Prognostic value of hyperthermic intraperitoneal chemotherapy in gastric cancer with synchronous peritoneal metastases: a real-world retrospective study.
Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.


The nucleotide sequence of the cloned rpoD gene for the RNA polymerase sigma subunit from E coli K12.
We have determined the nucleotide sequence of the rpoD gene which codes for the sigma subunit of RNA polymerase from E. coli K12. The gene, which we formerly cloned as a HindIII restriction fragment in the transducing phage, charon 25, was recloned into several plasmids. We have determined a 2600 base pair DNA sequence which includes the entire structural gene for sigma. The resulting amino acid sequence agrees with previous information obtained about sigma including the amino acid composition, partial sequence data for the N-terminus, the highly acidic nature of the polypeptide, and the cleavage pattern at cysteines. The molecular weight of 70,263 daltons calculated for the 613 amino acid polypeptides is significantly lower than had been determined previously by SDS polyacrylamide gel analysis.


A task-based analytical framework for ultrasonic beamformer comparison.
A task-based approach is employed to develop an analytical framework for ultrasound beamformer design and evaluation. In this approach, a Bayesian ideal-observer provides an idealized starting point and a way to measure information loss in practical beamformer designs. Different approximations of this ideal strategy are shown to lead to popular beamformers in the literature, including the matched filter, minimum variance (MV), and Wiener filter (WF) beamformers. Analysis of the approximations indicates that the WF beamformer should outperform the MV approach, especially in low echo signal-to-noise conditions. The beamformers are applied to five typical tasks from the BIRADS lexicon. Their performance is evaluated based on ability to discriminate idealized malignant and benign features. The numerical results show the advantages of the WF over the MV technique in general; although performance varies predictably in some contrast-limited tasks because of the model modifications required for the MV algorithm to avoid ill-conditioning.


Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors.
Testicular germ cell tumors (TGCTs) are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting. Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. However, a significant percentage of patients are, or become, refractory to cisplatin and die from progressive disease. Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting. Recently, this promise has been heightened by the realization that distinct (and perhaps pharmacologically replicable) epigenetic states, rather than fixed genetic alterations, may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies. In this review, it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.


[Quality of bacillus identification tests in the Federal District (Brazil)--a reliability testing].
In Brazil, one of the priorities in the fight against the tuberculosis is the evaluation of laboratories' performance through the quality control of baciloscopic tests. This study was meant to evaluate the reliability of the tests carried out by the Tuberculosis Control Program of the Federal District, Brazil. It is a descriptive study, made out of revised glass slides at the reference laboratory, from 1988 up to 1999. A double-blind comparison of the results of the smear readings obtained in the outskirts and central laboratories was made. The concordances/discrepancies were analyzed through Kappa and the Confidence Interval (CI). From a total of 62,487 glass slides, we evaluated 7,756 baciloscopic tests. The discrepancy results represented 1.9% of false-positive and 0.8% of false-negative. Until 1997, 66.5% of the positive baciloscopic tests had been revised, but when the quality control was implemented the results grew up to 90.1%. The Kappa obtained a very good reliability but didn't match with the CI results. The quality control will increase the reliability of the tuberculosis diagnose although the evaluation depends on the use of sensitive reproducing tests.


Effects of verapamil on myocardial performance in coronary disease.
Verapamil, a calcium antagonist, has been used extensively for treatment of cardiac arrhythmias. Concern persists, however, that it may seriously depress myocardial function in cardiac patients. To investigate this possibility, 20 patients with coronary artery disease (CAD) but no heart failure were given intravenous verapamil (0.1 mg/kg bolus, followed by 0.005 mg/kg/min infusion), and studied hemodynamically and angiographically. Verapamil markedly lowered mean aortic pressure (94 +/- 17 to 82 +/- 13 mm Hg, p less than 0.0005) and systemic vascular resistance (1413 +/- 429 to 1069 +/- 235 dyn-sec-cm5, p less than 0.0005). Simultaneously, all indices of left ventricular (LV) performance greatly improved: cardiac index rose from 2.8 +/- 0.6 to 3.1 +/- 0.7 1/min/m2 (p less than 0.0005), mean velocity of circumferential fiber shortening increased from 0.85 +/- 0.39 to 0.97 +/- 0.46 circ/sec (p less than 0.01), and ejection fraction improved from 55 +/- 16 to 61 +/- 18% (p less than 0.01). No significant changes were noted in the heart rate before and after verapamil administration, and verapamil did not worsen the extent of LV asynergy in the majority of patients. In patients with CAD, the intrinsic negative inotropic effect of verapamil is of negligible importance because its potent vasodilatory properties more than compensate for any intrinsic decrease in LV contractility, and thereby improve the overall cardiac function.


Preclinical evaluation of a liposome-encapsulated formulation of cisplatin in clinically normal dogs.
To determine the acute and short-term adverse effects of a liposome-encapsulated form of cisplatin at increasing dosages of up to twice the known maximally tolerated dose (MTD) of unencapsulated cisplatin in clinically normal dogs. 4 healthy 2.5-year-old sexually intact female hound-type dogs. 4 dosages (70, 100, 125, and 150 mg/m2) were evaluated, and the 4 dogs received a total of 9 infusions (1 to 3 infusions/dog). Dogs were monitored to detect changes in clinical and clinicopathologic status. Evaluations consisting of a physical examination, CBC, serum biochemical analysis, and urinalysis were performed before and 7 and 21 days after each infusion. Acute anaphylactic-like reactions to liposome-encapsulated cisplatin were common but clinically manageable. Nephrotoxicosis and substantial myelosuppression, toxic effects commonly associated with unencapsulated cisplatin, were not observed in dogs treated with liposome-encapsulated cisplatin at dosages equivalent to twice the known MTD of unencapsulated cisplatin. Liposome-encapsulated cisplatin can be safely administered to clinically normal dogs at dosages of up to 150 mg/m2 without the need for concurrent hydration protocols. This was a necessary prerequisite to enable phase I clinical trials in dogs with naturally developing cancers that could theoretically benefit from escalation in the dosage of cisplatin. Determination of an MTD, cumulative and long-term toxic effects, and efficacy can now be conducted in the context of phase I trials in tumor-bearing dogs.


PEGylation promotes hemoglobin tetramer dissociation.
Hemoglobin conjugated with poly(ethylene glycol) (PEG) acts as an oxygen carrier free in plasma, substituting red blood cells in supplementing oxygen in hypo-oxygenation pathologies. Given the complexity of oxygen delivery controls, subtle structural and functional differences in PEGylated hemoglobins might be associated with distinct physiological responses and, potentially, adverse effects. We have compared hemoglobin PEGylated under anaerobic conditions, called PEG-Hb(deoxy), with hemoglobin PEGylated under aerobic conditions, called PEG-Hb(oxy), a product that mimics Hemospan, produced by Sangart, Inc. SDS PAGE and MALDI-TOF analyses demonstrated that PEG conjugation yields products characterized by a broad distribution of PEG/hemoglobin ratios. The elution profiles in size-exclusion chromatography indicate that both products exhibit a more homogeneous distribution of molecular weight/hydrodynamic volume under deoxy conditions and at higher concentrations. PEG-Hb(oxy) shows high oxygen affinity, low modulation of allosteric effectors, almost no cooperativity, a fast and monophasic CO binding, and a limited dependence of functional properties on concentration, whereas PEG-Hb(deoxy) exhibits oxygen binding curves that significantly depend on protein concentration, and a slow CO binding, similar to native hemoglobin. PEGylated CO-hemoglobins, probed by flash photolysis, exhibited a lower amplitude for the geminate rebinding phase with respect to native hemoglobin and a negligible T state bimolecular CO rebinding phase. These findings are explained by an increased dissociation of PEGylated hemoglobins into dimers and perturbed T and R states with decreased quaternary transition rates. These features are more pronounced for PEG-Hb(oxy) than PEG-Hb(deoxy). The detected heterogeneity might be a source of adverse effects when PEGylated Hbs are used as blood substitutes.


In vivo photoacoustics and high frequency ultrasound imaging of mechanical high intensity focused ultrasound (HIFU) ablation.
The thermal effect of high intensity focused ultrasound (HIFU) has been clinically exploited over a decade, while the mechanical HIFU is still largely confined to laboratory investigations. This is in part due to the lack of adequate imaging techniques to better understand the in-vivo pathological and immunological effects caused by the mechanical treatment. In this work, we explore the use of high frequency ultrasound (US) and photoacoustics (PA) as a potential tool to evaluate the effect of mechanical ablation in-vivo, e.g. boiling histotripsy. Two mice bearing a neuroblastoma tumor in the right leg were ablated using an MRI-HIFU system conceived for small animals and monitored using MRI thermometry. High frequency US and PA imaging were performed before and after the HIFU treatment. Afterwards, the tumor was resected for further assessment and evaluation of the ablated region using histopathology. High frequency US imaging revealed the presence of liquefied regions in the treated area together with fragmentized tissue which appeared with different reflecting proprieties compared to the surrounding tissue. Photoacoustic imaging on the other hand revealed the presence of deoxygenated blood within the tumor after the ablation due to the destruction of blood vessel network while color Doppler imaging confirmed the blood vessel network destruction within the tumor. The treated area and the presence of red blood cells detected by photoacoustics were further confirmed by the histopathology. This feasibility study demonstrates the potential of high frequency US and PA approach for assessing in-vivo the effect of mechanical HIFU tumor ablation.


Limonene production in tobacco with Perilla limonene synthase cDNA.
Limonene synthase (LS) catalyses the stereo-specific cyclization of geranyl diphosphate (GPP) to form a monocyclic monoterpene, limonene. In an attempt to engineer monoterpene biosynthesis, three expression constructs of LS cDNA of Perilla frutescens, which were designed to be localized in either the plastid, the cytosol or the endoplasmic reticulum (ER), were introduced into tobacco in order to examine differences in enzyme activity and the productivity of limonene. High and moderate enzyme activity, respectively, was observed for plastid- and cytosol-localized LS, whereas no enzyme activity was seen for ER-localized LS, suggesting that the plastid is the preferred compartment for LS, while LS may also have an active form in the cytosol. The formation of limonene in vivo was confirmed by gas chromatography-mass spectrometry (GC-MS) in leaf extracts of both plastid- and cytosol-localized LS transgenic plants. The amount of limonene in plastid-localized LS transgenic plants was 143 ng g-1 fresh wt, whereas that in the cytosol-type was 40 ng g-1 fresh wt, and these limonene contents increased by 2.7-fold and 3.0-fold, respectively, with the addition of methyl jasmonate. The headspace analyses showed that the plastid- and the cytosol-localized LS transgenic plants (12 cm high) emitted 390 ng and 515 ng limonene per month, respectively. The possibility of genetically engineering monoterpene production is discussed.


The severity of addiction mediates loneliness and cortical volume in internet gaming disorder.
Internet gaming disorder (IGD) subjects reported higher loneliness scores than healthy controls. However, the neural correlates underlying the association between loneliness and IGD remain unclear. Thus, the aim of this study was to explore the relationship between loneliness, online gaming addiction and brain structure. In the current study, structural MRI data were acquired from 84 IGD subjects and 103 matched recreational game users (RGUs). We assessed and compared their addiction severity, loneliness scores, and cortical volumes and analyzed the correlations among these values. Significant correlations were found between loneliness scores and brain volumes in the postcentral cortex, the medial orbitofrontal cortex, the rostral anterior cingulate cortex, and the temporal cortex. In addition, the addiction severity scores partly mediated the relationship between loneliness score and cortical volume in IGD. The results showed that participants with extreme loneliness had significant correlations with brain regions responsible for executive control, social threat surveillance and avoidance. More importantly, the severity of addiction mediates loneliness and cortical volume. The findings shed new insight into the neural mechanisms of loneliness and IGD and have implications for potential treatment.


The NMR structures of the major intermediates of the two-domain tick carboxypeptidase inhibitor reveal symmetry in its folding and unfolding pathways.
There is a lack of experimental structural information about folding intermediates of multidomain proteins. Tick carboxypeptidase inhibitor (TCI) is a small, disulfide-rich protein consisting of two domains that fold and unfold autonomously through the formation of two major intermediates, IIIa and IIIb. Each intermediate contains three native disulfide bonds in one domain and six free cysteines in the other domain. Here we have determined the NMR structures of these two intermediates trapped and isolated at acidic pH in which they are stable and compared their structures with that of the native protein analyzed under the same conditions. Both IIIa and IIIb were found to contain a folded region that corresponds to the N- and C-terminal domains of TCI, respectively, with structures very similar to the corresponding regions of the native protein. The remainder of the polypeptide chains of the intermediates was shown to be unfolded in a random coil conformation. Solvent exchange measurements further indicated that the two protein domains are not completely independent, but affect each other in terms of dynamics and stability, in agreement with reported inhibitory activity data. The derived results provide structural evidence for symmetric TCI folding and unfolding mechanisms that converge in IIIa and IIIb and reveal the structural basis that accounts for the strong and simultaneous accumulation of both intermediates. Altogether, this work has important implications for a better understanding of the folding mechanisms of multidomain, disulfide-rich proteins.


Redefining the expression and function of the inhibitor of differentiation 1 in mammary gland development.
The accumulation of poorly differentiated cells is a hallmark of breast neoplasia and progression. Thus an understanding of the factors controlling mammary differentiation is critical to a proper understanding of breast tumourigenesis. The Inhibitor of Differentiation 1 (Id1) protein has well documented roles in the control of mammary epithelial differentiation and proliferation in vitro and breast cancer progression in vivo. However, it has not been determined whether Id1 expression is sufficient for the inhibition of mammary epithelial differentiation or the promotion of neoplastic transformation in vivo. We now show that Id1 is not commonly expressed by the luminal mammary epithelia, as previously reported. Generation and analysis of a transgenic mouse model of Id1 overexpression in the mammary gland reveals that Id1 is insufficient for neoplastic progression in virgin animals or to prevent terminal differentiation of the luminal epithelia during pregnancy and lactation. Together, these data demonstrate that there is no luminal cell-autonomous role for Id1 in mammary epithelial cell fate determination, ductal morphogenesis and terminal differentiation.


Promising therapeutic agents for the treatment of Parkinson's disease.
The therapeutic management of Parkinson's disease has not yet been fully resolved, with motor fluctuations and levodopa-induced dyskinesia representing special therapeutic challenges. Furthermore, no disease-modifying therapies are currently available. This review focuses on promising novel therapies that are at present under investigation in Phase I or Phase II trials. Special emphasis is placed on gene therapies: vectors, the utilized gene constructs and the side-effects. Moreover, the main risk factors of the gene therapy (the insertional mutagenesis, the uncontrolled overproduction of the expressed protein and the autoimmune and inflammatory responses) are described. Gene therapies represent a promising field in the therapeutic palette. In order to mitigate the side-effects of this therapy, the developments focus on the vectors applied. Gene therapy appears to be promising candidate for the management of motor complications in advanced stages of Parkinson's disease. In addition to dopamine replacement therapy, this field may also offer a solution for neurogenesis and neuroprotection.


Epidemiological survey of HIV infection in the Veneto region of Italy.
A seroepidemiological survey of the Veneto region was undertaken to determine the prevalence of HIV antibodies in the sera of subjects belonging to known risk groups for AIDS and related conditions. The sera were tested by ELISA and confirmed by radioimmunoassay (Western blot). Of the AIDS patients sero-positive for HIV antibodies, 55% (6/11) were from the intravenous drug abuser group and 18% (2/11) from the homosexual group. A similar trend was seen in seropositive LAS patients, 85% (88/104) belonged to the drug abuser group and 6% (6/104) to the homosexual group. In seropositive asymptomatic subjects 83.7% (426/509) came from the drug abuser group and 4.9% (25/509) from the homosexual group. Thus drug abusers appear to be the major risk group in the Veneto region. They give rise to another risk group namely children born to seropositive drug abuser women. The seropositivity for HIV antibodies was low (0.02%) in subjects not in any risk group. Antibodies to HIV can be detected in amniotic, vitreous and cerebrospinal fluids as well as in sera.


The prognostic value of mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A, and Ki67, alone and in combinations, in node-negative premenopausal breast cancer.
Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off ≥10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95%CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95%CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95%CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95%CI: 1.1-6.7), and cyclin A (HR=2.7, 95%CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found.


Efficacy and Safety of Glycogen Synthase Kinase 3 Inhibitors for Alzheimer's Disease: A Systematic Review and Meta-Analysis.
The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer's disease (AD) is unknown. A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients. We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure. Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = -0.25, p = 0.11, I2 = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = -0.41, p = 0.04; tideglusib subgroup: SMD = -0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, -0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments. Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed.


The Treatment of Pelvic Locoregional Recurrence of Cervical Cancer After Radical Surgery With Intensity-Modulated Radiation Therapy Compared With Conventional Radiotherapy: A Retrospective Study.
The aim of this study was to investigate the therapeutic response and toxicity of intensity-modulated radiation therapy (IMRT) or conventional radiotherapy (c-RT) as adjuvant therapy in patients with pelvic locoregional recurrence of cervical cancer after radical surgery. This retrospective study included 161 patients with unresectable pelvic locoregional recurrence of cervical cancer after radical surgery between March 2003 and May 2012. All patients were initially diagnosed with International Federation of Gynecology and Obstetrics stage IB-IIA cervical cancer and received radical hysterectomy and pelvic lymphadenectomy. A total of 82 patients were treated with c-RT, whereas the remaining 79 patients underwent IMRT. Intracavitary brachytherapy and concurrent chemotherapy were performed during external irradiation. The mean dose delivered to the planning target volume was significantly higher in the IMRT group than in the c-RT group (61.8 vs 50.3 Gy, P = 0.029). Intensity-modulated radiation therapy plans yielded better dose sparing of small bowel, bladder, and rectum than did c-RT (P < 0.05). Moreover, the IMRT patients experienced less acute and chronic toxicities (P < 0.05) and better short-term effects (complete response + partial response) than did those treated with c-RT (89.9% vs 63.4%, P = 0.03). Three- and 5-year overall survival rates were significantly higher in the IMRT group than in the c-RT group (3-year: 58.4% vs 39.1%, P = 0.012; 5-year: 35.4% vs 21.4%, P = 0.007). Furthermore, 5-year progression-free survival rates were significantly higher in the IMRT group than in the c-RT group (26.1% vs 15.1%, P = 0.031). Intensity-modulated radiation therapy achieved outcomes superior to c-RT in patients with pelvic locoregional recurrence of cervical cancer after radical surgery. The acute and chronic toxicities were acceptable, and the adjacent organs at risk were well protected.


Exercise treadmill test: estimating cardiovascular prognosis.
Abnormal hemodynamic responses to exercise treadmill testing may indicate an increased risk of coronary events and death, even if evidence of ischemia is absent. Exercise duration and the blood pressure, heart rate, and heart rhythm responses to exercise have prognostic significance.


[Differential diagnosis of gallbladder diseases in children].
To estimate the information content of different methods of diagnosing biliary diseases, 103 children aged 5 to 15 years, including 25 practically healthy children as control, were examined. Abdominal organs, particularly the liver and gallbladder were examined by echography. The duodenal contents was explored by microscopy of the sediment and biochemistry which included analysis in the vesicular and liver portions of the concentrations of phospholipids, activity of phospholipases A and C as well as measurements of creatine kinase, lactate dehydrogenase, alkaline phosphatase, C-reactive protein and of the diphenylamine index. Ultrasonography was found to be highly informative. The characteristic echographic alterations seen in dyskinesia of the biliary tract, dyscholias and chronic cholecystitis were defined. For differential diagnosis of dyscholia and chronic cholecystitis it is necessary to carry out biochemistry of the duodenal contents including measurements of phospholipids, activity of phospholipases A and C, alkaline phosphatase, creatine kinase, lactate dehydrogenase, C-reactive protein and the diphenylamine index. Based on the similarity of the alterations seen in children with different cholepathies, a concept is advanced of the mechanisms by which functional and organic diseases of the gallbladder are formed.


Coronary blood flow, metabolism, and function in dysfunctional viable myocardium before and early after surgical revascularisation.
To assess the link between perfusion, metabolism, and function in viable myocardium before and early after surgical revascularisation. Myocardial blood flow (MBF, thermodilution technique), metabolism (lactate, glucose, and free fatty acid extraction and fluxes), and function (transoesophageal echocardiography) were assessed in patients with critical stenosis of the left anterior descending coronary artery (LAD) before and 30 minutes after surgical revascularisation. Tertiary cardiac centre. 23 patients (mean (SEM) age 57 (1.7) years with LAD stenosis: 17 had dysfunctional viable myocardium in the LAD territory, as shown by thallium-201 rest redistribution and dobutamine stress echocardiography (group 1), and six had normally contracting myocardium (group 2). LAD MBF was lower in group 1 than in group 2 (58 (7) v 113 (21) ml/min, p < 0.001) before revascularisation and improved postoperatively in group 1 (129 (133) ml/min, p < 0.001) but not in group 2 (105 (20) ml/min, p = 0.26). Group 1 also had functional improvement in the LAD territory at intraoperative echocardiography (mean regional wall motion score from 2.6 (0.85) to 1.5 (0.98), p < 0.01). Oxidative metabolism, with lactate and free fatty acid extraction, was found preoperatively and postoperatively in both groups; however, lactate and free fatty acid uptake increased after revascularisation only in group 1. MBF is reduced and oxidative metabolism is preserved at rest in dysfunctional but viable myocardium. Surgical revascularisation yields immediate perfusion and functional improvement, and increases the uptake of lactate and free fatty acids.


Venous thromboembolism and bleeding in critically ill COVID-19 patients treated with higher than standard low molecular weight heparin doses and aspirin: A call to action.
Critically ill COVID-19 patients have a clear pattern of inflammation and hypercoagulable state. The main aim of the study was to evaluate the outcome of severe COVID-19 patients basing on prothrombotic risk factors (i.e. D-dimer). We also evaluated the impact of different doses of low molecular weight heparin (LMWH) on the incidence of bleedings. The data of forty-two patients admitted to the Intensive Care Unit (ICU) were retrospectively analyzed. On ICU admission, patients with D-dimer < 3000 ng/mL (Group 1) received enoxaparin 4000 UI (6000 UI, if body mass index >35) subcutaneously b.i.d. and patients with D-dimer ≥ 3000 ng/mL (Group 2) received enoxaparin 100 UI/kg every 12 h. Aspirin was administered to all patients once a day. Both groups presented a high incidence of perivascular thrombosis (40.9% in Group 1 and 30% in Group 2). Patients of Group 2 suffered a higher incidence of venous thromboembolism (VTE) than Group 1 (65% vs 13.6%, p = 0.001). One patient (4.5%) of Group 1 and three patients (15%) of Group 2 suffered from minor bleeding; no patient had major bleeding. Group 2 had a longer ICU and hospital stay than Group 1 (11.5 ± 5.6 vs 9.0 ± 4.8 and 30 ± 4.9 vs 21 ± 2.3, p < 0.05, respectively) as well as increased ICU mortality (25% vs 9.1%). More severe critically ill COVID-19 patients have a high incidence of VTE and worse outcome, despite the use of heparin at the therapeutic dose. However, the use of heparin did not increase the incidence of bleeding complications.


Electrolyte concentration during haemodialysis and QT interval prolongation in uraemic patients.
To assess the effect of different combinations of potassium and calcium concentrations on QT interval in the dialysis bath in uraemic patients. Sixteen haemodialysis (HD) patients underwent a 24 h Holter recording before and during HD sessions with six randomized combinations of electrolytes concentrations of the dialysis bath (K(+), 2 and 3 mmol/L; Ca(2+), 1.25, 1.5, and 1.75 mmol/L). The effect of different dialysis baths on QT interval was significant (P < 0.05). The longest mean QTc was observed with the lowest K(+) (2 mmol/L) and Ca(2+) concentrations (1.25 mmol/L), whereas the shortest mean QTc was observed with the highest K(+) (3 mmol/L) and Ca(2+) concentrations (1.75 mmol/L). QTc was >440 ms in 9 of 16 patients (56%) at the lowest Ca(2+) and K(+) concentrations, and in 3 of 16 patients (18%) at the highest electrolytes level. Changes in QTc during the HD sessions were inversely correlated with that in total Ca and Ca(2+) plasma concentrations (P < 0.0001). Changes in ventricular repolarization duration associated with HD largely depend on the concentrations of Ca(2+) and K(+) in the dialysis bath. These findings may have important implications for the choice of the electrolytes concentration of the dialysis bath during the HD session.


The Effects of Deregulated Ribosomal Biogenesis in Cancer.
Ribosomes are macromolecular ribonucleoprotein complexes assembled from RNA and proteins. Functional ribosomes arise from the nucleolus, require ribosomal RNA processing and the coordinated assembly of ribosomal proteins (RPs), and are frequently hyperactivated to support the requirement for protein synthesis during the self-biosynthetic and metabolic activities of cancer cells. Studies have provided relevant information on targeted anticancer molecules involved in ribosome biogenesis (RiBi), as increased RiBi is characteristic of many types of cancer. The association between unlimited cell proliferation and alterations in specific steps of RiBi has been highlighted as a possible critical driver of tumorigenesis and metastasis. Thus, alterations in numerous regulators and actors involved in RiBi, particularly in cancer, significantly affect the rate and quality of protein synthesis and, ultimately, the transcriptome to generate the associated proteome. Alterations in RiBi in cancer cells activate nucleolar stress response-related pathways that play important roles in cancer-targeted interventions and immunotherapies. In this review, we focus on the association between alterations in RiBi and cancer. Emphasis is placed on RiBi deregulation and its secondary consequences, including changes in protein synthesis, loss of RPs, adaptive transcription and translation, nucleolar stress regulation, metabolic changes, and the impaired ribosome biogenesis checkpoint.


Lipid profile in cirrhotic patients and its relation to clinical outcome.
Carriers of hepatitis C virus have lower levels of total cholesterol, high density lipoprotein-cholesterol, low density lipoprotein- cholesterol and triglycerides compared to uninfected patients. With the progression of liver disease, the values for cholesterol and its fractions reduce linearly, with reduction ratio of lipid profile and markers Child-Pugh and MELD. To determine the relationship between decrease dlipid profile with clinical outcome presented (liver transplantation or death pre-transplant). Was conducted a cross sectional analytical study of a follow-up study performed by reviewing medical records. Cirrhotic patients treated at theClinic of Gastroenterology from a large tertiary hospital with cirrhosis of viral etiology and/or alcohol were studied. The clinical characteristics (gender, age and etiology of cirrhosis) and lipid profile data from150 patients were collected in the year 2010.To analyze the occurrence of clinical outcomes (liver transplantation or death pre-transplant) patients were evaluated after four years. The prevalent cause was hepatitis C virus (53,3%), followed by alcohol (32%) and hepatitis C and alcohol (14,6%). Males represented 62% of the sample and the average age was 63.1±9.11 years. The prevalent lipid changes were hypocholesterolemia associated with hypotriglyceridemia (36,6%) and isolated hypocholesterolemia (34,6%). Analyzing groups of patients that showed abnormalities related to lipid profile, was identified a significant association between isolated hypocholesterolemia and clinical outcome-liver transplant(p <0.025) and 18% probability of performing liver transplantation in this group of patients. There was no association between decreased lipid profile and death. Isolated hypocholesterolemia contributes to assess the progression of liver disease, because of the association between lowering cholesterol and its fractions and the clinical outcome - liver transplant.


Biliary Dyskinesia in Stiff Person Syndrome: An Association Between Reduced GABA Production and Gastroenteric Dysmotility.
Stiff person syndrome (SPS) and biliary dyskinesia are two rare but potentially debilitating conditions that can significantly impact quality of life. SPS is a rare neurological disorder characterized by muscle stiffness, rigidity, and muscle spasms that primarily affect the trunk and limbs and is associated with extra-axial manifestations involving the gastrointestinal tract. Biliary dyskinesia is a gastrointestinal disorder characterized by abnormal gallbladder emptying, leading to symptoms of intense abdominal pain, nausea, and vomiting. Despite their distinct clinical presentations, studies have suggested a possible connection between the two disorders. This link may be due to involvement of similar neurotransmitters and autoantibodies in both conditions. In this report, we present a case of biliary dyskinesia in a 58-year-old male with prior history of chronic gastrointestinal symptoms, autoimmune disease, and SPS. Given the rarity of these conditions, there is a need for increased awareness and improved diagnostic modalities to facilitate early detection and management.


Interleukin 6 plasma concentration associates with cognitive decline: the northern Manhattan study.
Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic and Black people who often have a greater prevalence of vascular risk factors and are at an elevated risk of dementia than Whites. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free racially/ethnically diverse community-based sample from Northern Manhattan. We used mixed effects models to measure the effect of IL-6 on change in performance on the modified Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors. There were 1,224 participants with IL-6 levels (median 1.5 pg/ml, interquartile range 0.83-2.57 pg/ml) and TICS-m data available (mean = 31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person-years and a median 3.0 years of follow-up (interquartile range 1.1-4.0 years). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β = -0.17 points/year, p = 0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (p for interaction <0.001). There was no interaction by race/ethnicity, vascular risk factors, C-reactive protein, apolipoprotein ε4 allele status, or the metabolic syndrome among nondiabetics. IL-6 associated with cognitive decline among older participants in this racially/ethnically diverse sample independent of other vascular risk factors and C-reactive protein.


An interview with Peter H. Buschang.
Dr. Peter Buschang is regent professor and director of orthodontic research. He has been at Texas A&M University Baylor College of Dentistry since 1988. Dr. Buschang received his PhD in 1980 from the University of Texas at Austin; he spent 3 years as a NIDR postdoctoral fellow at the University of Connecticut, and five years as a FRSQ scholar at the University of Montreal. Every year, Dr. Buschang teaches in 16 different courses, 7 of which he directs. In addition to more than 100 lecture hours per year, he spends hundreds of hours mentoring students. For his teaching efforts, Dr. Buschang was awarded the Robert E. Gaylord Award of Excellence in Orthodontic education in 1992, 1998, 2004, and 2010. He also gives 1-2 day evidence-based CE courses throughout the world. The residents he has taught recently honored him by pledging to fund the Peter H. Buschang Endowed Professorship of Orthodontics. His research interests pertain to craniofacial growth and assessment of treatment effects. Dr. Buschang has been funded regularly over the years by the Medical Research Council of Canada, Fonds de le Recherche en Santé du Québec, the NIH, and the American Association of Orthodontics Foundation. He has mentored over 140 Master's and PhD students, and 49 dental students. Dr. Buschang has published over 250 peer-reviewed articles, 15 book chapters and 198 abstracts. He has given over 150 invited talks and lectures in 14 different countries. For his work with the American Board of Orthodontics, Dr. Buschang was awarded the Earl E. and Wilma S. Shepard Award. Dr. Buschang is the only non-orthodontist ever to have been made an honorary member of both the American Association of Orthodontics (2005) and the Edward H. Angle Society of Orthodontics (2009), the two most prestigious orthodontic groups.


Human papillomavirus infection and neoplasia. Speculations for the future.
Human papillomavirus infections of the skin and anogenital tract are common. The association of these viruses with neoplasia, particularly of the anogenital tract, has stimulated efforts to devise practical methods of detection and typing of HPV. Although experimental diagnostic tests are available, they are, for the most part, complex and time consuming and are limited to medical centers researching HPV. New methods for preparing probes with higher sensitivities for hybridization tests will allow use of in situ methods on formalin-fixed tissues and will probably be the method of choice. Antigen detection systems are not available, except for antisera directed against the common structural antigens. The most useful immunologic test will be directed toward detection of nonstructural antigens in fixed tissues; such a system could also be useful for virus typing. Therapies based on use of these antigens to stimulate the immune system may be applicable as an alternative to current therapies. Most intriguing are the prospects for a vaccine based on either structural or nonstructural viral antigens. It has been estimated that as many as 20% of cancer deaths in women worldwide are associated with HPV. Thus, use of an effective vaccine would relieve considerable human suffering. Until the host immune response to HPV infection is better defined, however, much of the effort dedicated to developing a vaccine may be futile.


Accumulated unhealthy behaviours and insomnia in Japanese dwellers with and without cardiovascular risk factors: a cross-sectional study.
To date, the association between accumulated unhealthy behaviours and insomnia in individuals stratified according to the presence or absence of major cardiovascular risk factors is unclear. This study aimed to examine the effect of accumulated unhealthy behaviours on insomnia in Japanese dwellers. Cross-sectional study. Baseline data between April 2012 and March 2015. Our study used cross-sectional data among Japanese aged 35-74 years in a rural community (N=9565), the attendees of annual municipal or work site health check-up programmes. Insomnia was assessed by Athens Insomnia Scale, which was set at 6 points and greater; other scales were given. Participants were categorised into three groups by their number of unhealthy behaviours (no exercise habit, smoking, alcohol drinking, skipping breakfast and obesity): 0-1, 2-3, 4 or more. The association between accumulated unhealthy behaviours and insomnia was estimated by logistic regression analysis. Further analysis was done after stratification of cardiovascular risk factors assessed by anthropometrics and clinical biochemistry measurements. The overall prevalence of insomnia was 13.3% for men and 19.3% for women. Men with unhealthy behaviour factors were more likely to have insomnia after adjusting for potential confounders, compared with the least unhealthy group (trend p=0.013). Women with four or more unhealthy behaviour factors were more likely to have insomnia, compared with the lowest groups (OR 1.175, 95% CI 1.077 to 1.282). Insomnia has an association with the unhealthy behaviours among men without cardiovascular risk factors (lowest groups: OR 1.133, 95% CI 1.037 to 1.238, trend p=0.026). Women without hypertension were more likely to have suspected insomnia, compared with the lowest group (OR 1.215, 95% CI 1.101 to 1.341). The results showed accumulated unhealthy behaviours were associated with increased risk of insomnia in Japanese dwellers. For healthy population without cardiovascular risk factors, unhealthy behaviours should be considered as background conditions for insomnia.


Covalent reaction intermediate revealed in crystal structure of the Geobacillus stearothermophilus carboxylesterase Est30.
Est30 is a thermophilic carboxylesterase cloned from Geobacillus stearothermophilus that showed optimal hydrolysis of esters with short acyl chains at 70 degrees C. Est30 is a member of a new family of carboxylesterases with representatives in other Gram-positive bacteria. The crystal structure has been determined at 1.63A resolution using multiple anomalous dispersion data. The two-domain crystal structure showed a large domain with a modified alpha/beta hydrolase core including a seven, rather than an eight-stranded beta sheet, and a smaller cap domain comprising three alpha helices. The catalytic triad consists of residues Ser94, Asp193, and His223. A 100Da tetrahedral ligand was observed to be covalently bound to the side-chain of Ser94. The propyl acetate ligand represents the first tetrahedral intermediate in the reaction mechanism. Therefore, this Est30 crystal structure will help understand the mode of action of all enzymes in the serine hydrolase superfamily.


Current practice in the management of patients with type 2 diabetes mellitus in Saudi Arabia.
To gather data on current practices in the management of patients with type 2 diabetes mellitus (T2DM) in Saudi Arabia and to evaluate the degree of compliance with international guidelines. This paper represents the results of the Saudi Arabia T2DM data collected at the cross-sectional part of Wave 2006 of the International Diabetes Management Practices Study (IDMPS). Data were collected on a case report form from 28 health centers all over the Kingdom of Saudi Arabia, in the period between 01/12/2006 and 30/12/2006. It included demographic and socioeconomic profile in addition to diabetes management and metabolic control. Three hundred and fifty-three Saudi T2DM diabetic patients were studied. The mean age was 51.61+/-10.84 years; average duration of diabetes was 8.25+/-6.49 years; 63-86% had never been screened for diabetes complications or cardiovascular risk factors during the previous year. Of all patients with T2DM, 7% were treated with insulin alone, 28% with oral glucose lowering drug (OGLD) + insulin and 64% with OGLD alone. The average last hemoglobin A1c (HbA1c) was 8.20+/-1.89% and among all patients, only 27% had reached the target HbA1c of <7% while 42% of patients had been considered as reached glycemic control by physicians. Sixteen percent attained the target blood pressure of <130/80, and 65% had lipid profile above the optimal level. The majority of patients did not attain the recommended target glycemic level. This indicates the presence of a gap between recommendations of the international guidelines and the actual practices.


Advancing knowledge of the plant nuclear periphery and its application for crop science.
In this review, we explore recent advances in knowledge of the structure and dynamics of the plant nuclear envelope. As a paradigm, we focused our attention on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, a structurally conserved bridging complex comprising SUN domain proteins in the inner nuclear membrane and KASH domain proteins in the outer nuclear membrane. Studies have revealed that this bridging complex has multiple functions with structural roles in positioning the nucleus within the cell, conveying signals across the membrane and organizing chromatin in the 3D nuclear space with impact on gene transcription. We also provide an up-to-date survey in nuclear dynamics research achieved so far in the model plant Arabidopsis thaliana that highlights its potential impact on several key plant functions such as growth, seed maturation and germination, reproduction and response to biotic and abiotic stress. Finally, we bring evidences that most of the constituents of the LINC Complex and associated components are, with some specificities, conserved in monocot and dicot crop species and are displaying very similar functions to those described for Arabidopsis. This leads us to suggest that a better knowledge of this system and a better account of its potential applications will in the future enhance the resilience and productivity of crop plants.


Acceptability and appropriateness of a novel parent-staff co-leadership model for childhood obesity prevention in Head Start: a qualitative interview study.
Peer leadership can be an effective strategy for implementing health programs, benefiting both program participants and peer leaders. To realize such benefits, the peer leader role must be appropriate for the community context. Also, peer leaders must find their role acceptable (i.e., satisfactory) to ensure their successful recruitment and retention. To date, parent peer leaders have seldom been part of early childhood obesity prevention efforts. Moreover, parents at Head Start preschools have rarely been engaged as peer leaders. The aim of this study is to evaluate the appropriateness and acceptability of an innovative model for engaging parents as peer leaders for this novel content area (early childhood obesity prevention) and setting (Head Start). Parents Connect for Healthy Living (PConnect) is a 10-session parent program being implemented in Head Start preschools as part of the Communities for Healthy Living early childhood obesity prevention trial. PConnect is co-led by a parent peer facilitator who is paired with a Head Start staff facilitator. In the spring of 2019, 10 PConnect facilitators participated in a semi-structured interview about their experience. Interview transcripts were analyzed by two coders using an inductive-deductive hybrid analysis. Themes were identified and member-checked with two interviewees. Themes identified applied equally to parent and staff facilitators. Acceptability was high because PConnect facilitators were able to learn and teach, establish meaningful relationships, and positively impact the parents participating in their groups, although facilitators did express frustration when low attendance limited their reach. Appropriateness was also high, as PConnect provided adequate structure and support without being overly rigid, and facilitators were able to overcome most challenges they encountered. The PConnect co-facilitation model was highly acceptable and appropriate for both the parent facilitators (peer leaders) and the staff facilitators. Including parents as peer leaders aligns to Head Start's emphasis on parent engagement, making it a strong candidate for sustained implementation in Head Start. The insights gained about the drivers of peer leadership appropriateness and acceptability in this particular context may be used to inform the design and implementation of peer-led health programs elsewhere. clinicaltrials.gov, NCT03334669 (7-11-17).


Association of adiponectin with cardiovascular events in diabetic and non-diabetic hemodialysis patients.
Adiponectin is a novel collagen-like protein synthesized by white adipose tissue. Its levels are decreased in obesity, type-2 diabetes and insulin-resistant states, and are increased in chronic renal failure. It has anti-inflammatory and anti-atherogenic properties. This study was planned to evaluate the levels of adiponectin in uremic patients with and without diabetes and to find any relationship between adiponectin levels and some cardiovascular risk factors, and to determine the possible predictive value of adiponectin for cardiovascular complications (CVC). The study included 100 subjects, 20 of them were healthy subjects and served as the control group (group I), 40 were uremic non-diabetic patients (group II) (half of them were without CVC, group IIA, and the other half were patients with CVC, group IIB) and, lastly, 40 uremic diabetic patients (group III) (half of them were without CVC, group IIIA, and the other half were patients with CVC, group IIIB). All subjects were subjected to complete clinical examination, including determination of mean arterial blood pressure (MABP), body mass index (BMI), waist to hip ratio, routine laboratory investigations, fasting plasma glucose, fasting plasma insulin, lipid profile (cholesterol, TG, LDL, HDL), determination of insulin resistance by homeostasis model assessment index (HOMA-IR) and estimation of serum levels of adiponectin. There was a significant increase in serum adiponectin levels in all the uremic patients (group II and group III) when compared with the control (group I) group, P <0.01; also, serum adiponectin levels were significantly decreased in uremic diabetic patients (group III) when compared with uremic non-diabetic patients (group II), P <0.01; but this was still higher than in the controls. The patients with CVC, whether uremic non-diabetic (group IIB) or uremic diabetic (group IIIB), had a significant decrease in serum adiponectin levels when compared with patients without CVC (group IIA and group IIIA), P <0.01. Serum adiponectin has a significant positive correlation with HDL and a significant negative correlation with MABP, BMI, plasma insulin, HOMA-IR, LDL, TG and cholesterol in all the patients. Therefore, it can be concluded that adiponectin levels in uremic patients, whether diabetic or non-diabetic, may be a good indicator of cardiovascular disease risk.


Going with the flow: preschoolers prefer nondissenters as informants.
In two experiments, 3- and 4-year-olds were tested for their sensitivity to agreement and disagreement among informants. In pretest trials, they watched as three of four informants (Experiment 1) or two of three informants (Experiment 2) indicated the same referent for an unfamiliar label; the remaining informant was a lone dissenter who indicated a different referent. Asked for their own judgment, the preschoolers sided with the majority rather than the dissenter. In subsequent test trials, one member of the majority and the dissenter remained present and continued to provide conflicting information about the names of unfamiliar objects. Children remained mistrustful of the dissenter. They preferred to seek and endorse information from the informant who had belonged to the majority. The implications and scope of children's early sensitivity to group consensus are discussed.


'Becoming human again': Exploring connections between nature and recovery from stress and post-traumatic distress.
Many military veterans are seeking ways beyond conventional treatments to manage their stress injuries. An increasing number is turning to nature, including hiking and fishing, farming and gardening, and building relationships with dogs or horses. Many continue to benefit from medication and therapy, but find that nature provides an additional measure of support, relief and healing in their lives. This paper examines reciprocal interactions between humans and nature during post-conflict recovery, with a focus on the experiences of four North American veterans who regard their personal recovery from stressful and traumatic military experiences as intimately tied to their nature experiences. Experience-centered narrative inquiry often sheds light on details and experiences concealed or overlooked by other research paradigms. In-depth interviews about post-military experiences with recovery were conducted with four veterans who suffer from stress and/or post-traumatic distress; these experiences are further illuminated by supporting interviews, and theories and praxis in ecopsychology, cognitive science, neuroscience, biophilia, and ecological intelligence. Through exploring themes of sensory experience, safety, sense of purpose, and renewed relationships, this research gives space to former soldiers' stories of experience and to their individual realizations that their embodied interconnections with nature provide alternative experiences to their military training and combat exposure. The veterans' experiences with nature and recovery are pointing towards an avenue of recovery that is little acknowledged in the mainstream literature and praxis, but deserving of attention.


Variability in premolar and molar root number in a modern population of Pan troglodytes verus.
While teeth are the most common fossil remains for hominoids, little is known of the tooth root morphology in Primates. With the exception of modern humans, the variability of the number of roots within a species is scarcely documented and not conclusively quantified. This lack of knowledge hinders the interpretation of observed evolutionary trends, such as the reduction of the number of roots of premolars within the hominins. Here, we present the first quantification of the variability of the number of roots in a nonhuman ape population including 405 specimens. Our sample is made of a single biological population of Pan troglodytes verus from Liberia, which is compared to other extant hominoids. Both permanent and deciduous teeth were analyzed and comprise premolars and molars from maxillaries and mandibles. The estimated variability is very low for each tooth position; more than 97% of the specimens displaying the same number of roots except for P4 (94%), M1 (89%), and P(4) (57%). No variability at all was observed for lacteal teeth. Males and females are statistically identical, and no difference linked to the tooth size (estimated by the occlusal surface) was observed. When compared to the observation in other hominoid species, these results emphasize that the difference of the number of roots observed between modern humans and apes is significant, and suggests that the evolution of premolar root number is mosaic, with the common ancestor of Pan and Homo probably displaying a reduced number of roots for P(4) and maybe P(3) , but a plesiomorphic morphology of the roots of lower premolars.


Evolutionary strategy for inverse charge measurements of dielectric particles.
We report a computational strategy to obtain the charges of individual dielectric particles from experimental observation of their interactions as a function of time. This strategy uses evolutionary optimization to minimize the difference between trajectories extracted from the experiment and simulated trajectories based on many-particle force fields. The force fields include both Coulombic interactions and dielectric polarization effects that arise due to particle-particle charge mismatch and particle-environment dielectric contrast. The strategy was applied to systems of free falling charged granular particles in a vacuum, where electrostatic interactions are the only driving forces that influence the particles' motion. We show that when the particles' initial positions and velocities are known, the optimizer requires only an initial and final particle configuration of a short trajectory in order to accurately infer the particles' charges; when the initial velocities are unknown and only the initial positions are given, the optimizer can learn from multiple frames along the trajectory to determine the particles' initial velocities and charges. While the results presented here offer a proof-of-concept demonstration of the proposed ideas, the proposed strategy could be extended to more complex systems of electrostatically charged granular matter.


Characterization of protein folding by a Φ-value calculation with a statistical-mechanical model.
The Φ-value analysis approach provides information about transition-state structures along the folding pathway of a protein by measuring the effects of an amino acid mutation on folding kinetics. Here we compared the theoretically calculated Φ values of 27 proteins with their experimentally observed Φ values; the theoretical values were calculated using a simple statistical-mechanical model of protein folding. The theoretically calculated Φ values reflected the corresponding experimentally observed Φ values with reasonable accuracy for many of the proteins, but not for all. The correlation between the theoretically calculated and experimentally observed Φ values strongly depends on whether the protein-folding mechanism assumed in the model holds true in real proteins. In other words, the correlation coefficient can be expected to illuminate the folding mechanisms of proteins, providing the answer to the question of which model more accurately describes protein folding: the framework model or the nucleation-condensation model. In addition, we tried to characterize protein folding with respect to various properties of each protein apart from the size and fold class, such as the free-energy profile, contact-order profile, and sensitivity to the parameters used in the Φ-value calculation. The results showed that any one of these properties alone was not enough to explain protein folding, although each one played a significant role in it. We have confirmed the importance of characterizing protein folding from various perspectives. Our findings have also highlighted that protein folding is highly variable and unique across different proteins, and this should be considered while pursuing a unified theory of protein folding.


Strive to Reduce Slurry Erosion and Cavitation in Pumps Through Flow Modifications, Design Optimization and Some Other Techniques: Long Term Impact on Process Industry.
Centrifugal pumps are being widely used in various industries for moving fluids that carry solids through pipelines where the need of head and flow rate is not high. Slurry erosion and cavitation are an extremely complex and not yet fully understood phenomenon that occur in centrifugal pumps; however, these undesirable phenomena can be reduced to a certain extent. Appropriate design and development of experiments is required to reasonably predict slurry erosion and cavitation. However, CFD methodology complements analytical solutions and experiments whenever testing of equipment has limitations. The current paper highlights the various slurry erosion and cavitation reduction techniques utilized by different researchers. Economic analysis conducted for a case study relevant to centrifugal pump (CP) usage in Pakistan shows that an 8% enhancement in pump efficiency can reduce the life cycle cost to about 17.6%, which could save up to USD 4281 for a single pump annually in Pakistan.


Segment convolutional neural networks (Seg-CNNs) for classifying relations in clinical notes.
We propose Segment Convolutional Neural Networks (Seg-CNNs) for classifying relations from clinical notes. Seg-CNNs use only word-embedding features without manual feature engineering. Unlike typical CNN models, relations between 2 concepts are identified by simultaneously learning separate representations for text segments in a sentence: preceding, concept1, middle, concept2, and succeeding. We evaluate Seg-CNN on the i2b2/VA relation classification challenge dataset. We show that Seg-CNN achieves a state-of-the-art micro-average F-measure of 0.742 for overall evaluation, 0.686 for classifying medical problem-treatment relations, 0.820 for medical problem-test relations, and 0.702 for medical problem-medical problem relations. We demonstrate the benefits of learning segment-level representations. We show that medical domain word embeddings help improve relation classification. Seg-CNNs can be trained quickly for the i2b2/VA dataset on a graphics processing unit (GPU) platform. These results support the use of CNNs computed over segments of text for classifying medical relations, as they show state-of-the-art performance while requiring no manual feature engineering.


The process values of university research. A new research funding system is needed for federal support of the process values of university research.
The process values of university research are important in the context of several significant social and economic trends in American life. These values are being taken into account in the design and administration of federal programs. Federal programs to support these values should be distinguished from programs to support the product values of research. Failure to distinguish between these two types of programs will lead to a further dilution of quality in programs designed to advance science as a legitimate end in itself. The scientific community can best protect its own interests by helping federal agencies and universities and colleges develop a funding system to support the process values of university research on a cooperative, regional basis.


Effects of acute and chronic administration of DDVP (dichlorvos) on distribution of brain acetylcholine in rats.
DDVP (dichlorvos), an irreversible cholinesterase (ChE) inhibitor, was administered acutely and chronically to rats in order to investigate effects on the distribution of brain acetylcholine (ACh). In acutely treated animals (4 mg/kg, singly), cholinergic signs were evident and accompanied with a 100, 146, 113, and 61 per cent increase in total, free, labile-bound and stable-bound ACh content of the brain, respectively, and a 66 per cent decrease in acetylcholinesterase (AChE) activity 20 min after injection. In no animals treated chronically with a low dose (0.2 mg/kg/day for 9 or 90 days, or 1 mg/kg/day for 9 or 30 days), any overt sign was shown during the experimental period, and the stable-bound ACh content of the brain was not altered. In the group given 0.2 mg/kg for 90 days and that given 1.0 mg/kg for 9 or 30 days, free ACh content increased slightly but significantly, and AChE activity decreased to 58 per cent. Total ACh content and labile-bound ACh content increased only in a group given 1 mg/kg of DDVP for 30 days. These results suggest that acute, as well as chronic, exposure to organophosphate may induce alteration in mobilization and storage of ACh in the central cholinergic nerves.


Fentanyl Sublingual Tablets Versus Subcutaneous Morphine for the Management of Severe Cancer Pain Episodes in Patients Receiving Opioid Treatment: A Double-Blind, Randomized, Noninferiority Trial.
Purpose Fentanyl sublingual tablets (FST) are a potentially useful alternative to parenteral opioids such as subcutaneous morphine (SCM) to treat severe cancer pain episodes. No direct comparison between FST and SCM is available. The aim of this study was to test noninferiority of FST versus SCM during the first 30 min postadministration. Methods Patients receiving stable opioid therapy and experiencing a severe pain episode were randomly assigned to either 100 µg FST or 5 mg SCM in a double-blind, double-dummy trial. Average pain intensity (PI) assessed on a 0 to 10 numerical rating scale at 10, 20, and 30 min postadministration was the main end point. Analysis of covariance, adjusted by baseline PI, was the main analysis. The noninferiority margin (NIm) for the between-group difference was set at -0.6, that is, equal to one third of the minimum clinically important PI difference of two points. Results A total of 114 patients were randomly assigned to either FST (n = 58) or SCM (n = 56). One patient (in the FST group) withdrew consent before drug administration and was excluded from analysis. Baseline mean PIs were 7.5 in both groups; mean average PIs assessed at 10, 20, and 30 min postadministration were 5.0 and 4.5 for FST and SCM, respectively, with the 95% CI of the between-group difference including the NIm (-0.49; 95% CI, -1.10 to 0.09). Patients taking FST received a second drug dose after 30 min more frequently than did patients taking SCM (51% v 37%, respectively; risk difference, -13%; 95% CI, -30% to 3%). Both treatments were well tolerated, with average follow-up adverse event scores below the response of "A Little." Ninety-three percent of patients preferred the sublingual administration. Conclusion This trial did not show noninferiority of FST versus SCM within the chosen NIm. Both treatments were safe, and patients preferred the sublingual route of administration. FST provides analgesia with modest to moderate increased risk of lower efficacy compared with SCM.


Joint Content Placement and Storage Allocation Based on Federated Learning in F-RANs.
With the rapid development of mobile communication and the sharp increase of smart mobile devices, wireless data traffic has experienced explosive growth in recent years, thus injecting tremendous traffic into the network. Fog Radio Access Network (F-RAN) is a promising wireless network architecture to accommodate the fast growing data traffic and improve the performance of network service. By deploying content caching in F-RAN, fast and repeatable data access can be achieved, which reduces network traffic and transmission latency. Due to the capacity limit of caches, it is essential to predict the popularity of the content and pre-cache them in edge nodes. In general, the classic prediction approaches require the gathering of users' personal information at a central unit, giving rise to users' privacy issues. In this paper, we propose an intelligent F-RANs framework based on federated learning (FL), which does not require gathering user data centrally on the server for training, so it can effectively ensure the privacy of users. In the work, federated learning is applied to user demand prediction, which can accurately predict the content popularity distribution in the network. In addition, to minimize the total traffic cost of the network in consideration of user content requests, we address the allocation of storage resources and content placement in the network as an integrated model and formulate it as an Integer Linear Programming (ILP) problem. Due to the high computational complexity of the ILP problem, two heuristic algorithms are designed to solve it. Simulation results show that the performance of our proposed algorithm is close to the optimal solution.


Cigarette Smokers Versus Cousers of Cannabis and Cigarettes: Exposure to Toxicants.
Cannabis and tobacco couse is common and could expose users to higher levels of toxicants. No studies have examined biomarkers of toxicant exposure in cousers of cannabis and cigarettes, compared with cigarette smokers (CS). Adult daily CS were recruited from 10 US sites for a study of reduced nicotine cigarettes. In this analysis of baseline data, participants were categorized as either cousers of cannabis and tobacco (cousers; N = 167; urine positive for 11-nor-9-carboxy-Δ 9-tetrahydrocannnabinol and self-reported cannabis use ≥1×/week), or CS (N = 911; negative urine and no self-reported cannabis use). Participants who did not meet either definition (N = 172) were excluded. Self-reported tobacco and cannabis use and tobacco and/or combustion-related biomarkers of exposure were compared between groups. Compared to CS, cousers were younger (couser Mage = 38.96, SD = 13.01; CS Mage = 47.22, SD = 12.72; p < .001) and more likely to be male (cousers = 67.7%, CS = 51.9%, p < .001). There were no group differences in self-reported cigarettes/day, total nicotine equivalents, or breath carbon monoxide, but cousers had greater use of non-cigarette tobacco products. Compared to CS, cousers had higher concentrations of 3-hydroxypropylmercapturic acid, 2-cyanoethylmercapturic acid, S-phenylmercapturic acid, 3-hydroxy-1-methylpropylmercapturic acid (ps < .05), and phenanthrene tetraol (p < .001). No biomarkers were affected by number of cannabis use days/week or days since last cannabis use during baseline (ps > .05). Cousers had higher concentrations of biomarkers of exposure than CS, but similar number of cigarettes per day and nicotine exposure. Additional studies are needed to determine whether cannabis and/or alternative tobacco products are driving the increased toxicant exposure. Cousers of cannabis and tobacco appear to be exposed to greater levels of harmful chemicals (ie, volatile organic compounds and polycyclic aromatic hydrocarbons), but similar levels of nicotine as CS. It is unclear if the higher levels of toxicant exposure in cousers are due to cannabis use or the increased use of alternative tobacco products compared with CS. It is important for studies examining biomarkers of exposure among CS to account for cannabis use as it may have a significant impact on outcomes. Additionally, further research is needed examining exposure to harmful chemicals among cannabis users.


Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage.
When pluripotent cells are exposed to a uniform culture environment they routinely display heterogeneous gene expression. Aspects of this heterogeneity, such as Nanog expression, are linked to differences in the propensity of individual cells to either self-renew or commit towards differentiation. Recent findings have provided new insight into the underlying causes of this heterogeneity, which we summarise here using Nanog, a key regulator of pluripotency, as a model gene. We discuss the role of transcription factor heterogeneity in facilitating the intrinsically dynamic and stochastic nature of the pluripotency network, which in turn provides a potential benefit to a population of cells that needs to balance cell fate decisions.


Fluorescence, CD, attenuated total reflectance (ATR) FTIR, and 13C NMR characterization of the structure and dynamics of synthetic melittin and melittin analogues in lipid environments.
The structure and dynamics of synthetic melittin (MLT) and MLT analogues bound to monomyristoylphosphatidylcholine micelles, dimyristoylphosphatidylcholine vesicles, and diacylphosphatidylcholine films have been investigated by fluorescence, CD, attenuated total reflectance (ATR) FTIR, and 13C NMR spectroscopy. All of these methods provide information about peptide secondary structure and/or about the environment of the single tryptophan side chain in these lipid environments. ATR-FTIR data provide additional information about the orientation of helical peptide segments with respect to the bilayer plane. Steady-state fluorescence anisotropy, fluorescence lifetime, and 13C NMR relaxation data are used in concert to provide quantitative information about the dynamics of a single 13C-labeled tryptophan side chain at position 19 in lipid-bound MLT, and at positions 17, 11, and 9, respectively, in lipid-bound MLT analogues. Peptide chain dynamics are probed by NMR relaxation studies of 13C alpha-labeled glycine incorporated into each of the MLT peptides at position 12. The cumulative structural and dynamic data are consistent with a model wherein the N-terminal alpha-helical segment of these peptides is oriented perpendicular to the bilayer plane. Correlation times for the lysolipid-peptide complexes provide evidence for binding of a single peptide monomer per micelle. A model for the membranolytic action of MLT and MLT-like peptides is proposed.


[Combination of central venous-to-arterial PCO2 difference with central venous oxygen saturation to guide the shock resuscitation].
Central venous oxygen saturation (ScvO2) is a useful therapeutic target in septic shock and high-risk postoperative patients. We tested the hypothesis that central venous-to-arterial carbon dioxide difference (ΔPCO(2)) combine with ScvO2 to guide shock resuscitation is better than ScvO2 only. A retrospective study was conducted for 93 septic shock and high-risk postoperative patients. They underwent resuscitation through early goal-directed therapy. We calculate whether there were correlations between the ΔPCO(2) and tissue perfusion index or blood flow index, including the beginning of resuscitation (T0) and after 6 hour resuscitation (T6). They were divided into 4 groups according to ΔPCO(2) and ScvO2. Then the clearance of lactate was compared between the groups. No correlation existed between ΔPCO(2) and tissue perfusion index. But there was some correlation between ΔPCO(2) and the indices of blood flow such as CO, ScvO2 and clearance of lactate. At T0, the correlation (r) between ΔPCO(2) and cardiac index was -0.858 (P = 0.029) and the correlation between ΔPCO(2) and ScvO2 -0.403 (P = 0.000). At T6, the correlation (r) between ΔPCO(2) and ScvO2 was -0.363 (P = 0.000) and the correlation between ΔPCO(2) and clearance of lactate -0.314 (P = 0.002). After continuous 6-hour resuscitation, there was significant difference in clearance of lactate between the groups. The clearance of lactate was the highest in the group of patients achieving the goals of both ScvO2 > 70% and ΔPCO(2) < 6 mm Hg. We further analysis the ΔPCO(2) < 6 mm Hg and ScvO2 > 70% subgroup and found that the 6 h lactate clearance rate were statistically significant difference. The combination of ΔPCO(2) and ScvO2 may guide the shock resuscitation. It helps identify the inadequately resuscitated when the ScvO2 goal is reached.


Extraosseous talotarsal stabilization using HyProCure® in adults: a 5-year retrospective follow-up.
The purpose of this retrospective study was to determine long-term functional outcomes and device tolerance achieved in adult patients who chose to undergo an extraosseous talotarsal stabilization procedure HyProCure(®) for the treatment of flexible talotarsal joint deformity. Eighty-three adult patients participated in this study. Postoperative subjective assessment of device performance was evaluated using Maryland Foot Scores, which were collected at a mean follow-up period of 51 months. The mean postoperative Maryland Foot Score was 88 out of 100; postoperatively, 52% of cases reported complete alleviation of foot pain, 69% of cases had no limitations on their foot functional abilities, and 80% of cases reported complete satisfaction with the appearance of their feet. The implant was removed in 7 out of 117 cases (removal rate: 6%) due to prolonged pain of the anterior talofibular ligament (4 cases), psychogenic reaction (2 cases), and postoperative infection (1 case). The long-term positive subjective outcomes and excellent patient satisfaction obtained in this study may imply that extraosseous talotarsal stabilization was effective in stabilizing the talotarsal joint complex and eliminating excessive abnormal pronation, thus reducing pain and improving quality of life of the patients; it represents a possible treatment option for partial talotarsal dislocation in cases with flexible and reducible deformity.


The independence of insulin release and ambient insulin in vitro.
The effect of insulin on its own secretion was tested in three independent experimental models using insulin concentrations that approached physiologic values. The collected secretions from glucose-stimulated islet tissue had no effect on insulin release from other islets. Perifused insulin had no effect on the release of endogenous insulin even when the assay was completely controlled for dilutional effects. Perifused insulin had no effect on the release of prelabeled insulin from glucose-stimulated islets. Similarly, proinsulin did not affect insulin release. Porcine insulin did not affect the function of porcine or canine islets. These studies strongly support the independence of glucose-stimulated insulin secretion and ambient insulin.


Nicotinamide mononucleotide and related metabolites induce disease resistance against fungal phytopathogens in Arabidopsis and barley.
Nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), is known to act as a functional molecule in animals, whereas its function in plants is largely unknown. In this study, we found that NMN accumulated in barley cultivars resistant to phytopathogenic fungal Fusarium species. Although NMN does not possess antifungal activity, pretreatment with NMN and related metabolites enhanced disease resistance to Fusarium graminearum in Arabidopsis leaves and flowers and in barley spikes. The NMN-induced Fusarium resistance was accompanied by activation of the salicylic acid-mediated signalling pathway and repression of the jasmonic acid/ethylene-dependent signalling pathways in Arabidopsis. Since NMN-induced disease resistance was also observed in the SA-deficient sid2 mutant, an SA-independent signalling pathway also regulated the enhanced resistance induced by NMN. Compared with NMN, NAD and NADP, nicotinamide pretreatment had minor effects on resistance to F. graminearum. Constitutive expression of the NMNAT gene, which encodes a rate-limiting enzyme for NAD biosynthesis, resulted in enhanced disease resistance in Arabidopsis. Thus, modifying the content of NAD-related metabolites can be used to optimize the defence signalling pathways activated in response to F. graminearum and facilitates the control of disease injury and mycotoxin accumulation in plants.


Computational haemodynamic analysis of patient-specific virtual operations for total cavopulmonary connection with dual superior venae cavae.
This study set out to design different types of total cavopulmonary connections (TCPC) with dual superior venae cavae (SVC), taking into account different sites for anastomosis from venae cavae to pulmonary arteries (PAs), and to compare haemodynamic features in these virtual operative designs. The geometries of bilateral bidirectional Glenn (BBDG) connection and inferior vena cava (IVC) connected extracardiac conduit were reconstructed to three-dimensional configurations according to the magnetic resonance images (MRIs) of two patients at the same age, and virtual operations were designed to create four possible TCPC models under the guidance of paediatric cardiac surgeons. Computational fluid dynamic (CFD) simulations were performed in each model at five predetermined pulmonary flow splits, to predict postoperative blood flows. The same boundary conditions were applied on each model, in order to simplify the analysis of the influence of configurations on the flow characteristics. Control volume power losses and energy efficiency in different models were calculated and compared. Flow patterns in the models were demonstrated by streamlines corresponding to the venae cavae. When the flow rate of the right pulmonary artery (RPA) was 40-60% of the total pulmonary flow, control volume power loss was lower than the other three models in the model of TCPC 2 and was higher than the other three models in the model of TCPC 4. For this patient, anastomosing the left superior vena cava (LSVC) and right superior vena cava (RSVC) on the PAs close together will cause higher power loss and lower energy efficiency in the TCPC connection. If the LSVC and RSVC had been connected to the PAs as near as possible to stimulate growth of the central PAs when performing I-stage BBDG procedure, the extracardiac conduit from IVC would be better connected just under the anastomotic site in the following TCPC procedure to avoid high power loss.


High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage.
Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.


An expensive adult measles outbreak and response in office buildings during the era of accelerated measles elimination, Beijing, China.
Few measles outbreaks among adults are reported in China, and outbreak response costs are seldom documented. We report an adult measles outbreak and response in 4 linked office buildings in Beijing and its associated costs. The World Health Organization measles case definitions were used to determine suspected and confirmed measles cases. Surveillance data were used to describe the outbreak, and records and interviews of response staff were used to describe the response. Costs were determined by use of retrospective surveys of cases, review of records, and interviews of staff. The outbreak lasted 19days, and involved 22 cases aged 23-49years. Nineteen cases had a local household registration. All cases were employed by 8 companies in 4 linked office buildings. Among the 22 cases, 8 had temperature less than 38.5 degree, 18 had no Koplik spots and none had complications or hospitalizations. A total of 7930 contacts were identified, and of these, 6869 were employees in the office buildings. All the child contacts aged 8months-14years had been up-to-date for measles-containing vaccine (MCV); no adult could document their vaccination or measles history. Of contacts, about 96% were offered post-exposure vaccination. The total household costs were $13,298, or $605 per case. Control costs were $384,594, or $17,481 per case. Involved companies paid for 90.7% of control costs. Office buildings provide a mechanism for measles transmission. Timely control activities were challenged by the highly infectious nature of measles and mild presentations of cases. The outbreak response was very costly. Financial support by involved companies can provide needed resources for outbreak management.


Capture myopathy in pronghorns in Alberta, Canada.
From 1971 to 1975, inclusive, 594 pronghorns (Antilocapra americana) were drive trapped in Alberta; subsequently, 74 of these animals were transported to enclosures. Deaths attributable to capture myopathy (CM) occurred in 20 of the trapped pronghorns and in 17 of the pronghorns that were trapped and subsequently transported. Two neonatal pronghorns that had been pursued died with signs and lesions similar to those seen in adult pronghorns affected with CM. The diagnosis of CM was based on history, clinical signs, clinico-pathologic findings, and gross and histologic lesions. Clinical signs of CM included depression, stiffness, weakness, incoordination, recumbency, and paralysis; myoglobinuria was observed in 1 neonatal animal. Of the pronghorns that died, fewer than one-half died acutely during processing, whereas the remainder died from 1 to 13 days following their release. Gross and histologic lesions were observed in the large muscles of the hindlimbs of most affected pronghorns. Values for serum enzymes, potassium, glucose, and creatinine, were higher for drive-trapped pronghorns than for tame, hand-reared pronghorns. These findings indicated extensive damage to muscle and to other organs as a result of the capture procedures.


Bursting of thalamic neurons and states of vigilance.
This article addresses the functional significance of the electrophysiological properties of thalamic neurons. We propose that thalamocortical activity, is the product of the intrinsic electrical properties of the thalamocortical (TC) neurons and the connectivity their axons weave. We begin with an overview of the electrophysiological properties of single neurons in different functional states, followed by a review of the phylogeny of the electrical properties of thalamic neurons, in several vertebrate species. The similarity in electrophysiological properties unambiguously indicates that the thalamocortical system must be as ancient as the vertebrate branch itself. We address the view that rather than simply relays, thalamic neurons have sui generis intrinsic electrical properties that govern their specific functional dynamics and regulate natural functional states such as sleep and vigilance. In addition, thalamocortical activity has been shown to be involved in the genesis of several neuropsychiatric conditions collectively described as thalamocortical dysrhythmia syndrome.


Complete Genome Sequence of Salmonella enterica Serovar Typhimurium Myophage Mushroom.
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a leading cause of foodborne illness worldwide. Over the past two decades, strains resistant to antibiotics have begun to emerge, highlighting the need for alternative treatment strategies such as bacteriophage therapy. Here, we present the complete genome of Mushroom, an S. Typhimurium myophage.


Colon-Accumulated Gold Nanoclusters Alleviate Intestinal Inflammation and Prevent Secondary Colorectal Carcinogenesis via Nrf2-Dependent Macrophage Reprogramming.
Inflammatory bowel disease (IBD) is one of the main factors leading to colitis-associated colorectal cancer (CAC). Therefore, it is critical to develop an effective treatment for IBD to prevent secondary colorectal carcinogenesis. M2 macrophages play crucial roles in the resolution phase of intestinal inflammation. However, traditional drugs rarely target intestinal M2 macrophages, and they are not easily cleared. Gold nanoclusters are known for their in vivo safety and intrinsic biomedical activities. In this study, a glutathione-protected gold nanocluster is synthesized and evaluated, namely, GA. Interestingly, GA specifically accumulates in the colon during IBD. Furthermore, GA not only promotes M2 differentiation of IL-4-treated peritoneal macrophages but also reprograms macrophage polarization from M1 to M2 in a pro-inflammatory environment. Mechanistically, this regulatory effect is exerted through activating the antioxidant Nrf2 signaling pathway, but not traditional STAT6. When applied in IBD mice, we found that GA elevates M2 macrophages and alleviates IBD in an Nrf2-dependent manner, evidenced by the abolished therapeutic effect upon Nrf2 inhibitor treatment. Most importantly, GA administration significantly suppresses AOM/DSS-induced CAC, without causing obvious tissue damage, providing critical evidence for the potential application of gold nanoclusters as nanomedicine for the treatment of IBD and CAC.


Association between albuminuria and proteinuria in the general population: the AusDiab Study.
The relationship between urinary albumin and total protein excretion and the appropriateness of one test over the other are unclear due to the paucity of large epidemiological studies of albuminuria and proteinuria. In screening for renal and cardiovascular disease, whether to measure albuminuria, proteinuria or both, is currently an unanswered question. Random urine samples from 10,596 (94.2%) participants of the Australian Diabetes, Obesity and Lifestyle Study were tested for albuminuria (urine albumin:creatinine > or =30 mg/g) and proteinuria (urine protein:creatinine > or =0.20 mg/mg). This study was a representative sample of the national non-institutionalized population drawn from 42 randomly selected urban and non-urban areas (census collector districts) across Australia. Among a representative cross-section of the Australian adult population, urine albumin excretion was strongly correlated with total protein excretion, particularly among the elderly, and those with diabetes mellitus, hypertension, obesity and renal impairment (P <0.001). Albuminuria performed well as a screening test for proteinuria: sensitivity 91.7% [95% confidence interval (CI) 87.7-94.5%], specificity 95.3% (95% CI 94.9-95.7%) and negative predictive value 99.8% (95% CI 99.7-99.9%). However, among those with proteinuria, 8% excreted albumin within the normal range. While albuminuria may be a suitable test for general population screening for renal and cardiovascular disease, it should not replace testing for proteinuria in those with known or suspected renal disease.


Thiazide diuretics affect osteocalcin production in human osteoblasts at the transcription level without affecting vitamin D3 receptors.
Besides their natriuretic and calciuretic effect, thiazide diuretics have been shown to decrease bone loss rate and improve bone mineral density. Clinical evidence suggests a specific role of thiazides on osteoblasts, because it reduces serum osteocalcin (OC), an osteoblast-specific protein, yet the mechanisms implicated are unknown. We therefore investigated the role of hydrochlorothiazide (HCTZ) on OC production by the human osteoblast-like cell line MG-63. HCTZ dose-dependently (1-100 microM) inhibited 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-induced OC release by these cells (maximal effect, -40-50% and p < 0.005 by analysis of variance [ANOVA]) as measured by ELISA. This effect of HCTZ on OC release was caused by a direct effect on OC gene expression because Northern blot analysis revealed that OC messenger RNA (mRNA) levels were reduced in the presence of increasing doses of the diuretic (-47.2+/-4.0%; p < 0.0001 by paired ANOVA with 100 microM 13.6+/-0.49 pmol/mg protein/15 minutes; p < 0.05) in MG-63 cells. Reducing extracellular Ca2+ concentration with 0.5 mM EDTA or 0.5 mM ethylene glycol-bis(beta-amino ethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) only partly prevented the inhibitory effect of the diuretic on OC secretion (maximal effect, -22.5+/-6.9%), suggesting that thiazide-dependent Ca2+ influx is not sufficient to elicit the inhibition of OC secretion. Because OC production is strictly dependent on the presence of 1,25(OH)2D3 in human osteoblasts, we next evaluated the possible role of HCTZ on vitamin D3 receptors (VDR) at the mRNA and protein levels. Both Northern and Western blot analyses showed no effect of HCTZ (1-100 microM) on VDR levels. The presence of EGTA in the culture media reduced slightly the VDR mRNA levels under basal condition but this was not modified in the presence of increasing levels of HCTZ. The OC gene promoter also is under the control of transcription factors such as Yin Yang 1 (YY1) and cFOS. Western blot analysis revealed no changes in YY1 levels in response to HCTZ either in the presence or in the absence of 0.5 mM EGTA in the culture media. In contrast, HCTZ induced a dose-dependent increase in cFOS levels (p < 0.002 by ANOVA), a situation prevented by incubation with EGTA. These studies indicate that HCTZ inhibits OC mRNA expression independently of an effect on VDR, YY1, or extracellular Ca2+ levels but involves changes in cFOS levels. As OC retards bone formation/mineralization, the inhibition of OC production by HCTZ could explain its preventive role in bone loss rate.


Aggregation of coronene: the effect of carboxyl and amine functional groups.
The aggregation of coronene is relevant to understand the formation of carbon nanomaterials, including graphene quantum dots (GQDs) that show exceptional photophysical properties. This article evaluates the influence of carboxyl and amine substituting groups on the aggregation of coronene by performing a global optimization study based on a new potential energy surface. The structures of clusters with substituted coronene are similar to those formed by un-substituted monomers, that is, stacked (non-stacked) motifs are favoured for small-size (large-size) clusters. Nonetheless, the presence of carboxyl and amine groups leads to an increase of the number of local minima of comparable energy. The clusters with substituted monomers have also shown to enhance the attractive component interaction, which can be attributed to weak induction and charge transfer effects and to stronger electrostatic contributions. Moreover, the calculated height of magic-number structures of the clusters in this work is compatible with the morphology of the GQDs reported in the literature.