incorporate R(H) into oligonucleotides by the standard phosphoramidite solid phase method, R(H) was converted into its phosphoramidite derivative and the solid support linked to a controlled pore glass resin. Chemically modified RNAs possessing R(H) at the 3'-overhang region were easily prepared in good yields. siRNAs containing R(H) showed moderate nuclease-resistance and a desirable knockdown effect.


Action of metiamide on the lower esophageal sphincter.
The action of metiamide, an H2 antagonist, was tested for its effect upon lower esophageal sphincter (LES) function in the anesthetized opossum. Intravenous infusions of metiamide gave a dose-related increase in LES pressure. A maximum increase in pressure of 17 mm Hg was attained at 2.0 mg per kg-hr of metiamide. This dose of metiamide abolished acid secretion in response to gastrin I, but augmented the maximal LES response to this hormone. Studies in vitro showed that metiamide augmented the maximal LES muscle responses to gastrin I or histamine but had no effect on other agonist responses. Metiamide alone did not alter LES muscle tension. An inhibitory response to gastrin I or histamine could be demonstrated in the presence of atropine or diphenhydramine, respectively, on muscle which had first been depolarized with KCl. These inhibitory responses were antagonized by metiamide. These studies indicate that metiamide: (a) increases LES pressure; (b) selectively augments LES muscle excitatory responses to gastrin I or histamine; and (c) selectively antagonizes inhibitory muscle responses to histamine or gastrin I.


Medicine and money: the ethical transformation of medical practice.
To explore the generalised application of a discourse of cost reduction in the practice of medicine in the USA. Changes in the health services industry over the last 20 years have left much concern in the hearts and minds of many, providers and patients alike. Even for the millions of Americans who are able to purchase health insurance, the standard of care has changed. In some ways, the current managed-care climate has created an atmosphere of distrust between patients and their providers, and, more significantly, a general sense of dissatisfaction with the state of health care in the USA. In the midst of this discontent, health providers have begun to question their own roles in what is increasingly a for-profit health care system. Not surprisingly, medical educators now question whether the current health system is creating a new generation of doctors who are concerned with reducing costs without adequate review of clinical data. This paper examines the rationale applied in the management of a patient with end-stage liver disease in a teaching hospital. The case is re-socialised by situating it in an ethical discourse linked to the function of the for-profit health system. The decision about whether to give human albumin to an insured patient serves as a lens through which to examine how uncritical appeals to the discourse of 'cost-effectiveness' can supersede a patient- and data-oriented approach to medical decision making. This case illustrates the permeation of economic considerations into the core values of medicine, highlighting a detrimental ethical shift occurring in the field. The training of new doctors represents a site from which to resist this unwelcome transformation.


Should specific patient clinical characteristics discourage adrenal surgeons from performing laparoscopic transperitoneal adrenalectomy?
Although laparoscopic transperitoneal adrenalectomy (LTA) has become a standard operative approach to patients with benign adrenal masses, some authors have suggested that LTA should be avoided in obese patients, patients who have had previous abdominal surgery, and in cases of bilateral adrenalectomy. We sought to determine whether LTA in these clinical situations is associated with worse outcomes. Consecutive patients who underwent LTA at a tertiary care center (1/2002-8/2014) were reviewed retrospectively. Study endpoints included operative time, duration of stay, conversion to open procedure, and postoperative complications. Statistical analyses were performed by use of Wilcoxon rank sum test, Kruskal-Wallis test, Fisher exact test, χ(2) test, and binary logistic regression analyses. A total of 365 patients had a planned LTA, 6 of whom were converted to an open adrenalectomy. Obesity, history of previous abdominal surgery, and bilateral adrenalectomy were not associated with greater conversion rates or postoperative complications. Male sex, tumor size ≥ 4 cm and obesity (body mass index ≥ 30 kg/m(2)) were significant factors associated with increased operative time. Bilateral adrenalectomy, age, and pheochromocytomas were associated with increased hospital stays. Obesity, history of prior abdominal surgery and bilateral adrenalectomy should not be used to discourage experienced adrenal surgeons from performing LTA.


Can the resource curse be avoided? An empirical examination of the nexus between crude oil price and economic growth.
This paper revisits the resource curse hypothesis by examining the nexus between crude oil price and economic growth for a panel of 32 Sub-Saharan Africa countries from 1980 to 2017. Employing the panel vector autoregression (VAR) estimation technique, we found evidence of a significant positive effect of crude oil price on economic growth both in the short run and long run. However, after splitting the panel into net oil exporters and importers, the results for net oil importers remain consistent with those obtained for the whole panel, unlike those for net oil exporters revealing a positive and negative effect of crude oil price on economic growth in the short-run and long-run periods, respectively. This confirms the resource curse hypothesis for oil-exporting countries under consideration. Moreover, we found evidence of bidirectional causality between crude oil price and real GDP. Consequently, to boost economic growth in Sub-Saharan Africa, various governments should encourage economic diversification, increase investments in human capital in view of enhancing the development of the oil sector by ensuring an efficient management of oil revenues, as well as intensifying the fight against corruption. The online version contains supplementary material available at 10.1007/s43546-021-00179-x.


The Value of Lymph Node Dissection in the Surgery of Colorectal Cancer Liver Metastases.
Liver resection is the best treatment for metastatic colorectal cancer (CRC). Hepatic lymph node metastases are considered as extrahepatic disease and represent an unfavorable prognostic factor. However, extrahepatic disease, when resectable, provides no contraindication for surgical therapy. The aim of this study was to evaluate the prevalence of hepatic lymph node involvement in our patients' cohort. Twenty patients submitted to resection for colorectal liver metastases were studied prospectively. Three areas for lymph node dissection were defined and analyzed separately. Lymph nodes were examined by hematoxylin and eosin staining and immunohistochemistry for Pan-Keratin. In average, 5 lymph nodes were harvested per patient. Macroscopic enlargement was not a definite sign for metastatic involvement. No morbidity or mortality was associated with lymphadenectomy. In our patients' collective, no cases of lymph node metastases occurred. There is no evidence of a survival benefit after lymph node dissection in patients with CRC liver metastases in the literature. Systematic lymphadenectomy can, however, provide a prognostic tool to better plan further treatment.


Allele-specific PCR and Next-generation sequencing based genetic screening for Congenital Adrenal Hyperplasia in India.
Genetic screening of Congenital Adrenal Hyperplasia (CAH) is known to be challenging due to the complexities in CYP21A2 genotyping and has not been the first-tier diagnostic tool in routine clinical practice. Also, with the advent of massive parallel sequencing technology, there is a need for investigating its utility in screening extended panel of genes implicated in CAH. In this study, we have established and utilized an Allele-Specific Polymerase Chain Reaction (ASPCR) based approach for screening eight common mutations in CYP21A2 gene followed by targeted Next Generation Sequencing (NGS) of CYP21A2, CYP11B1, CYP17A1, POR, and CYP19A1 genes in 72 clinically diagnosed CAH subjects from India. Through these investigations, 88.7% of the subjects with 21 hydroxylase deficiency were positive for eight CYP21A2 mutations with ASPCR. The targeted NGS assay was sensitive to pick up all the mutations identified by ASPCR. Utilizing NGS in subjects negative for ASPCR, five study subjects were homozygous positive for other CYP21A2 variants: one with a novel c.1274G>T, three with c.1451G>C and one with c.143A>G variant. One subject was compound heterozygous for c.955C>T and c.1042G>A variants identified using ASPCR and NGS. One subject suspected for a Simple Virilizing (SV) 21 hydroxylase deficiency was positive for a CYP19A1:c.1142A>T variant. CYP11B1 variants (c.1201-1G>A, c.1200+1del, c.412C>T, c.1024C>T, c.1012dup, c.623G>A) were identified in all six subjects suspected for 11 beta-hydroxylase deficiency. The overall mutation positivity was 97.2%. Our results suggest that ASPCR followed by targeted NGS is a cost-effective and comprehensive strategy for screening common CYP21A2 mutations and the CAH panel of genes in a clinical setting.


Corrections to "Learning to Learn Adaptive Classifier-Predictor for Few-Shot Learning".
In the above article [1], the results of "Fully-supervised (Upper bound)" in Tables III and IV were inadvertently set to intermediate records that were used as placeholders. This error has no effect on any of the interpretations and conclusions. Tables I and II of this amendment show the corrected results (highlighted in italics) of the original Tables III and IV.


Genetics of Biomphalaria glabrata: linkage analysis of genes for pigmentation, enzymes, and resistance to Schistosoma mansoni.
The snail, Biomphalaria glabrata, is a major intermediate host of the human blood fluke, Schistosoma mansoni, in the Americas. The inheritance and linkage relationships of a gene enabling adult snails to resist infection by a Puerto Rican strain of the parasite were analyzed using two laboratory stocks that differed in susceptibility, pigmentation, and five electrophoretically detectable enzyme markers. Segregation ratios in second-generation intraspecific hybrids between susceptible (M-stock) and resistant (10-R2-stock) snails indicate that the susceptibility gene is not linked to the enzyme (ACON-1, ACP, EST-2, PEP-2, PGD) or pigmentation loci studied. These seven loci assort independently of one another. Observed rates of infection among F1 and F2 progeny are consistent with Richards' finding that adult susceptibility to the PR-1 strain of S. mansoni is controlled by a single locus with resistance dominant. No association between allozymes of acid phosphatase and snail susceptibility to PR-1 was seen in the snail-parasite combinations studied.


Comparison of measures of insulin sensitivity in early-lactation dairy goats.
This experiment aimed to investigate the correlations between surrogate indices of insulin resistance (IR)-namely, the homeostasis model of IR, the quantitative insulin sensitivity check index, and the revised quantitative insulin sensitivity check index-and measures of IR obtained from an intravenous glucose tolerance test (IVGTT) performed in early-lactation dairy goats. Saanen goats (n = 26) with varying levels of milk production (1.7-4.8 kg/d) were selected and underwent an IVGTT on 43 ± 0.7 d postpartum (mean ± standard deviation). Data from the IVGTT were fitted in the minimal model to calculate parameters of glucose-insulin dynamics such as insulin sensitivity index and acute insulin response to glucose. Surrogate indices were computed using the average of the IVGTT basal samples. Correlation analysis revealed no relationship between surrogate indices of IR and measures of IR derived from the IVGTT (e.g., insulin sensitivity index, glucose clearance rate, glucose area under the curve). Therefore, our results suggest that surrogate indices of IR are not suitable for assessing the insulin sensitivity of peripheral tissue in early-lactation goats.


Effects of xylitol versus glucose on urea synthesis and alanine metabolism in rats.
The relation between xylitol concentration (1.0 and 5.5 mmol/1), the Capacity of Urea-N Synthesis, and the rate of Alanine Metabolism was investigated in nephrectomized rats of 200 g and compared with the effect of glucose at concentrations between 5.5 and 15.5 mmol/1. The xylitol and glucose concentrations were controlled by "clamp" techniques and the endogenous hormonal effects by somatostatin. The Capacity of Urea-N Synthesis was determined during alanine infusion to constant amino acid concentrations within the interval 7.3-11.6 mmol/1. The rate of alanine metabolism was assessed as alanine infusion rate corrected for changes in alanine concentration. At normal hormonal response, xylitol at 1.0 mmol/1 and 5.5 mmol/1 reduced urea synthesis from 10.3 +/- 1.1 mumol/(min.100 g) in controls to on average 6.2 +/- 0.9 mumol/(min.100 g) (mean +/- SD, n = 2 x 10, p < 1.01). Alanine metabolism was reduced to the same extent. Glucose concentration increased from 5.4 +/- 1.0 mmol/1 in controls to 8.1 +/- 1.4 mmol/1 at both xylitol concentrations. Xylitol reduced plasma glucagon concentration to one third and tripled plasma insulin concentration. During somatostatin and blood glucose maintained above 8 mmol/1, the Capacity of Urea-N Synthesis fell to 6.1 +/- 1.0 mumol/(min.100 g). In that situation, xylitol at 1.0 mmol/1 reduced neither urea synthesis nor alanine metabolism, whereas xylitol at 5.5 mmol/1 further reduced urea synthesis to 3.4 +/- mumol/(min.100 g) (n = 10, p < 0.05) and almost stopped alanine metabolism. Thus xylitol, independently of glucose and hormonal responses, inhibited urea synthesis and alanine metabolism. This may have therapeutic implications at catabolic conditions.


Heart rate and use of β-blockers in Mexican stable outpatients with coronary artery disease.
To evaluate the use of β-blockers and to monitor heart rate in Mexican patients with coronary artery disease. CLARIFY is an outpatients registry with stable CAD. A total of 33,283 patients from 45 countries were enrolled between November 2009 and July 2010 from which 1342 were Mexican patients. The mean HR pulse was 70 bpm (beats per minute). Patients in Mexico were compared with the remaining global CLARIFY population. Patients in Mexico had a higher incidence of acute myocardial infarction and percutaneous coronary intervention, and lower incidence of revascularization surgery compared with the remaining CLARIFY population. More often, Mexican patients presented with diabetes, but less often hypertension and stroke. These patients were split into three mutually exclusive groups of HR ≤ 60 (N=263), HR 61-69 (N=356) and HR ≥ 70 (N=722). Patients with elevated HR had a higher incidence of diabetes and higher diastolic blood pressure on average than those with controlled HR. Regarding the use of β-blockers, they were used in 63.3% of patients, 2.7% showed intolerance or contraindication to treatment to monitor heart rate, and ivabradine was used in 2.3%. Out of approximately 849 patients receiving treatment of β-blockers, 52.1% had ≥ 70 bpm HR. In a large proportion of Mexican patients with stable coronary disease the HR remain elevated, > 70 bpm, even with the use of β-blockers; this requires further attention.


Duplicate gene expression in diploid and tetraploid loaches (Cypriniformes, Cobitidae).
Botia macracantha and B. modesta have been demonstrated to be tetraploid species on the basis of their karyotypes and on the basis of the expression of a number of isozymes encoded by duplicate loci. A rather low percentage of duplicate loci was detected by electrophoresis, compared to that for other tetraploid Cypriniformes. Several hypotheses have been advanced to account for the low levels of duplicate gene expression observed. Lastly, many of the duplicate loci have diverged to unique patterns of expressions in different tissues or different levels of activity within a single tissue.


Production of carboxylic acids from hydrolyzed corn meal by immobilized cell fermentation in a fibrous-bed bioreactor.
Corn meal hydrolyzed with amylases was used as the carbon source for producing acetic, propionic, and butyric acids via anaerobic fermentations. In this study, corn meal, containing 75% (w/w) starch, 20% (w/w) fibers, and 1.5% (w/w) protein, was first hydrolyzed using amylases at 60 degrees C. The hydrolysis yielded approximately 100% recovery of starch converted to glucose and 17.9% recovery of protein. The resulting corn meal hydrolyzate was then used, after sterilization, for fermentation studies. A co-culture of Lactococcus lactis and Clostridium formicoaceticum was used to produce acetic acid from glucose. Propionibacterium acidipropionici was used for propionic acid fermentation, and Clostridium tyrobutylicum was used for butyric acid production. These cells were immobilized on a spirally wound fibrous matrix packed in a fibrous-bed bioreactor (FBB) developed for multi-phase biological reactions or fermentation. The bioreactor was connected to a stirred-tank fermentor that provided pH and temperature controls via medium circulation. The fermentation system was operated at the recycle batch mode. Temperature and pH were controlled at 37 degrees C and 7.6, respectively, for acetic acid fermentation, 32 degrees C and 6.0, respectively, for propionic acid fermentation, and 37 degrees C and 6.0, respectively, for butyric acid production. The fermentation demonstrated a yield of approximately 100% and a volumetric productivity of approximately 1 g/(1 h) for acetic acid production. The propionic acid fermentation achieved an approximately 60% yield and a productivity of 2.12 g/(1 h), whereas the butyric acid fermentation obtained an approximately 50% yield and a productivity of 6.78 g/(1 h). These results were comparable to, or better than those fermentations using chemically defined media containing glucose as the substrate, suggesting that these carboxylic acids can be efficiently produced from direct fermentation of corn meal hydrolyzate. The corn fiber present as suspended solids in the corn meal hydrolyzate did not cause operating problem to the immobilized cell bioreactor as is usually encountered by conventional immobilized cell bioreactor systems. It is concluded that the FBB technology is suitable for producing value-added biochemicals directly from agricultural residues or commodities such as corn meal.


Tear osmolarity and subjective dry eye symptoms in migraine sufferers.
Previous studies have suggested an association between dry eye and migraine. In a busy ophthalmologist clinic, quick identification of dry eye in migraine sufferers may improve their quality of life. Tear osmolarity is an objective and reliable tool for diagnosing dry eye. It has not been investigated in any population with migraine. Using tear osmolarity and questionnaires, we aimed to explore the relationship between dry eye and clinical symptoms in patients with migraine. Prospective cross-sectional study. Thirty-four adults with migraine sequentially recruited from a single neurologist's practice. Patients were assessed for subjective and objective signs of migraine and dry eye by using the Migraine Disability Assessment Score, the Ocular Surface Disease Index, and tear osmolarity (TearLab). Headache characteristics were compared by using χ2, Fisher's exact, and Mann-Whitney U tests. Osmolarity scores were compared with scores for headache features. Median age of patients was 38 years, and 76.5% were females. Severe migraine disability was reported in 75.6%, and 34.5% reported moderate to severe dry eye symptoms. Objectively, 49.5% had evidence of dry eye, significantly higher than the 20% recognized in the general population (p < 0.0001). Aura was found to occur more frequently with dry eye (43.8% vs 5.9%; p = 0.02). Those with daily headaches were also more likely to have higher tear osmolarity with marginal significance (median osmolarity 310 mOsm/L vs 299 mOsm/L; p = 0.08). Patients with migraine, especially those with aura, appear more likely to have dry eye, as indicated by tear osmolarity. Tear osmolarity may also be greater in those who suffer from daily headaches.


Isolation of an Arabidopsis thaliana cDNA by complementation of a yeast abc1 deletion mutant deficient in complex III respiratory activity.
The yeast Abc1 protein acts as a chaperone-like protein essential for the proper conformation and efficient functioning of the respiratory complex III. By functional complementation of a yeast abc1 mutant, we have identified an Arabidopsis thaliana cDNA that corresponds to a single copy gene and encodes a protein sharing 45% similarity with the yeast Abc1p protein. Cytochrome spectra and respiratory activity measurements have shown that the plant protein allows a partial restoration of the complex III activity. No major difference in the steady-state level of ABC1At mRNA was observed in various plant tissues, suggesting that ABC1At is constitutively expressed in A. thaliana. Phylogenetic analysis revealed that the Abc1At protein belongs to a large family of proteins composed of two eukaryotic and one prokaryotic subgroups differing by their degree of similarity and probably by their function.


Staged procedure to prevent major adverse events in extensive aortic aneurysm repair.
Surgical management of extensive thoracoabdominal aortic aneurysms is associated with high rates of mortality and morbidity, including spinal cord ischemia. We report a successful three-stage repair combining open and endovascular surgery in a patient presenting with an ascending, arch, and thoracoabdominal aneurysm. Spinal cord protective measures included a staged approach, preserved antegrade flow to the left subclavian and hypogastric arteries, absence of aortic cross-clamping, and aggressive perioperative hemodynamic monitoring.


Circulating free DNA integrity index and promoter methylation of tumor suppressor gene P16, DAPK and RASSF1A as a biomarker for oropharyngeal squamous cell carcinoma.
Circulating free DNA (cfDNA) is in use for the non-invasive diagnosis of tumors. Methylation of tumor suppressor genes (TSGs) is an early event in carcinogenesis and may serve as tumor biomarker. We have investigated cfDNA integrity and methylation of tumor suppressor genes P16, DAPK and RASSF1A in serum cfDNA of oropharyngeal squamous cell carcinoma (OPSCC) comparing paired serum and tumor tissue samples to evaluate their diagnostic use. Prospective case-control study, paired serum and tissue samples from 56 OPSCC, and 15 normal controls (NC). Sybr green Quantitate real time PCR was used for cfDNA quantification through amplification ALU 115 and 247 fragments. Promoter methylation of was analyzed in paired samples using methylation specific PCR. There was significantly high cfDNA integrity in OPSCC compared to normal control (p = < 0.0001). The cfDNA integrity values were significantly higher and associated with nodal status (p = 0.016). The AUC for cfDNA integrity was 0.967. The P16, DAPK and RASSF1 promoters were significantly hypermethylated in serum of OPSCC compared to NC with high concordance in tissue (up to 96.55 %). The gene promoter methylation of P16 was associated with smoking (p = 0.030), RASSF1A with stage (p = 0.011). The combination of ALU115 with cfDNA integrity and combination of gene methylation increases diagnostic sensitivity. In followup samples the cfDNA change was not different. Liquid biopsy approach including cfDNA integrity, methylation profiling in cfDNA, in combination or separately can assist in the diagnosis of OPSCC along with radio diagnostic scan. Serum changes represent changes in tissue with very high concordance.


Strength Development and Hydration Behavior of Self-Activation of Commercial Ground Granulated Blast-Furnace Slag Mixed with Purified Water.
In this study, ground granulated blast-furnace slag (GGBFS) samples from Singapore, Korea, and the United Arab Emirates were hydrated with purified water to estimate the cementing capabilities without activators. Raw GGBFS samples and hardened pastes were characterized to provide rational explanations for the strengths and hydration products. The slag characteristics that influenced the best strength of raw GGBFS were identified. Although it is widely recognized that GGBFS alone generally shows little cementing capability when hydrated with water, the GGBFSs examined in this study demonstrated various strength developments and hydration behaviors; one of the GGBFS samples even produced a high strength comparable to that of alkali- or Ca(OH)₂-activated GGBFS. In particular, as the GGBFS exhibited a greater number of favorable slag characteristics for hydraulic reactivity, it produced more C-S-H and ettringite. The results demonstrated a reasonable potential for commercial GGBFS with calcium sulfates to function as an independent cementitious binder without activators.


An N-halamine-based rechargeable antimicrobial and biofilm controlling polyurethane.
An N-halamine precursor, 5,5-dimethylhydantoin (DMH), was covalently linked to the surface of polyurethane (PU) with 1,6-hexamethylene diisocyanate (HDI) as the coupling agent. The reaction pathways were investigated using propyl isocyanate (PI) as a model compound. The results suggested that the imide and amide groups of DMH have very similar reactivities toward the isocyanate groups on PU surfaces activated with HDI. After bleach treatment the covalently bound DMH moieties were transformed into N-halamines. The new N-halamine-based PU provided potent antimicrobial effects against Staphylococcus aureus (Gram-positive bacterium), Escherichia coli (Gram-negative bacterium), methicillin-resistant Staphylococcus aureus (MRSA, drug-resistant Gram-positive bacterium), vancomycin-resistant Enterococcus faecium (VRE, drug-resistant Gram-positive bacterium), and Candida albicans (fungus), and successfully prevented bacterial and fungal biofilm formation. The antimicrobial and biofilm controlling effects were stable for longer than 6 months under normal storage in open air. Furthermore, if the functions were lost due to prolonged use they could be recharged by another chlorination treatment. The recharging could be repeated as needed to achieve long-term protection against microbial contamination and biofilm formation.


[Usefulness of long-term endoscopic follow-up of gastric ulcer. Study of related epithelial dysplasia].
Over the period from January 1980 to March 1988 the frequency of dysplastic abnormalities associated wits 202 apparently benign gastric ulcers was determined and their course monitored. The relevant data were then evaluated separately for the various subgroups the ulcers were divided into on the basis of their natural history. No correlation was detected between natural history of gastric ulcer, dysplasia and onset of cancer. Though all dysplastic forms (mild, moderate and severe) may regress, all three showed a possibility of progression to EGC, obviously in increasing percentages: mild dysplasia: 2.53%; moderate dysplasia: 4.76%; severe dysplasia: 14.29%. The last of these three values appears to indicate a greater risk of cancer onset than in simple gastric ulcer and thus proves a useful marker for a more thorough monitoring of such patients.


Aging, Spatial Disparity, and the Sound-Induced Flash Illusion.
The present study examined age-related differences in multisensory integration and the effect of spatial disparity on the sound-induced flash illusion--an illusion used in previous research to assess age-related differences in multisensory integration. Prior to participation in the study, both younger and older participants demonstrated their ability to detect 1-2 visual flashes and 1-2 auditory beep presented unimodally. After passing the pre-test, participants were then presented 1-2 flashes paired with 0-2 beeps that originated from one of five speakers positioned equidistantly 100 cm from the participant. One speaker was positioned directly below the screen, two speakers were positioned 50 cm to the left and right from the center of the screen, and two more speakers positioned to the left and right 100 cm from the center of the screen. Participants were told to report the number of flashes presented and to ignore the beeps. Both age groups showed a significant effect of the beeps on the perceived number of flashes. However, neither younger nor older individuals showed any significant effect of spatial disparity on the sound-induced flash illusion. The presence of a congruent number of beeps increased accuracy for both older and younger individuals. Reaction time data was also analyzed. As expected, older individuals showed significantly longer reaction times when compared to younger individuals. In addition, both older and younger individuals showed a significant increase in reaction time for fusion trials, where two flashes and one beep are perceived as a single flash, as compared to congruent single flash trials. This increase in reaction time was not found for fission trials, where one flash and two beeps were perceived as two flashes. This suggests that processing may differ for the two forms for fission as compared to fusion illusions.


Apoptosis and antiphospholipid antibodies.
To analyze the potential links between antiphospholipid antibodies (aPL) and apoptosis in the pathogenesis of the antiphospholipid antibody syndrome (APS). A review was undertaken of the most relevant scientific literature on apoptosis and autoimmune phenomena. Experimental and human pathology were reviewed to substantiate the hypothesis that apoptosis is involved in the generation of aPL. Several considerations suggest that exposure of phospholipids (PL) during apoptosis may be a driving antigenic stimulus to the production of aPL. Furthermore, the molecular PL-protein complexes formed during apoptosis are targeted by "pathogenic" aPL. The binding and the clearance of apoptotic cells by these autoantibodies likely further enhances the aPL immune response. Experimental models and human pathology suggest that a restricted genetic background is key to the development of this immune response. Abnormalities of apoptosis observed in the course of autoimmune conditions likely provide an antigenic stimulus to the production of aPL.


Site-directed mutations in the third intracellular loop of the serotonin 5-HT(1A) receptor alter G protein coupling from G(i) to G(s) in a ligand-dependent manner.
The effect of mutations (V344E and T343A/V344E) in the third intracellular loop of the serotonin 5-HT(1A) receptor expressed transiently in human embryonic kidney 293 cells have been examined in terms of receptor/G protein interaction and signaling. Serotonin, (R)-8-hydroxy-2-dipropylaminotetralin [(R)-8-OH-DPAT], and buspirone inhibited cyclic AMP production in cells expressing native and mutant 5-HT(1A) receptors. Serotonin, however, produced inverse bell-shaped cyclic AMP concentration-response curves at native and mutant 5-HT(1A) receptors, indicating coupling not only to G(i)/G(o), but also to G(s). (R)-8-OH-DPAT, however, induced stimulation of cyclic AMP production only after inactivation of G(i)/G(o) proteins by pertussis toxin and only at the mutant receptors. The partial agonist buspirone was unable to induce coupling to G(s) at any of the receptors, even after pertussis toxin treatment. The basal activities of native and mutant 5-HT(1A) receptors in suppressing cyclic AMP levels were not found to be significantly different. The receptor binding characteristics of the native and mutant receptors were investigated using the novel 5-HT(1A) receptor antagonist [(3)H]NAD-299. For other receptors, analogous mutations have produced constitutive activation. This does not occur for the 5-HT(1A) receptor, and for this receptor the mutations seem to alter receptor/G protein coupling, allowing ligand-dependent coupling of receptor to G(s) in addition to G(i)/G(o) proteins.


Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126.
Emerging data suggest that exosomal microRNA (miRNA) may provide potential biomarkers in acute ischemic stroke. However, the effects of ischemia-reperfusion on total versus exosomal miRNA responses in circulating blood remain to be fully defined. Here, we quantified levels of miR-126 in whole serum versus exosomes extracted from serum and compared these temporal profiles against reperfusion and outcomes in a rat model of acute focal cerebral ischemia. First, in vitro experiments confirmed the vascular origin and changes in miR-126 in brain endothelial cultures subjected to oxygen-glucose deprivation. Then in vivo experiments were performed by inducing permanent or transient focal cerebral ischemia in rats, and total serum and exosomal miR-126 levels were quantified, along with measurements of infarction and neurological outcomes. Exosomal levels of miR-126 showed a transient reduction at 3 h post-ischemia that appeared to normalize back close to pre-ischemic baselines after 24 h. There were no detectable differences in exosomal miR-126 responses in permanent or transient ischemia. Serum miR-126 levels appeared to differ in permanent versus transient ischemia. Significant reductions in serum miR-126 were detected at 3 h after permanent ischemia but not transient ischemia. By 24 h, serum miR-126 levels were back close to baseline in both permanent and transient ischemia. Overall, there were no correlations between serum miR-126 and exosomal miR-126. This proof-of-concept study suggests that changes in serum miR-126 may be able to distinguish severe permanent ischemia from milder injury after transient ischemia.


A case of Schwartz-Jampel syndrome with unusual muscle biopsy findings.
A case of Schwartz-Jampel syndrome with electrical, radiographic, biopsy, and pharmacological studies is presented along with a summary of the 12 other reported cases. Radiological study showed nonspecific but definite abnormalities. The muscle biopsy revealed myopathic and neurogenic features. No drug was effective in reducing our patient's stiffness.


The molecular characterization and associations of porcine cardiomyopathy asssociated 5 (CMYA5) gene with carcass trait and meat quality.
The cardiomyopathy associated 5 (CMYA5) gene was also called TRIM76, which was belonged to the tripartite motif super family of proteins (TRIM). It was a direct transcriptional target for MEF2A and it played an important role in myofibrillogenesis. In the present study, a 12056 bp cDNA sequence of the porcine CMYA5 gene was obtained by RT-PCR. The sequence encoded a large protein consisting of 4003 amino acids and the carboxyl terminus of the predicted CMYA5 protein comprised of a B-box coiled-coil, two fibronectin type III (FN3) repeats, and SPRY domains. The porcine CMYA5 gene was assigned to chromosome 2q21-24 by using the radiation hybrid (IMpRH) panel, and it was significantly linked to microsatellite Sw1602 with LOD scores of 6.74. Semi-quantitative RT-PCR revealed that the porcine CMYA5 gene was broadly expressed in all seven tissues(heart, liver, spleen, lung, kidney, skeletal muscle and adipose)harvested from different developmental stages(new born, five weeks and adult tongcheng pigs), with a high level in heart and skeletal muscle. One SNP (A7189C), leading to the amino acid alteration from the Ile residue to the Leu residue, was found and detected by BspTI PCR-restriction fragment length polymorphism. The association analysis revealed that the substitution of A7189C had significant associations with the percentage of ham (p < 0.05), water loss (p < 0.01) and intramuscular fat (p < 0.05). These results provide the evidence that the porcine CMYA5 gene can act as a potential candidate gene affecting pig meat quality.


Clinical Outcomes Associated with Co-infection of Carbapenem-Resistant Enterobacterales and other Multidrug-Resistant Organisms.
Infections with carbapenem-resistant Enterobacterales (CRE) are associated with increased risk of death. Polymicrobial infections with antimicrobial-resistance may add to the burden of clinical care and patients' clinical prognosis. To examine the impact of CRE co-infection with other multi-drug resistant organisms (MDRO) on patient clinical outcomes. A retrospective observational study was conducted to compare the clinical outcomes of CRE patients who were co-infected with carbapenem-resistant Pseudomonas aeruginosa (CRPA), multidrug-resistant Acinetobacter baumannii (MDRA) and Methicillin-resistant Staphylococcus aureus (MRSA). A total of 224 CRPA and 209 MDRA co-infections with CRE were identified from 4,236 cases from 2015-2020. The overall 90-day all-cause mortality was 21.6% but increased to 35.0% and 33.5% among patients who were co-infected with CRPA and MDRA, respectively. The odds of all-cause mortality among CRE patients who were co-infected with CRPA was twice that of patients identified with CRE alone [adjusted odds ratio (AOR) = 2.02, 95% confidence interval (CI): 1.18-3.46]. Further, the odds of all-cause mortality among CRE patients who were concomitantly identified with MRSA was more than twice that of patients who were not identified with MRSA [AOR = 2.16, 95%CI:1.31-3.56]. The clinical outcome of patients with CRE did not differ significantly depending on the presence of carbapenemase genes. The results show that CRPA and CRE co-infections have synergistic effects on clinical outcomes. Further investigation is necessary to understand the mechanism. Screening high risk patients for concomitant antimicrobial-resistant infections may have a significant clinical impact, including effective therapies, antibiotic stewardship, and infection control policies.


GN-SCCA: GraphNet based Sparse Canonical Correlation Analysis for Brain Imaging Genetics.
Identifying associations between genetic variants and neuroimaging quantitative traits (QTs) is a popular research topic in brain imaging genetics. Sparse canonical correlation analysis (SCCA) has been widely used to reveal complex multi-SNP-multi-QT associations. Several SCCA methods explicitly incorporate prior knowledge into the model and intend to uncover the hidden structure informed by the prior knowledge. We propose a novel structured SCCA method using Graph constrained Elastic-Net (GraphNet) regularizer to not only discover important associations, but also induce smoothness between coefficients that are adjacent in the graph. In addition, the proposed method incorporates the covariance structure information usually ignored by most SCCA methods. Experiments on simulated and real imaging genetic data show that, the proposed method not only outperforms a widely used SCCA method but also yields an easy-to-interpret biological findings.


Monoclonal antibody Cat-301 selectively identifies a subset of nuclei in the cat's somatosensory thalamus.
Recently it has been demonstrated that the monoclonal antibody Cat-301 is capable of identifying functionally related neurons in the mammalian visual thalamus. We have examined the possibility that this antibody might display a similar capacity in nonvisual thalamic areas. We demonstrate that in the cat's somatosensory thalamus the distribution of Cat-301-positive cells and neuropil is restricted to a subset of nuclei. These include the ventroposterior medial, ventroposterior lateral, and ventroposterior inferior nuclei. Staining with Cat-301 provides a clear visualisation of the entire somatotopic map within these nuclei. The somatosensory sector of the thalamic reticular nucleus and the perireticular nucleus, which may have a somatosensory sector, are also Cat-301-positive. In contrast, cells that do not express the Cat-301 antigen are located in the ventroposterior oralis nucleus, the ventroposterior shell region, the medial and lateral divisions of the posterior nuclear group, and the inner small cell region adjacent to the thalamic reticular nucleus. In comparison with previous physiological studies, cells that express the Cat-301 antigen most likely represent subpopulations in only a few of the somatic submodality-specific groups. These include cells in the small-field and Pacinian cutaneous-responsive groups, excluding cells in the wide-field cutaneous-, muscle-, joint-, and noxious-responsive groups. Taken together these findings indicate that monoclonal antibody Cat-301 is capable of selectively identifying neurons with distinct functional properties in the mammalian somatosensory thalamus.


Recurrent epistaxis, chronic pancytopenia and nasal mycosis.
A 52-year-old man with chronic, profound pancytopenia associated with a four-year history of Waldenstrom's macroglobulinemia refractory to chemotherapy began to experience major epistaxes requiring hospital admission for control. A diagnosis of invasive Aspergillus was made on nasal mucosal biopsy. A regimen of bi-weekly intravenous and sixth-hourly topical amphotericin B drops with adjuvant rifampicin successfully eradicated local nasal pain as well as the epistaxis. Resolution of infection was documented by gallium scan. It is suggested that, in addition to the aggressive craniofacial mycoses already described, lower grade nasal mycoses occur. The roles of biopsy and gallium scan in immunocompromised hosts with epistaxis are discussed.


A new clerodane furano diterpene glycoside from Tinospora cordifolia triggers autophagy and apoptosis in HCT-116 colon cancer cells.
Tinospora cordifolia is a miraculous ayurvedic herb used in the treatment of innumerable diseases such as diabetes, gonorrhea, secondary syphilis, anaemia, rheumatoid arthritis, dermatological diseases, cancer, gout, jaundice, asthma, leprosy, in the treatment of bone fractures, liver & intestinal disorders, purifies the blood, gives new life to the whole body; (rejuvenating herb) and many more. Recent studies have revealed the anticancer potential of this plant but not much work has been done on the anticancer chemical constituents actually responsible for its amazing anticancer effects. This prompted us to investigate this plant further for new potent anticancer molecules. The present study was designed to isolate and identify new promising anticancer candidates from the aqueous alcoholic extract of T. cordifolia using bioassay-guided fractionation. The structures of the isolated compounds were determined on the basis of spectroscopic data interpretation and that of new potent anticancer molecule, TC-2 was confirmed by a single-crystal X-ray crystallographic analysis of its corresponding acetate. The in vitro anti-cancer activity of TC-2 was evaluated by SRB assay and the autophagic activity was investigated by immunofluorescence microscopy. Annexin-V FITC and PI dual staining was applied for the detection of apoptosis. The studies on Mitochondrial Membrane potential and ROS (Reactive oxygen species) production were also done. Bioassay guided fractionation and purification of the aqueous alcoholic stem extract of Tinospora cordifolia led to the isolation of a new clerodane furano diterpene glycoside (TC-2) along with five known compounds i.e. cordifolioside A (β-D-Glucopyranoside,4-(3-hydroxy-1-propenyl)- 2,6-dimethoxyphenyl 3-O-D-apio-β-D-furanosyl) (TC-1), β-Sitosterol(TC-3), 2β,3β:15,16-Diepoxy- 4α, 6β-dihydroxy-13(16),14-clerodadiene-17,12:18,1-diolide (TC-4), ecdysterone(TC-5) and tinosporoside(TC-6). TC-2 emerged as a potential candidate for the treatment of colon cancer. The overall study on the bioassay guided isolation of T.cordifolia identified and isolated a new clerodane furano diterpenoid that exhibited anticancer activity via induction of mitochondria mediated apoptosis and autophagy in HCT116 cells. We have reported a promising future candidate for treating colon cancer.


Human liver alpha-L-fucosidase. Purification, characterization, and immunochemical studies.
Human liver alpha-L-fucosidase has been purified 6300-fold to apparent homogeneity with 66% yield by a two-step affinity chromatographic procedure utilizing agarose epsilon-aminocaproyl-fucosamine. Isoelectric focusing revealed that all six isoelectric forms of the enzyme were purified. Polyacrylamide gel electrophoresis of the purified alpha-L-fucosidase demonstrated the presence of six bands of protein which all contained fucosidase activity. The purified enzyme preparation was found to contain only trace amounts of seven glycosidases. Quantitative amino acid analysis was performed on the purified fucosidase. Preliminary carbohydrate analysis indicated that only about 1% of the molecule is carbohydrate. Gel filtration on Sepharose 4B indicated an approximate molecular weight for alpha-L-fucosidase of 175,000 +/- 18,000. High speed sedimentation equilibrium yielded a molecular weight of 230,000 +/- 10,000. Sodium dodecyl sulfate polyacrylamide gels indicated the presence of a single subunit of molecular weight, 50,100 +/- 2,500. The enzyme had a pH optimum of 4.6 with a suggested second optimum of 6.5. Apparent Michaelis constants and maximal velocities were determined on the purified enzyme with respect to the 4-methylumbelliferyl and the p-nitrophenyl substrates and were found to be 0.22 mM and 14.1 mumol/mg of protein/min and 0.43 mM and 19.6 mumol/mg of protein/min, respectively. Several salts had little or no effect on fucosidase activity although Ag+ and Hg2+ completely inactivated the enzyme. Antibodies made against the purified fucosidase were dound to be monospecific against crude human liver supernatant fluids and the pure antigen. No cross-reacting material was detected in the crude liver supernatant fluid from a patient who died with fucosidosis.


RETINAL INFILTRATION IN A CASE OF CHRONIC MYELOID LEUKEMIA.
To describe a case of chronic myeloid leukemia with retinal leukemic infiltration identified by optical coherence tomography (OCT) and OCT angiography. Case report. A 64-year-old man presented with bilateral painless blurred vision and three weeks of fatigue, unintentional weight loss, and complete hearing loss. Dilated fundus examination of both eyes showed peripheral intraretinal hemorrhages with white centers, vascular tortuosity, and peripheral nonperfusion. No macular lesions were identified by slit-lamp examination, fundus photography, fundus autofluorescence, or fluorescein angiography. Optical coherence tomography through the macula revealed multiple hyperreflective lesions throughout the inner retinal layers. Some of these lesions showed intrinsic flow by OCT angiography, but many lesions did not. The bone marrow biopsy confirmed chronic myeloid leukemia, and these intraretinal lesions were deemed to be leukemic infiltrates. The patient regained vision after systemic chemotherapy with resolution of the retinal infiltrates over time. Primary leukemic retinal involvement can be challenging to diagnose, especially when the macula appears normal clinically. Optical coherence tomography and OCT angiography are useful imaging modalities for the detection of retinal leukemic infiltration. Completing a thorough review of systems and initiating an urgent, systemic work-up are warranted in cases of retinal infiltration.