Diffuse "encephalitic" cerebral toxoplasmosis in AIDS. Report of four cases.
Four patients with AIDS presented with a rapidly fatal global neurological illness. CT did not show any focal lesion and gross post mortem examination of the brain was normal in three of the four cases. Microscopic examination revealed numerous widespread microglial nodules in the brain parenchyma, most containing central toxoplama cysts or free tachyzoites. Such diffuse, non-necrotic, "encephalitic" forms of cerebral toxoplasmosis appear unique to AIDS and, to our knowledge, have not been documented previously. They represent a treatable, often misdiagnosed cause of diffuse neurological involvement in AIDS patients.


Gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4BD), and gamma-butyrolactone (GBL) intoxication: A state-of-the-art review.
γ-hydroxybutyrate (GHB) is synthesized endogenously from γ-aminobutyric acid (GABA) or exogenously from 1,4-butanediol (butane-1,4-diol; 1,4-BD) or γ-butyrolactone (GBL). GBL, and 1,4-BD are rapidly converted to GHB. The gastric absorption time, volume of distribution, and half-life of GHB are between 5 and 45 min, 0.49 ± 0.9 L/kg, and between 20 and 60 min, respectively. GHB and its analogues have a dose-dependent effect on the activation of GHB receptor, GABA-B, and GABA localized to the central nervous system. After ingestion, most patients present transient neurological disorders (lethal dose: 60 mg/kg). Chronic GHB consumption is associated with disorders of use and a withdrawal syndrome when the consumption is discontinued. GHB, GBL, and 1,4-BD are classified as narcotics but only the use of GHB is controlled internationally. They are used for drug facilitated (sexual) assault, recreational purposes, slamsex, and chemsex. To confirm an exogenous intake or administration of GHB, GBL, or 1-4-BD, the pre-analytical conservation is crucial. The antemortem cutoff doses for detection are 5 and 5-15 mg/L, with detection windows of 6 and 10 h in the blood and urine, respectively Control of GHB is essential to limit the number of users, abuse, associated risks, and death related to their consumption.


Specialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules.
T cells undergo rigorous selection in the thymus to ensure self-tolerance and prevent autoimmunity, with this process requiring innocuous self-antigens (Ags) to be presented to thymocytes. Self-Ags are either expressed by thymic stroma cells or transported to the thymus from the periphery by migratory dendritic cells (DCs); meanwhile, small blood-borne peptides can access the thymic parenchyma by diffusing across the vascular lining. Here we describe an additional pathway of thymic Ag acquisition that enables circulating antigenic macromolecules to access both murine and human thymi. This pathway depends on a subset of thymus-resident DCs, distinct from both parenchymal and circulating migratory DCs, that are positioned in immediate proximity to thymic microvessels where they extend cellular processes across the endothelial barrier into the blood stream. Transendothelial positioning of DCs depends on DC-expressed CX3CR1 and its endothelial ligand, CX3CL1, and disrupting this chemokine pathway prevents thymic acquisition of circulating proteins and compromises negative selection of Ag-reactive thymocytes. Thus, transendothelial DCs represent a mechanism by which the thymus can actively acquire blood-borne Ags to induce and maintain central tolerance.


Proline-serine-threonine-repeat region of MDC1 mediates Chk1 phosphorylation and the DNA double-strand break repair.
MDC1, a mediator of DNA damage response, recruits other repair proteins on double-strand break (DSB) sites. MDC1 is necessary for activating checkpoint kinases Chk1 and Chk2. It is unclear whether Chk1 interacts with MDC1. MDC1 also comprises many discrete domains. The role of the proline-serine-threonine (PST)-repeat domain of MDC1 in the DNA damage response is unclear. Here, we showed that MDC1 directly binds Chk1 through this PST-repeat region. Phosphorylation of Chk1 by ionizing radiation (IR) also required this PST-repeat domain. Degradation of intact MDC1 was accelerated depending on the PST-repeat domain after IR exposure. In the IR damage response, the PST-repeat-deleted MDC1 levels remained elevated with slow degradation. This abnormal regulation of MDC1 was F-box- and WD40 repeat-containing 7 (FBXW7)-dependent. The mutation of lysine 1413 within the PST-repeat of MDC1 deregulated MDC1 with or without damage. K1413R mutant and PST-deleted MDC1 displayed reduced ability to repair the damaged genome post-IR exposure. These results provide that the PST domain of MDC1 is involved in Chk1 and DNA repair activation. The findings suggest new insights into how MDC1 connects the checkpoint and DNA repair in the DNA damage response.


Choroidal neovascularization in fellow eyes of patients with advanced senile macular degeneration. Role of laser photocoagulation.
Choroidal neovascularization in fellow eyes of patients with advanced disciform macular scars usually has an unfavorable prognosis. Fifty-two such fellow eyes were treated, using the monochromatic green argon laser. The neovascular membranes were foveal in 24 eyes, juxtafoveal in ten eyes, and perifoveal in 18 eyes. Complete closure of the choroidal new vessels after treatment was seen in 46 eyes. Only one eye in the foveal group and five eyes in the juxtafoveal group had residual new vessels. After an average follow-up period of 16 months, improvement or stabilization of vision was seen in 36 eyes--18 eyes in the foveal group, four in the juxtafoveal group, and 14 in the perifoveal group. In view of the rewarding anatomical and functional results, photocoagulation, using the monochromatic green argon laser, should be considered in these high-risk eyes. Treatment of foveal neovascular membranes seems to be indicated if the visual acuity is 20/70 or worse.


Efficacy of long pulse Nd:YAG laser versus fractional Er:YAG laser in the treatment of hand wrinkles.
There are different modalities for hand rejuvenation. Fractional Er:YAG laser and long pulse Nd:YAG laser were introduced for treating hand wrinkles. We plan to compare fractional Er:YAG laser and long pulse Nd:YAG laser in a randomized controlled double-blind design with multiple sessions and larger sample size in comparison with previous studies. Thirty-three participants with hand wrinkles entered this study. They were randomly allocated to undergo three monthly laser treatments on each hand, one with a fractional Er:YAG laser and the other with a long pulse Nd:YAG laser. The evaluations included assessment of clinical improvement determined by two independent dermatologists not enrolled in the treatment along with measuring skin biomechanical property of hands using a sensitive biometrologic device with the assessment of cutaneous resonance running time (CRRT). Moreover, potential side effects and patients' satisfaction have been documented at baseline, 1 month after each treatment, and 3 months after the final treatment session. Clinical evaluation revealed both modalities significantly reduce hand wrinkles (p value < 0.05), with no significant difference between two lasers. Mean CRRT values also decreased significantly after the laser treatment compared to those of the baseline in both laser groups. There was no serious persistent side effect after both laser treatments. Both fractional Er:YAG and long pulse Nd:YAG lasers show substantial clinical improvement of hand skin wrinkles with no serious side effects. However, combination treatment by these lasers along with the other modalities such as fat transfer could lead to better outcomes in hand rejuvenation. IRCT2016032020468N4.


Cystathionine-γ-lyase gene silencing with siRNA in monocytes/ macrophages attenuates inflammation in cecal ligation and puncture-induced sepsis in the mouse.
Hydrogen sulphide is an endogenous inflammatory mediator produced by cystathionine-γ-lyase (CSE) in macrophages. To determine the role of H2S and macrophages in sepsis, we used small interference RNA (siRNA) to target the CSE gene and investigated its effect in a mouse model of sepsis. Cecal ligation puncture (CLP)-induced sepsis is characterized by increased levels of myeloperoxidase (MPO) activity, morphological changes in liver and pro-inflammatory cytokines and chemokines in the liver and lung. SiRNA treatment attenuated inflammation in the liver and lungs of mice following CLP-induced sepsis. Liver MPO activity increased in CLP-induced sepsis and treatment with siRNA significantly reduced this. Similarly, lung MPO activity increased following induction of sepsis with CLP while siRNA treatment significantly reduced MPO activity. Liver and lung cytokine and chemokine levels in CLP-induced sepsis reduced following treatment with siRNA. These findings show a crucial pro-inflammatory role for H2S synthesized by CSE in macrophages in sepsis and suggest CSE gene silencing with siRNA as a potential therapeutic approach for this condition.


Efficacy of Vemurafenib Treatment in 43 Metastatic Melanoma Patients with BRAF Mutation. Single-Institute Retrospective Analysis, Early Real-Life Survival Data.
BRAF inhibitor vemurafenib achieved improved overall survival over chemotherapy and have been approved by the FDA and EMA for the treatment of BRAF-mutated metastatic melanoma. The aim of our retrospective analysis was to determine the efficacy and safety of vemurafenib therapy for BRAF mutated metastatic melanoma and subsequently to prove the clinical benefit for the studied 43 patients, based on real-life data. From November 2012 to October 2015 we have selected 43 BRAF mutated, metastatic melanoma patients, treated with vemurafenib. The median follow-up time was 15.9 months. We evaluated progression free survival (PFS), overall survival (OS) and toxicities. According to the AJCC staging system 70% of the patients had stage M1c metastasis, including 6 with stable brain metastasis. Objective responses were noted in 51.1%, the disease control rate was achieved in 79% of the patients. Complete responses were attained by 5 patients (11.6%). Median PFS was 6.48 (95% CI:4.8-15.0) months, median OS was 11.47 (95% CI:8.08-NA) months. We found significant association between LDH level and OS in univariate (p = 0.000613) and multivariate analysis (p = 0.0168). The most common adverse events (AEs) included follicular hyperkeratosis, rash, arthralgia and photosensitivity. Grade 3 AEs, such as cutaneous squamous-cell carcinoma, QTcB interval prolongation, rash, arthralgia were reported in 7 patients (17%). We had no Grade 4 side effects. Similar to the previously published data our analysis confirms the improved survival with vemurafenib treatment (11.47 months) in patients with BRAF V600 mutation. Vemurafenib therapy was well tolerated, the AE profile was almost consistent with the previously reported data of randomised clinical trials.


The effect of zinc ion on the absorption and emission spectra of glutathione derivative: predication by ab initio and DFT methods.
Relying on the reaction of o-phthalaldehyde (OPA) with glutathione (GSH) to form a highly fluorescence derivative GSH-OPA has been widely used to measure reduced glutathione. In order to better understand spectra property of the GSH-OPA and the effect of zinc ion on it, the ground and the lowest singlet excited state properties, the electronic absorption and emission spectra are predicted by ab initio and DFT methods. The absorption spectra are simulated using time dependent DFT method (TD-DFT) whereas the emission spectra are approximated by optimizing the lowest singlet excited state by HF/CI-Singles and then subsequently using this geometry for the TD-DFT calculations. The solvent effects on transition energies have been described within the conductor-like polarizable continuum model (CPCM). The calculated transition energies (absorption and emission) are in agreement with available experimental information.


Epicardial atrial defibrillation: successful treatment of postoperative atrial fibrillation.
Atrial fibrillation is the most common complication after cardiac surgery. Current medical treatment using antiarrhythmics and anticoagulants has a significant morbidity. The goal of this study was to determine if epicardial atrial defibrillation can be safely performed and return patients to sinus rhythm. A prospective analysis of patients undergoing cardiac surgery was performed. Patients with a prior pacemaker/defibrillator, history of arrhythmia, preoperative antiarrhythmic, age greater than 85 years, history of stroke, or intraaortic balloon pump were excluded. Temporary epicardial atrial cardioversion wires were placed on the right and left atrium. Bipolar atrial and ventricular pacing wires were also placed. The wires were tested in the operating room. Patients who went into postoperative arial fibrillation were cardioverted with 3 J, 6 J, or 9 J. There were 45 patients enrolled. Sixteen patients (35%) went into postoperative arial fibrillation during their hospital stay. Mean time to onset of arial fibrillation was 2.6 +/- 1.4 days after surgery. Fifteen patients were successfully cardioverted to sinus rhythm on the primary cardioversion, with mean of 5.7 +/- 2.4 J. One patient was cardioverted at 6 hours after onset of arial fibrillation, at 6 J. Recurrent arial fibrillation occurred in 4 patients during their hospital stay. All 4 of these patients were cardioverted with a mean of 6.4 +/- 2.6 J. All wires were removed the day before patients were discharged. There were no complications with wire insertion or removal. There were no adverse neurologic events. The mean hospital stay was 5.1 +/- 2.2 days. All patients were in sinus rhythm at 1 month follow-up. The use of a temporary atrial defibrillator to resynchronize patients in postoperative arial fibrillation is safe and effective.


Acquired pyruvate kinase deficiency. The effect of maleic acid upon human erythrocyte pyruvate kinase.
1. Maleic acid is shown to be able to bind the thiol compound 2-mercaptoethanol. This is fully consistent with the data of Morgan and Friedman (1938). 2. Human erythrocyte pyruvate kinase dissolved and quantitated in Tris-maleate shows a loss of positive homotropic interactions, as compared to the same preparation in Tris-HCl. Hill coefficients (n) of n = 1.0-1.2 and n = 1.6-1.8 are obtained in Tris-maleate and Tris-HCl respectively. Half saturation [S] 0.5 and Vmax remain unchanged. Pyruvate kinase in Tris-maleate is slightly more stable to heating at 60 degrees C than in Tris-HCl. Incubation of the enzyme in Tris-maleate for one h with high concentrations of dithiotreitol restores the positive homotropic interactions. 3. It is proposed, that the abnormalities of the pyruvate kinase of some patients with acquired pyruvate kinase deficiency, obtained from a study in Tris-maleate, may partly be induced by the buffer itself.


New diketone based vanadium complexes as insulin mimetics.
Since 1985, when Heyliger et al. first reported the in vivo insulin mimetic activity of oral vanadate, extensive studies exploring vanadium chemistry, including the synthesis of novel complexes and their biological effects both in vitro and in vivo have been pursued. Such complexes have emerged as possible potential agents for diabetes therapy. Among the several existing compounds, diketone based vanadium complexes have been chosen for the current study. Two new complexes namely bisdimethylmalonatooxovanadium(IV) and bisdiethylmalonatooxovanadium(IV) have been synthesized and characterized by UV-visible, FTIR and mass spectral studies. The antidiabetic activity of the complexes was proved by animal study. The results show that the above complexes have comparable antidiabetic potential with respect to the standard drug as well as with bisacetylacetonatooxovanadium(IV) which has been studied earlier by Reul et al.


Transcriptional profiles discriminate patients with pulmonary tuberculosis from non-tuberculous individuals depending on the presence of non-insulin diabetes mellitus.
Our objective was to identify transcriptional biomarkers in peripheral blood mononuclear cells (PBMC) that discriminate individuals with latent tuberculosis infection (LTBI) from those with pulmonary tuberculosis (PTB) in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and in individuals without NIDDM. Using gene expression microarrays we identified differentially expressed genes from lungs of mice infected with Mycobacterium tuberculosis (Mtb) or a mutant (ΔsigH) representing a non-inflammatory model. Genes expressed in blood, with inflammatory related functions were evaluated in humans by RT-qPCR. NCF1 and ORM transcripts have the better discriminatory capacity to identify PTB subjects from LTBI and non-infected controls (NICs) independently of the presence of NIDDM. The sequential evaluation of the mRNA levels of NCF1 and ORM as multiple diagnostic tests showed 95% Sensitivity (Se) and 80% Specificity (Sp). In addition, FPR2 promises to be a good biomarker for the PTB detection in subjects with NIDDM (Se=100%; Sp=90%).


Organizational influences on the use of low-value care in primary health care - a qualitative interview study with physicians in Sweden.
The aim was (1) to explore organizational factors influencing the use of low-value care (LVC) as perceived by primary care physicians and (2) to explore which organizational strategies they believe are useful for reducing the use of LVC. Qualitative study with semi-structured focus group discussions (FGDs) analyzed using qualitative content analysis. Six publicly owned primary health care centers in Stockholm. The participants were 31 primary care physicians. The number of participants in each FGD varied between 3 and 7. Categories and subcategories reporting organizational factors perceived to influence the use of LVC and organizational strategies considered useful for reducing the use of LVC. Four types of organizational factors (resources, care processes, improvement activities, and governance) influenced the use of LVC. Resources involved time to care for patients, staff knowledge, and working tools. Care processes included work routines and the ways activities and resources were prioritized in the organization. Improvement activities involved performance measurement and improvement work to reduce LVC. Governance concerned organizational goals, higher-level decision making, and policies. Physicians suggested multiple strategies targeting these factors to reduce LVC, including increased patient-physician continuity, adjusted economic incentives, continuous professional development for physicians, and gatekeeping functions which prevent unnecessary appointments and guide patients to the appropriate point of care. . The influence of multiple organizational factors throughout the health-care system indicates that a whole-system approach might be useful in reducing LVC.KEY POINTSWe know little about how organizational factors influence the use of low-value care (LVC) in primary health care.Physicians perceive organizational resources, care processes, improvement activities, and governance as influences on the use of LVC and LVC-reducing strategies.This study provides insights about how these factors influence LVC use.Strategies at multiple levels of the health-care system may be warranted to reduce LVC.


Bowdenol, a new 2,3-dihydrobenzofuran constituent from Bowdichia virgilioides.
From the stem bark of Bowdichia virgilioides, lupeol, lupeol acetate, sitosterol, stigmasterol and methyl-3-[2-(1-hydroxymethylvinyl)-2,3-dihydrobenzo[b]furan-5-yl]-(E)-2-propenoate have been isolated. The latter is a new compound and it has been named as bowdenol. Their structures were elucidated with the aid of spectroscopic techniques, mostly 1 and 2D NMR. The biogenetic pathway for bowdenol has been suggested.


Factors associated with in-hospital recurrence of intestinal intussusception in children.
A minority of children experience in-hospital recurrence of intestinal intussusception after treatment. This study investigated the factors associated with in-hospital recurrence of intussusception in pediatric patients in China. This retrospective study included patients aged 0-18 years-old with intestinal intussusception treated at Hainan Women and Children's Medical Center between January 2019 and December 2019. Demographic and clinical characteristics were extracted from the medical records. Factors associated with in-hospital recurrence of intussusception were identified by logistic regression analysis. The analysis included 624 children (400 boys) with a median age of 1.8 years (range, 2 months and 6 days to 9 years). Seventy-three children (11.7%) had in-hospital recurrence of intussusception after successful reduction with air enema. Multivariate logistic regression analysis identified age > 1 year-old (odds ratio [OR]: 7.65; 95% confidence interval [95%CI]: 2.70-21.71; P < 0.001), secondary intestinal intussusception (OR: 14.40; 95%CI: 4.31-48.14; P < 0.001) and mesenteric lymph node enlargement (OR: 1.90; 95%CI: 1.13-3.18; P = 0.015) as factors independently associated with in-hospital recurrence of intussusception. Age > 1 year-old, secondary intussusception and mesenteric lymph node enlargement were independently associated with increased odds of in-hospital recurrence of intussusception after successful reduction with air enema.


Gallium containing bioactive materials: A review of anticancer, antibacterial, and osteogenic properties.
The incorporation of gallium into bioactive materials has been reported to enhance osteogenesis, to influence blood clotting, and to induce anti-cancer and anti-bacterial activity. Gallium-doped biomaterials prepared by various techniques include melt-derived and sol-gel-derived bioactive glasses, calcium phosphate bioceramics, metals and coatings. In this review, we summarize the recently reported developments in antibacterial, anticancer, osteogenesis, and hemostasis properties of Ga-doped biomaterials and briefly outline the mechanisms leading to Ga biological effects. The key finding is that gallium addition to biomaterials has great potential for treating bone-related diseases since it can be efficiently transferred to the desired region at a controllable rate. Besides, it can be used as a potential substitute for antibiotics for the inhibition of infections during the initial and advanced phases of the wound healing process. Ga is also used as an anticancer agent due to the increased concentration of gallium around excessive cell proliferation (tumor) sites. Moreover, we highlight the possibility to design different therapeutic approaches aimed at increasing the efficiency of the use of gallium containing bioactive materials for multifunctional applications.


Remote cerebellar hemorrhage after spinal procedures (part 2): a systematic review.
A remote cerebellar hemorrhage (RCH) is a spontaneous bleeding in the posterior fossa, which can be rarely observed as a complication of spine surgery. As well as for RCH reported after supratentorial procedures, it shows a characteristic bleeding pattern defined "zebra sign". Nowadays, RCH pathophysiology still remains unknown. We performed a comprehensive review, collecting all cases of RCH after spine surgery reported in literature in order to identify the procedures most frequently associated with RCH and the possible risk factors. We assessed percentages of incidence and 95 % confidence interval of all demographic, neuroradiological, and clinical features. Univariate and multivariate analyses were used to evaluate their association with outcome. We included 44 articles reporting 57 patients with mean age of 57.6 ± 13.9 years and a male/female ratio of 23/34. A RCH was more frequently reported as a complication of decompressive procedures for spinal canal stenosis, particularly when associated with instrumented fusion, followed by spinal tumor debulking and disc herniation removal. In the majority of cases, RCH occurrence was characterized by progressive impairment of consciousness, whereas some patients complained non-specific symptoms. Coagulation disorders, hypertension, and placement of postoperative subfascial drainages were the most frequently reported risk factors. The occurrence of intraoperative dural lesions was described in about 93 % of patients. Zebra sign was the most common bleeding pattern (about 43 % of cases) followed by parenchymal hematoma (37.5 %) and mixed hemorrhage (about 20 %). Impairment of consciousness at clinical onset and intake of anticoagulants/antiplatelets appeared associated with poor outcome at univariate analysis. However, more than 75 % of patients showed a good outcome and a RCH often appeared as a benign and self-limiting condition, which usually did not require surgical treatment, but only prolonged clinical surveillance, unless of the occurrence of complications.


The association between operator confidence and accuracy of ultrasonography performed by novice emergency physicians.
The variable accuracy of emergency department (ED) ultrasound described in the literature has limited its utility as the sole imaging modality in critical decision making. Although ultrasound accuracy is highly dependent upon the technical abilities of the operator and conditions unique to each patient, no previous study of ED ultrasound has included estimates of operator confidence. This prospective observational study explores the association between operator confidence and the accuracy of ED ultrasound. Ultrasound was not performed in our ED until a formal training module was instituted. Patients were enrolled prospectively for the first year following the training module if they underwent one of the following ultrasound studies: abdominal examination for intraperitoneal fluid, right upper quadrant examination for gallstones, renal examination for hydronephrosis, pelvic examination for intrauterine pregnancy, abdominal examination for aorta diameter > 3 cm, or cardiac examination for pericardial fluid. In addition, formal ultrasound, computed tomography, magnetic resonance imaging, or an invasive procedure was required as a "gold standard" for each patient. Operators recorded their interpretation of the ED ultrasound and rated their confidence with the analysis before the formal imaging study or procedure. Test performance characteristics for each examination type and for all studies together were determined. The association between operator confidence and accuracy was explored using logistic regression and by determining test performance characteristics with patients stratified by confidence value. A total of 276 ED ultrasound studies were included. There were no significant differences in accuracy between ED attendings and residents. Overall accuracy, sensitivity, specificity, LR+, and LR- were 90%, 92%, 86%, 6.8, and 0.09, respectively. With confidence scores of 9 or 10 (n = 113), these values improved to 96%, 99%, 90%, 9.6, and 0.01, respectively. Logistic regression revealed an association between confidence and ED ultrasound accuracy (p < 0.001). It is concluded that a significant association exists between operator confidence and the accuracy of ED ultrasound. High confidence values are associated with clinically useful test performance characteristics.


Fate of chronic myeloid leukemia patients treated with allogeneic bone marrow transplantation or chemotherapy and/or interferon at a single center: long-term results.
From April 1981 to February 2000, 105 patients with chronic myeloid leukemia (CML) underwent BMT from HLA-identical related donors at a single center. Eighty-eight patients were in chronic phase (CP), 11 patients in accelerated phase and six patients in blast crisis. Ten of these patients received a second BMT (BMT2). Comparison of BMT in CP with chemotherapy and/or alpha-IFN (n=70) was also made. Patients were given cyclophosphamide (CY) and single-dose TBI (CYTBI, n=38) or busulfan (BU) and CY (BUCY, n=67). Overall 54 patients are alive and 52 of them are disease-free with a median follow-up of 11.3 (range 1.1-19.4) years. Ten-year disease-free survival (DFS) in CP patients was better after BUCY, 61% (95% CI, 47-68%) than after CYTBI, 41% (95% CI, 23-61%) (P=0.07). For 88 patients who received a transplant in CP, results were significantly improved when BMT was performed within 1 year after diagnosis (P=0.02) or at an age < or = 25 years old (P=0.01). Ten-year survival in patients who received BMT in CP was better than in patients treated with chemotherapy (56% vs 10%; P=0.0001) or alpha-IFN-based treatment (33%; P=0.09) with survival curves crossing at 4.2 years and at 4 years, respectively. The probability of DFS after BMT2 was 60% (95% CI, 26-87%). CP patients who received BMT after CYTBI had a higher probability of relapse and transplant-related mortality than patients receiving BUCY (53% and 58% vs 9% and 34%; P=0.002 and P=0.08, respectively). All but six patients are currently on no medication and have resumed all activities without any limitation. These long-term results confirm that allogeneic BMT is the only curative approach for CML patients and should be offered to all patients with a suitable donor as soon after diagnosis as possible.


Allostatic Load and Mortality: A Systematic Review and Meta-Analysis.
Allostatic load, a measure of stress-related physiologic dysregulation, is associated with numerous mortality risk factors. This systematic review and meta-analysis examines the relationship between high allostatic load (i.e., increased dysregulation versus low dysregulation) and mortality (cardiovascular disease and all-cause mortality). Systematic searches of 2 databases conducted in May 2021 yielded 336 unique records; 17 eligible studies (2001-2020) were included. High allostatic load was associated with increased risk of all-cause mortality across all the 17 individual studies (hazard ratio=1.08-2.75) and in 6 of 8 studies examining cardiovascular disease mortality (hazard ratio=1.19-3.06). Meta-analyses indicated that high allostatic load was associated with increased risk of all-cause mortality, overall (hazard ratio=1.22, 95% CI=1.14, 1.30, n=10) and across subgroups (hazard ratio=1.11-1.41), and similarly for cardiovascular disease mortality (hazard ratio=1.31, 95% CI=1.10, 1.57, n=6). Although studies were generally of good quality (n=13), heterogeneity was high in most pooled estimates (I2>90%). In this review of relatively good-quality studies, high allostatic load was associated with an increased mortality risk of 22% for all-cause mortality and 31% for cardiovascular disease mortality. Thus, allostatic load is an emerging and potent modifiable risk factor for all-cause and cardiovascular disease mortality that shows promise as a prognostic indicator for mortality. The heterogeneity in allostatic load assessment across studies highlights the need for standardized measurement. The findings underscore the importance of allostatic load's dynamic nature, which may be especially relevant for mitigating mortality risk in younger adults. Because older adults are oversampled, future allostatic load research should prioritize younger adults and longitudinal monitoring and specific cardiovascular disease mortality risk associations and individualize behavioral and lifestyle targets for reducing allostatic load.


Studies on avian infectious bronchitis virus (IBV). III. Interferon induction by and sensitivity to interferon of IBV.
The induction of interferon by avian infectious bronchitis virus (IBV) and the sensitivity of IBV to interferon were studied. The results of experiments with ten IBV strains are summarized as follows. 1. All the IBV strains tested induced interferon in chick embryo (CE) cells, chicken kidney (CK) cells and embryonated eggs. The Iowa-609 strain induced about 1000 units of interferon in CE cells while the Beaudette-42 strain induced about 200 units of interferon in embryonated eggs; the interferon titers induced by other strains usually ranged from 5 to 60 units. No IBV strain induced interferon in HeLa or BHK-21 cells. 2. IBV particles inactivated by ultraviolet irradiation or by heating lost their ability to induce interferon. 3. The properties of the interferon produced in the present study are similar to those of other interferons produced in chicken cells. 4. HeLa or BHK-21 cells did not acquire resistance to virus infection, after incubation with interferon produced in CE cells. On the other hand, CK cells acquired the same degree of resistance to virus infection as CE cells after incubation with interferon produced in CE cells. 5. All the IBV strains tested were sensitive to interferon in CK cells. The sensitivities of Massachusetts-41 and Holte strains to interferon were similar to that of vesicular stomatitis virus.


Tracking prey or tracking the prey's resource? Mechanisms of movement and optimal habitat selection by predators.
We synthesize previous theory on ideal free habitat selection to develop a model of predator movement mechanisms, when both predators and prey are mobile. We consider a continuous environment with an arbitrary distribution of resources, randomly diffusing prey that consume the resources, and predators that consume the prey. Our model introduces a very general class of movement rules in which the overall direction of a predator's movement is determined by a variable combination of (i) random diffusion, (ii) movement in the direction of higher prey density, and/or (iii) movement in the direction of higher density of the prey's resource. With this model, we apply an adaptive dynamics approach to two main questions. First, can it be adaptive for predators to base their movement solely on the density of the prey's resource (which the predators do not consume)? Second, should predator movements be exclusively biased toward higher densities of prey/resources, or is there an optimal balance between random and biased movements? We find that, for some resource distributions, predators that track the gradient of the prey's resource have an advantage compared to predators that track the gradient of prey directly. Additionally, we show that matching (consumers distributed in proportion to resources), overmatching (consumers strongly aggregated in areas of high resource density), and undermatching (consumers distributed more uniformly than resources) distributions can all be explained by the same general habitat selection mechanism. Our results provide important groundwork for future investigations of predator-prey dynamics.


Hemolytic potential of miltefosine is dependent on cell concentration: Implications for in vitro cell cytotoxicity assays and pharmacokinetic data.
Miltefosine possesses antiparasitic, antibacterial, antifungal and antitumor activities; however, its mechanism of action is not well established. In the current work, the miltefosine concentrations required to achieve 50% hemolysis in PBS were shown to vary from 600 μM using 5×10(9) cells/mL to ~2.9 μM for ~5×10(6) cells/mL. This cell concentration-dependent hemolytic potential was described using an equation that included the membrane-water partition coefficient (K) and miltefosine concentrations in the cell membrane (cm) and aqueous medium (cw) as variables. The best-fit values for the 50% hemolysis data were log K=4.68, cm=110.8 mM, and cw=2.3 μM. Hemolysis measurements in whole blood were used to determine the erythrocyte membrane-plasma partition coefficient of miltefosine (Log KM/P=1.77). Additionally, miltefosine concentration in whole blood was found to be ~86% of that in plasma. Previously reported clinical pharmacokinetics data indicate that the plasma concentration of miltefosine peaks at ~90 μg/mL when treating visceral leishmaniasis. Using this concentration, which corresponds to ~77 μg/mL miltefosine in whole blood, we found only 2.8% hemolysis. Significant hemolysis (5.4%) was observed only after doubling the concentration to 180 μg/mL. Recently reported data indicate that miltefosine inhibitory concentrations in Leishmania are also dependent on cell concentration. The biophysical parameters assessed in the current study indicated that this type of response is associated with the accumulation of the drug in the cell membrane, which becomes damaged when critical drug concentrations are reached.


Prioritization of patients on scheduled waiting lists: validation of a scoring system for hip and knee arthroplasty.
The hip and knee replacement priority criteria tool (HKPT) is 1 of 5 tools developed by the Western Canada Waiting List Project for setting priorities among patients awaiting elective procedures. We set out to assess the validity of the HKPT priority criteria score (PCS) and map the maximum acceptable waiting times (MAWTs) for patients to levels of urgency. Two studies were used to assess convergent and discriminant validity. In study 1, consecutive patients on a waiting list for hip or knee arthroplasty were assessed by orthopedic surgeons from the 4 provinces in Western Canada, using the HKPT and data on patient age, gender, joint site, type of surgery (primary or revision), 2 measures of surgeon-rated patient urgency, and diagnosis. In study 2, 6 patients were videotaped during a consultation interview with the surgeon and were assessed by a group of experts. We measured function with the PCS and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In study 1, we assessed 394 patients, and in study 2, 19 raters assessed the 6 patients. Correlations between the PCS and other measures of physician-rated urgency were strong, ranging from 0.78 to 0.89. For a subgroup of 60 patients, correlation between the PCS and function as measured with the WOMAC was 0.48, and correlation was greater (0.45-0.56) between items measuring similar constructs (e.g., pain at rest) than those measuring different constructs (0.21-0.40). In study 2, median MAWTs ranged from 4 to 24 weeks for 5 levels of urgency based on PCS percentiles. Results from this study support the validity of the PCS as a measure of surgeon-rated urgency for hip or knee arthroplasty. Evaluative studies are needed to assess the validity and acceptability of the tools and the establishment of MAWTs in clinical practice.


Clinical and immunological correlates of chest X-ray abnormalities in HIV-infected South African children with limited access to anti-retroviral therapy.
The chest X-ray (CXR) abnormalities of human immunodeficiency virus (HIV)-infected children in low/middle income countries (LMIC's) have not been well studied. To describe the CXR abnormalities and associated clinical/immunological features in HIV-infected South African children. A prospective study of HIV-infected children who underwent baseline chest radiography and clinical and immunological HIV-staging. CXR abnormalities were stratified as grade 1 (mild) or grade 2 (moderate/severe). Univariate and multiple logistic regression analyses assessed associations between radiological severity and clinical/immunological parameters. Three hundred thirty children (53% male), median age 23.8 months, were included; 303 (92%) had moderate/severe clinical disease and 225 (68%) moderate/severe immune suppression; 52 (16%) had a normal CXR; 169 (51%) had grade 2 CXR abnormalities, manifesting as: confluent opacification (n = 91, 28%), nodules (n = 37, 11%), or nodules with opacification (n = 41, 12%) Grade 2 abnormality was associated with more advanced clinical HIV disease (OR: 6.9; 95% CI: 1.9-25.6), CD4+ less than 20% (OR: 1.8; 95% CI: 1.0-3.0) and age over 24 months (OR: 4.1; 95% CI: 2.1-8.0). CXR abnormalities are common in HIV-infected children in LMIC's. The extent of radiological abnormality correlates with age and clinical and immunological severity of HIV-disease.


Integrating molecular modelling methods to advance influenza A virus drug discovery.
Since the discovery of the anti-influenza drugs oseltamivir and zanamivir using computer-aided drug design methods, there have been significant applications of molecular modelling methodologies applied to influenza A virus drug discovery, such as molecular dynamics (MD) simulation, molecular docking, and virtual screening (VS). In this review, we provide a brief general introduction to molecular modelling in the context of drug discovery and then focus on the advances and impact of integrating these methods with specific reference to potential influenza A antiviral drug targets.


Effect of Cassia alata leaf extract on hyperglycemic rats.
The oral effectiveness of Cassia alata leaf extract on streptozotocin-induced hyperglycemia in rats has been studied and the results compared with glybenclamide. While the extract has no effect on glucose levels in normoglycemic animals, it reduced the blood sugar value in streptozotocin-induced hyperglycemic animals.


Neuroregulation of protein synthesis in odontoblasts of the first molar of the rat after wounding.
Odontoblasts respond to occlusal trauma by increased elaboration of a matrix which is subsequently calcified to form reparative dentin. The purpose of the present study was to analyze quantitatively and compare the ability of odontoblasts to synthesize collagen after wounding in rats with an intact innervation (baseline) and in rats with sensory (inferior alveolar nerve, IAN) and/or sympathetic (superior cervical ganglion, SCG) surgical denervation. Surgery was performed 7 days prior to wounding. All rats had 1 mm of enamel and dentin removed from the occlusal surface of the first mandibular molar (resected side) with the contralateral tooth serving as a control. Rats were killed 1 h after injection with 3H-proline on days 0, 5, 10 or 15 after wounding, and mandibles were removed and processed for autoradiography. Grain counts were performed over odontoblasts throughout the pulp horns for each time period and for control and experimental molars in intact (baseline) and denervated groups. When compared to the control baseline, the experimental baseline data showed increased 3H-proline uptake throughout the study with a peak at 5 days. When compared to the baseline data, IAN and SCG results demonstrated a delay or attenuation of the protein synthetic response. The results indicate that the sensory and sympathetic neural components may regulate odontoblastic response to wounding.


Low level of consanguinity in moroccan families at high risk of breast cancer.
Breast cancer is worldwide the most common cancer in women and is a major public health problem. Genes with high or low penetrance are now clearly implicated in the onset of breast cancer, mostly the BRCA genes. All women in families at high risk of breast cancer do not develop tumours, even when they carry the familial mutation, suggesting the existence of genetic and environmental protective factors. Several studies have shown that consanguinity is linked to a decreased or an increased risk of breast cancer, but to the best of our knowledge, there is no study concerning the association between consanguinity and the occurrence of tumours in women with high risk of breast cancer. The objective of this study was to examine whether parental consanguinity in families with genetic predisposition to breast cancer affect the risk of siblings for having this cancer. Over a six-year period, 72 different patients with a histological diagnosis of breast or ovarian cancer from 42 families were recruited for genetic counselling to the Department of Medical Genetics, Rabat. Consanguinity rate was determined in cases and compared to the consanguinity rate in the Moroccan general population. Consanguinity rates were 9.72% in patients and 15.3% in controls, but the difference was statistically not significant (p>0.001) and the mean coefficient of consanguinity was lower in breast cancer patients (0.0034) than in controls (0.0065). Despite the relatively small sample size of the current study, our results suggest that parental consanguinity in Moroccan women might not be associated with an altered risk of breast cancer. Large scale studies should be carried out to confirm our results and to develop public health programs.


[Extended access to revision knee replacement : Intraoperative possibilities for improved joint exposure in complex knee arthroplasty procedures].
In most cases, a standard access via a medial parapatellar arthrotomy with a carefully performed release technique is sufficient for a good exposure of the knee joint in the revision situation. Crucial steps are targeted scar removal, sufficient soft tissue release and recreation of the shifting layers. Tuberosity osteotomy is an effective option for extended exposure at the distal joint region, facilitating a patella replacement to correct abnormalities in the patellofemoral joint. Extended exposure to the proximal joint is possible with the rectus snip and the VY plasty technique. Due to the rather poor results, a quadriceps turndown should be seen more historically and should no longer be used. In extreme cases, a femoral peel or an osteotomy of the medial epicondyle can help achieve the reconstruction of a joint. The latter techniques are reserved for selected cases and always require a linked implant.


Primary mucinous cystadenocarcinoma of the renal pelvis misdiagnosed as ureteropelvic junction stenosis with renal pelvis stone: a case report and literature review.
Primary mucinous adenocarcinoma of the renal pelvis is extremely rare, with only ~100 cases reported till now. Its presumed pathogenesis includes glandular metaplasia of the urothelium of the calyces and the pelvis and malignant transformation of the metaplasia. Unfortunately, it has no characteristic symptoms or radiological features. We report a case of primary mucinous adenocarcinoma of the renal pelvis misdiagnosed as ureteropelvic junction stenosis with a renal pelvis stone. A 50-year-old man presented with discomfort in his right flank after a fall. A physical examination was normal except mild costovertebral angle tenderness on the right side. The results of most laboratory tests were within normal limits. Plain radiography of the kidneys, ureter, and urinary bladder showed a large radio-opaque mass in the right kidney. Abdominal computed tomography showed a hyperdense mass with 2.62 × 5.70 cm size in the right renal pelvis and severe hydronephrosis and cortical thinning. Diuretic-enhanced 99mTc DTPA renal scanning showed that the relative function of the right versus the left kidney was 20 versus 80 %. On the basis of the imaging findings, kidney dysfunction due to ureteropelvic junction stenosis with a large stone was initially diagnosed. However, the drained urine volume was almost zero, and gelatinous material was aspirated when percutaneous nephrostomy was performed for decompression of hydronephrosis. Although the cytopathology of gelatinous material was negative for malignancy, we could not rule out other disease, such as hidden malignancies of the kidney. We therefore performed radical nephrectomy, and pathological examination of the kidney uncovered a mucinous cystadenocarcinoma in the renal pelvis. A bone scan and positron emission tomography showed no evidence of other malignancies, metastasis, or remnant cancer. The patient has been well, without evidence of tumour recurrence or metastasis, for 20 months after surgery. Primary mucinous adenocarcinomas of the renal pelvis are extremely rare, and most are diagnosed via post-operative analysis of resected specimens. Although preoperative diagnosis is difficult, urologists should consider the possibility of primary mucinous adenocarcinoma in patients with severe hydronephrosis accompanied by renal stones and chronic inflammation.


Seminal vesicle abscesses associated with ipsilateral multicystic dysplastic kidney in an infant.
Seminal vesicle cysts are rare lesions and usually asymptomatic. However, when symptoms occur it is typically during the early sexually active period. Furthermore, seminal vesicle abscesses (SVAs) are extremely rare and often difficult to diagnose due to the absence of any typical clinical signs. We herein describe a 2-month-old boy with a left SVA and ipsilateral multicystic dysplastic kidney (MCDK) who presented with a recurrent urinary tract infection (UTI). Magnetic resonance imaging proved to be a valuable diagnostic tool in our patient. Percutaneous transrectal puncture and aspiration were performed, because of recurrent UTI when intravenous antibiotic therapy had been stopped. Three weeks after the procedure, however, the SVA recurred, and, therefore, a transperitoneal laparoscopic excision of the left SVA, ureteral remnant and dysplastic renal tissue was performed. To the best of our knowledge, this is the first case of infantile SVA associated with ipsilateral MCDK. Pediatric clinicians should consider this urological anomaly in boys presenting with intractable UTI, although it is extremely rare.


Granular indigenous microalgal-bacterial consortium for wastewater treatment: Establishment strategy, functional microorganism, nutrient removal, and influencing factor.
Granular indigenous microalgal-bacterial consortium (G-IMBC) system integrates the advantages of the MBC and granular activated sludge technologies, also with superior microalgal wastewater adaptation capacity. In this review, the concept of IMBC was firstly described, followed by its establishment and acclimation strategies. Characteristics and advantages of G-IMBC system compared to other IMBC systems (i.e., attached and floc IMBC systems) were then introduced. Moreover, the involved functional microorganisms and their interactions, as well as nutrient removal mechanisms were systematically and critically reviewed. Finally, the influencing factors including wastewater characteristics and operation factors were discussed. This study aims to provide a comprehensive up-to-date summary of the G-IMBC system for sustainable wastewater treatment.


A comparative study on mesozooplankton abundance and diversity between a protected and an unprotected coastal area of Andaman Islands.
The study was carried out to understand the variability in phytoplankton production (Chlorophyll a) and mesozooplankton diversity from two different shallow coastal regions of south Andaman viz. Port Blair Bay (PBB), the only real urban area among the islands and Mahatma Gandhi Marine National Park, a Marine Protected Area (MPA) at Wandoor. Seasonal sampling was carried out during the Northeast monsoon (NEM--November 2005), Intermonsoon (IM--April 2006), and Southwest monsoon (SWM--August 2006). Significant (P < 0.05) seasonal variation was observed in the environmental variables at both the regions. Higher average chlorophyll a (Chl. a) and mesozooplankton standing stock were observed at PBB compared to MPA, but the seasonal variation observed was marginal at both the study areas. Chl. a showed a steep increasing gradient from outer to the inner regions of the PBB. The number of zooplankton taxa recorded at both areas was quite similar, but marked differences were noticed in their relative contribution to the total abundance. Eventhough the Copepoda dominated at both the areas, the non-copepod taxa differed significantly between the regions. Dominance of carnivores such as siphonophores and chaetognaths were noticed at PBB, while filter feeders such as appendicularians and decapod larvae were more abundant at MPA. A total of 20 and 21 copepod families was recorded from PBB and MPA, respectively. Eleven species of chaetognaths were observed as common at both areas. Larval decapods were found to be predominant at MPA with 20 families; whereas, at PBB, only 12 families were recorded. In the light of the recent reports on various changes occurring in the coastal waters of the Andaman Islands, it is suspected that the difference in Chl. a as well as the mesozooplankton standing stock and community structure observed between the two study areas may be related to the various anthropogenic events influencing the coastal waters.


Radiotherapy resources in Brazil (RT2030): a comprehensive analysis and projections for 2030.
The demand for radiotherapy in Brazil is unfulfilled, and the scarcity of data on the national network hampers the development of effective policies. We aimed to evaluate the current situation, estimate demands and requirements, and provide an action plan to ensure access to radiotherapy for those in need by 2030. The Brazilian Society for Radiation Oncology created a task force (RT2030) including physicians, medical physicists, policy makers, patient advocates, and suppliers, all of whom were major stakeholders involved in Brazilian radiotherapy care. The group was further divided into seven working groups to address themes associated with radiotherapy care in Brazil. From March 1, 2019, to Aug 3, 2020, there were monthly meetings between the group's leaders and the Central Committee and six general meetings. First, a comprehensive search of all different national databases was done to identify all radiotherapy centres. Questionnaires evaluating radiotherapy infrastructure and human resources and assing the availability, distribution, capacity, and workload of resources were created and sent to the radioprotection supervisor of each centre. Results were analysed nationally and across the country's regions and health-care systems. A pre-planned review of available databases was done to gather data on active radiation oncology centres and the distribution of radiotherapy machines (linear accelerators [LINACs]) across Brazil. We used national population and cancer incidence projections, recommended radiotherapy usage from the medical literature, and national working patterns to project radiotherapy demands in 2030. An action plan was established with suggestions to address the gaps and meet the demands. The database search yielded 279 centres with an active radiotherapy registry. After applying predefined exclusion criteria, 263 centres were identified that provided external beam radiotherapy machines with or without brachytherapy. All 263 operational centres answered the questionnaires sent on Dec 9, 2019, which were then returned between Jan 1 and June 30, 2020. There were 409 therapy machines, 646 radiation oncologists, 533 physicists, and 230 989 patients undergoing radiotherapy (150 628 [65·2%] in the public health-care system and 80 937 [35·0%] in private). The mean annual occupation rate was 566 patients per treatment machine (SD 250). The number of residents per treatment machine ranged from 258 333 to 1 800 000. Technology availability varied considerably among regions and systems. In 2030, 639 994 new cancer cases are expected, which will require 332 797 radiotherapy courses. Therefore, 530 LINACs, 1079 radiation oncologists, and 1060 medical physicists will be needed. The expected increase in cancer incidence in the coming years will probably increase the disparities in cancer care and the burden for Brazilian patients. We provide a roadmap of the current situation and the particularities of the Brazilian radiotherapy network, which can serve as a starting point for cancer policy planning to improve this scenario. Accuray, BRAINLAB, Elekta, IBA, ONE medical solution, SUN NUCLEAR corporation, VARIAN, and ZIGMA.


Analysis of FOXL2 detects three novel mutations and an atypical phenotype of blepharophimosis-ptosis-epicanthus inversus syndrome.
Mutations in FOXL2 are known to cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), variably associated with premature ovarian failure. In this study, we report results of mutational screening in a Czech and Slovak patient population with BPES. Case series. Thirteen probands of Czech and one proband of Slovak origin with BPES and their available family members. Sanger sequencing and multiplex ligation-dependent probe amplification in 14 probands with BPES. Targeted mutational screening in first-degree relatives. Genetic characterization and phenotype evaluation in Czech and Slovak individuals with BPES and their family members. Eight different mutations were detected including three novel ones: c.5T>G; p.(Met2Arg), c.197C>A; p.(Ala66Glu) and c.701_702insTGCAGCCGCAGCGGCTGCAGCAGCTGCGGCTGCAGCCGC; p.(Ala222_Ala234dup). In one family, the molecular genetic cause of disease was not identified by the methodology used. In 13 pedigrees, a negative family history suggested a de novo origin, which could be confirmed by targeted mutational screening in four families. One 62-year-old female with the c.663_692dup30 mutation had an atypical phenotype presenting as moderate ptosis compensated by frontalis muscle contraction, no epicanthus inversus and no premature ovarian failure. The de novo mutation rate in FOXL2 is exceptionally high compared with other dominant disorders manifesting with an ocular phenotype. In cases reporting a negative family history, careful examination of both parents is important to exclude mild features of the BPES phenotype.


Photodegradation of malachite green under natural sunlight irradiation: kinetic and toxicity of the transformation products.
This article describes the photolytic degradation of malachite green (MG), a cationic triphenylmethane dye used worldwide as a fungicide and antiseptic in the aquaculture industry. Photolysis experiments were performed by direct exposure of a solution of MG in water to natural sunlight. The main transformation products (TPs) generated during the process were identified by liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) and gas chromatography mass spectrometry (GC-MS). The 28 TPs identified with this strategy indicate that MG undergoes three main reactions, N-demethylation, hydroxylation and cleavage of the conjugated structure forming benzophenone derivatives. These processes involve hydroxyl radical attack on the phenyl ring, the N,N-dimethylamine group and the central carbon atom. The Vibrio fischeri acute toxicity test showed that the solution remains toxic after MG has completely disappeared. This toxicity could be assigned, at least in part, to the formation of 4-(dimethylamine)benzophenone, which has an EC(50,30 min) of 0.061 mg l(-1), and is considered "very toxic to aquatic organisms" by current EU legislation.


Comparing compression models for authorship attribution.
In this paper we compare different compression models for authorship attribution. To this end, three different types of compressors, Lempel-Ziv type (GZip), block sorting type (BZip) and statistical type (PPM), along with two different similarity measures were considered in our experiments. Besides, two different attribution methods are analyzed in this paper. Through a series of experiments performed on two different databases, we were able to show that all the compressors behave similarly, but the similarity measures can vary considerably depending on the strategy used for authorship attribution. Our results corroborate with the literature in the sense that compression models are a good alternative for authorship attribution surpassing traditional pattern recognition systems based on classifiers and feature extraction.


Delusional infestation: a clinical profile.
Delusional infestation or delusional parasitosis is a form of monodelusional disorder, a condition sometimes encountered in psychiatric or primary care practice. The outcome of this condition is good when compliance can be ensured. In the present study, a series of 50 consecutive cases of delusional infestation is reported. A majority of cases (94%) had insidious onset. The duration of symptoms in all but 3 cases was 6 months or more. Twenty-eight cases presented with a delusion of infestation by insects over the body and 20 cases with a delusion of insects crawling over the scalp. Two cases had associated diabetes mellitus, 3 cases had leprosy, 2 cases had dementia, 5 cases had depression, and 4 cases presented with trichotillomania. Among the second generation antipsychotics, risperidone was used in 12 cases, olanzapine in 9 cases, amisulpride in 7 cases, etc. Thirty-four cases (68%) showed complete remission while receiving pharmacotherapy, 13 cases showed partial improvement, and 3 cases did not respond to treatment. The study demonstrates the utility of second generation antipsychotics in the treatment of this disorder. Further studies are warranted to study the treatment and outcome of this important psychiatric disorder.


A multivariate analysis of risk factors for cytomegalovirus infection in liver-transplant recipients.
Thirty-three consecutive liver-transplant recipients were prospectively studied over a 37-mo period for evidence of cytomegalovirus infection. Sixteen (48%) episodes of cytomegalovirus infection were identified; 9 were primary infections and 7 were recurrent infections. Beginning with patient 8, gamma-globulin prophylaxis was routinely administered to most patients. Twelve potential risk factors for cytomegalovirus infection were evaluated and included pretransplant cytomegalovirus serological status of donor and recipient; recipient's age, sex, race, and liver disease; number and type of blood products transfused; type and intensity of immunosuppression; and occurrence of rejection. The Cox proportional hazards model identified positive donor cytomegalovirus serology as the single most important risk factor for subsequent development of cytomegalovirus infection, regardless of recipient cytomegalovirus serological status. In addition, use of gamma-globulin prophylaxis seemed to be protective against the occurrence of disseminated cytomegalovirus disease.


Brain engraftment of autologous macrophages transduced with a lentiviral flap vector: an approach to complement brain dysfunctions.
Transplantation of ex vivo gene-corrected autologous cells represents an attractive therapeutic approach for brain diseases. Among the cells of the central nervous system, brain macrophages are promising candidates due to their role in tissue homeostasis and their implication in several neurological diseases. Up to now, gene transfer into macrophages has proven difficult by most currently available gene delivery methods. We describe herein, an efficient transduction of rat bone marrow-derived and brain macrophages with an HIV-1-derived vector containing a central DNA flap and encoding the GFP reporter gene (TRIP-DeltaU3-GFP). In primary cultures of macrophages our results show that more than 90% of the cells were transduced by the TRIP vector and that GFP expression remained stable for 1 month without cytopathic effect. In vivo, transplants of transduced macrophages into the striatum of adult rats exhibited long-term expression of GFP up to 3 months. Transduced macrophages were observed around the brain injection site and exhibited the brain macrophage/microglia phenotype. There was no significant sign of astrogliosis around the graft. These results confirm the potential of lentiviral vectors for efficient and stable ex vivo transduction of macrophages. Moreover, transduced autologous macrophages appear as a valuable vehicle for long-term and localized gene expression into the brain.


Sexual reproduction and variation in floral morphology in an ephemeral vernal lily, Eyythronium americanum.
In a riparian population of Erythronium americanum (Liliaceae) in central New Jersey, experimentally self-pollinated plant produced markedly fewer fruit and fewer seeds per fruit than hand-outcrossed and open pollinated plants, even though differences were not evident between pollen tubes that penetrated stigmas from self or foreign pollen. This weak self-compatibility and a positive relation between the percentage of seeds set by outcrossed plants and the distance between pollen donor and recipient plants indicate that this population could be susceptible to inbreeding depression.Limited resources for seed development apparently constrained maximal seed production, based on low seed set (40.6%) by hand-pollinated plants and positive correlations for these plants between plant size and the number and size of seeds set. In contrast, naturally-pollinated plants set a smaller proportion of their ovules, suggesting that limited pollinator service reduced the quantity of seeds produced in this population. Free-foraging bees usually removed more than half of the available pollen in a single visit, so that individual plants probably have few opportunities to disseminate their pollen.Even though sexually reproductive ramets produce only a single flower per year, less than a third of variation in floral morphology is associated with variation in plant size. Within the flower, the sizes of some closely associated structures, such as the style and ovary, and the anthers and filaments, vary essentially independently of one another. Production of nectar and pollen, the ultimate attractors of pollinating insects, was positively correlated with flower size.


A systematic approach to measure the contents of mono- and di-sulfonates in petroleum sulfonates by the novel method of acid-base titration coupled with traditional two-phase titration.
Petroleum sulfonates are broadly employed to increase the oil recovery efficiency in tertiary recovery, while the content of di-sulfonates in petroleum sulfonates is a critical factor in the flushing efficiency, because it adversely impacts the decrease of oil-water interfacial tension. Thus far, no methods have been considered convenient and reliable to determine the contents of mono- and di-sulfonates besides the traditional extraction method. This study established a simple and practical approach of acid-base titration coupled with traditional two-phase titration to measure the contents of mono- and di-sulfonates in petroleum sulfonates. To judge the reliability of the approach, the actives of petroleum sulfonates were separated into mono- and di-sulfonates using the traditional extraction method, the separation effect of which was confirmed using infrared spectroscopy and main elemental analysis. As the results demonstrated, all the contents of di-sulfonates in four petroleum sulfonates measured by the acid-base titration method are similar to those found by the extraction method. The contents of di-sulfonates (%) in four petroleum sulfonate samples were measured by comparing acid-base titration with the extraction method; respectively they were 8.57/8.19, 5.67/5.98, 5.61/5.35 and 2.37/2.15; the relative error of the measured di-sulfonates is about 6%, which satisfies the titration accuracy of petroleum sulfonates. In parallel experiments, the results of five acid-base titrations are very close, and the precision of the acid-base titration method was about 3%. Accordingly, this systematic approach by combining the new acid-base titration and traditional two-phase titration is of great significance to develop the evaluation system of petroleum sulfonates.


Surgical Management for Vertical Maxillary Excess.
Orthognathic surgery is an effective approach to correct vertical maxillary excess (VME), which is a common maxillofacial deformity and exhibits excessive vertical development of maxilla. This review summarizes different clinical features of total, anterior and posterior VME, as well as corresponding surgical managements guided by preoperative computer-assisted surgical planning. The virtual simulation will do favor to the final determination of individual surgical plans to achieve satisfactory outcomes. Finally, a typical clinical case will be presented to demonstrate the surgical management of VME.


Peroxisome proliferator-activated receptors (PPARs)-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice.
Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. Mice were fed a diet containing 30 en% beef tallow (B diet) for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet). Each group was further divided into two groups which were administered PPARα and γ antagonists or vehicle once a day for three weeks. The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway-independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils.


Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.
We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.


TRPV1 activation results in disruption of the blood-brain barrier in the rat.
We have examined the role of TRPV1 activation in disrupting the blood-brain barrier by measuring the permeability of single pial venular capillaries in anaesthetized rats. Capsaicin application to the brain surface resulted in increased permeability, maximal 2.1+/-0.12 x 10(-6) cm s(-1) (mean+/-s.e.m.) with log EC50 -4.5+/-0.10. Substance P methyl ester gave a similar response (maximal 2.0+/-0.07, n = 6, log EC50 -4.8+/-0.07), but the selective NK2 agonist, beta-Ala8-NKA(4-10) peptide, had no effect. Although CGRP decreased the permeability of venules (log EC50 10.3+/-0.11), its receptor antagonist CGRP(8-37) had no effect on the response to capsaicin. The TRPV1 antagonist capsazepine (1 mM) reduced the response to capsaicin (100 microM), from 1.78+/-0.15 to 0.63+/-0.10 (n = 4). The NK1 receptor antagonists GR205171 (100 microM) and SDZ NKT 376 (1 mM) also reduced the response to capsaicin (from 1.75+/-0.14 to 0.46+/-0.08; n = 6, and from 1.85+/-0.13 to 0.48+/-0.05; n = 5, respectively), indicating that capsaicin acts via TRPV1 in series with NK(1). Starch microspheres were used to produce transient focal ischaemia. Permeability was increased on reperfusion to a greater extent and more rapidly in vessels with diameter greater than 40 microm than those less than 15 microm. Capsazepine given intraperitoneally during ischaemia reduced the permeability increase in small venules from 5.9+/-0.3 to 2.4+/-0.1, and from 11.4+/-0.8 to 5.1+/-0.9 in large venules. In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeability-increasing effect via substance P. It also plays a role in the immediate blood-brain barrier disruption following ischaemia-reperfusion.


Mitochondrial DNA intra-individual variation in a bumblebee species: A challenge for evolutionary studies and molecular identification.
Mitochondrial DNA (mtDNA) regions have been widely used as molecular markers in evolutionary studies and species identification. However, the presence of heteroplasmy and NUMTs may represent obstacles. Heteroplasmy is a state where an organism has different mitochondrial haplotypes. NUMTs are nuclear pseudogenes originating from mtDNA sequences transferred to nuclear DNA. Evidences of heteroplasmy were already verified in the bumblebee Bombus morio in an earlier study. The present work investigated in more detail the presence of intra-individual haplotypes variation in this species. Heteroplasmy was detected in individuals from all the ten sampled locations, with an average of six heteroplasmic haplotypes per individual. In addition, some of these heteroplasmic haplotypes were shared among individuals from different locations, suggesting the existence of stable heteroplasmy in B. morio. These results demonstrated that heteroplasmy is likely to affect inferences based on mtDNA analysis, especially in phylogenetic, phylogeographic and population genetics studies. In addition, NUMTs were also detected. These sequences showed divergence of 2.7% to 12% in relation to the mitochondrial haplotypes. These levels of divergence could mislead conclusions in evolutionary studies and affect species identification through DNA barcoding.


Factors Underlying Patient and Surgeon Willingness to Participate in a Placebo Surgery Controlled trial: A Qualitative Investigation.
To investigate the factors underlying willingness to participate in a hypothetical trial among patients and surgeons, to inform the design of future placebo surgery controlled trials. Placebo surgery controlled trials are the gold standard for testing the efficacy of surgical procedures. However, these trials commonly fail to meet the target sample size and terminate underpowered. From October 2019 to July 2020, eligible patients were identified from the orthopedic waiting list at a single tertiary hospital and surgeons were identified from orthopedic clinics at three tertiary hospitals in Australia. Qualitative interviews explored factors underlying willingness to participate in a hypothetical trial, including understanding of trial concepts; attitudes; and trial design preferences. Data collection and analysis were conducted in parallel. Recruitment ceased when no new concepts emerged. Interview data were analyzed using reflexive thematic analysis. The majority of surgeons and only a few patients indicated a willingness to participate in a placebo surgery controlled trial. Factors underlying willingness were captured in four themes: (1) Understanding and attitudes toward placebo; (2) Attitudes towards randomization/perception of equipoise; (3) Perception of risk; and (4) Ethical concerns. To optimize recruitment in the future, trialists may consider embedding strategies into the recruitment process that validate patients' symptoms, encourage an altruistic mindset, address surgeon biases, and involve surgeons in explaining trial concepts to patients. Trialists may also consider designing three arm trials that meet surgeons' preferences for a "low" and "high" fidelity placebo.


Human first-trimester chorionic villi have a myogenic potential.
First-trimester chorionic-villi-derived cells (FTCVs) are the earliest fetal material that can be obtained for prenatal diagnosis of fetal disorders such as Duchenne muscular dystrophy (DMD). DMD is a devastating X-linked disorder characterized by the absence of dystrophin at the sarcolemma of muscle fibers. Currently, a limited number of treatment options are available for DMD, although cell therapy is a promising treatment strategy for muscle degeneration in DMD patients. A novel candidate source of cells for this approach is FTCVs taken between the 9th and 11th weeks of gestation. FTCVs might have a higher undifferentiated potential than any other tissue-derived cells because they are the earliest fetal material. We examined the expression of mesenchymal stem cell and pluripotent stem cell markers in FTCVs, in addition to their myogenic potential. FTCVs expressed mesenchymal stem cell markers and Nanog and Sox2 transcription factors as pluripotent stem cell markers. These cells efficiently differentiated into myotubes after myogenic induction, at which point Nanog and Sox2 were down-regulated, whereas MyoD, myogenin, desmin and dystrophin were up-regulated. To our knowledge, this is the first demonstration that FTCVs can be efficiently directed to differentiate in vitro into skeletal muscle cells that express dystrophin as the last stage marker of myogenic differentiation. The myogenic potential of FTCVs reveals their promise for use in cell therapy for DMD, for which no effective treatment presently exists.


Improved sensitivity and mass range in time-of-flight bioaerosol mass spectrometry using an electrostatic ion guide.
Bioearosol mass spectrometry (BAMS) analyzes single particles in real time from ambient air, placing strict demands on instrument sensitivity. Modeling of the BAMS reflectron time of flight (TOF) with SIMION revealed design limitations associated with ion transmission and instrument sensitivity at higher masses. Design and implementation of a BAMS linear TOF with electrostatic ion guide and delayed extraction capabilities has greatly increased the sensitivity and mass range relative to the reflectron design. Initial experimental assessment of the new instrument design revealed improved sensitivity at high masses as illustrated when using standard particles of cytochrome C (m/z approximately 12,000), from which the compound's monomer, dimer (m/z approximately 24,000) and trimer (m/z approximately 36,000) were readily detected.


Patterns of low acuity patient presentations to emergency departments in New South Wales, Australia.
To explore the patterns of low acuity patient (LAP) presentations to EDs in New South Wales (NSW), Australia. Retrospective study of NSW public hospital ED presentations between January 2013 and December 2014 that were registered in the NSW Emergency Department Data Collection (n = 409 035). LAPs were defined according to the Australian Institute of Health and Welfare (AIHW), Sprivulis and multiple ACEM methods. Multivariable logistic regression was used to assess the adjusted odds of LAP ED presentation by a suite of sociodemographic factors. The percentage of LAPs varied considerably by definition, being as high as 54.7% (inner regional areas) and as low as 3.2% (major cities) using revised ACEM methods modified to contain unlimited consultation times or consultation times of 15 min or less, respectively. For each method, higher proportions of LAPs were observed in inner regional and remote/very remote areas relative to major cities. LAP ED presentations, based on ACEM definition with 1 h or 15 min consultation times, were greater in younger patients, increased during out of business hours and weekends, and decreased with increasing general practitioner (GP) density. The percentage of LAPs varied substantially by definition, and further work is required to validate the methods, particularly around the appropriateness of length of consultation time with ACEM, between different hospitals and remoteness areas. Age was strongly associated with low acuity, with substantial effects also observed for GP density, and attendances during out of hours and weekends.


Alcohol and the oculomotor system.
The influence of alcohol on the oculomotor system was observed by means of the caloric eye tracking pattern (CETP) test, the visual suppression test on caloric nystagmus, and the positional nystagmus, eye tracking and gaze nystagmus tests. In Group A (nine cases whose CETP before the intake of alcohol was normal), the influence of alcohol consumption appeared regularly and consistently in the following order: abnormality of CEPT greater than or equal to positional alcohol nystagmus greater than or equal to abnormality of the eye tracking pattern greater than or equal to alcohol gaze nystagmus. On the contrary, in Group B (eight cases whose CETP before the consumption of alcohol was already abnormal), with one exception, the regularity noted in Group A was not observed. This phenomenon may be attributable to the presence of latent disorders of the oculomotor system. In both groups, the duration of the caloric nystagmus itself was slightly shortened and its amplitude somewhat suppressed after the consumption of alcohol. The results were confirmed by experiments in which the subjects kept their eyes open in darkness. On the other hand, when the eyes were kept open in light surroundings, the duration and amplitude of the caloric nystagmus were exaggerated in appearance because the mechanism of visual suppression was disturbed by alcohol.


Extensive necrosis of visceral melanoma metastases after immunotherapy.
The prognosis for metastatic melanoma remains poor even with traditional decarbazine or interferon therapy. 5-year survival is markedly higher amongst patients undergoing metastatectomy. Unfortunately not all are suitable for metastatectomy. Alternative agents for systemic therapy have, to date, offered no greater rates of survival beyond traditional therapy. A toll-like receptor 9 agonist, PF-3512676 (formerly known as CPG 7909) is currently being evaluated for its potential. We present the case of a 54-year-old Caucasian male with completely resected metastatic cutaneous melanoma after immunotherapy. The patient initially progressed during adjuvant high-dose interferon, with metastases to the liver, spleen, and pelvic lymph nodes. During an 18-month treatment period with PF-3512676 (formerly known as CPG 7909), a synthetic cytosine-phosphorothioate-guanine rich oligodeoxynucleotide, slow radiologic disease progression was demonstrated at the original disease sites. Subsequent excision of splenic and pelvic nodal metastases was performed, followed by resection of the liver metastases. Histologic examination of both hepatic and splenic melanoma metastases showed extensive necrosis. Subsequent disease-free status was demonstrated by serial positron emission tomography (PET). Existing evidence from phase I/II trials suggests systemic treatment with PF-3512676 is capable of provoking a strong tumor-specific immune response and may account for the prolonged tumor control in this instance.


Re-evaluation of the approach to an enlarging head in infancy.
Computerized axial tomography is a safe, non-invasive technique for measurement of ventricular size. A review of 44 children without myelodysplasia who were evaluated for inappropriately enlarging heads, documented a group of 20 children presenting at five months to two years of age with megalencephaly or mild communicating hydrocephalus. Of these, only two required shunts. At their most recent examination, the great majority of these children are developmentally normal. Serial neurological examination, developmental evaluation and head-circumference measurements, in association with computerized axial tomography, have proved effective in the assessment and management of this particular group of children with large heads.


Gastroenterologists' Views of Shared Decision Making for Patients with Inflammatory Bowel Disease.
There is limited information on gastroenterologists' perspectives of shared decision making (SDM) in discussions of therapeutic agents with inflammatory bowel disease (IBD) patients. To examine gastroenterologists' perspectives about SDM with IBD patients, using a novel statistical hybrid approach to analyze qualitative data. Physician interviews and online surveys were conducted from a panel of gastroenterologists in April 2012. Gastroenterologists were asked about their barriers to SDM, SDM practices, relationship to their patients, knowledge of SDM, and insights into SDM implementation. Key audio excerpts adapted from the interviews were used for moment-to-moment affect trace analysis in an online survey. Cluster analysis was used to segment gastroenterologists into mutually exclusive provider groups. One hundred and six gastroenterologists completed the survey (88 % male; 55 % ≤ 50 years of age). Over three-fourths of gastroenterologists were familiar with SDM (77 %). The vast majority of gastroenterologists (80 %) tried to use a form of SDM with their patients; only 12 % stated that they have a systematic, consistent, and formally documented approach to SDM. Three unique physician clusters were identified: SDM Believers (20 %, n = 20); SDM Skeptics (47 %, n = 47); and SDM Enthusiasts (34 %, n = 34). The three key barriers to practicing SDM were lack of the following: time (74 %), reimbursement (70 %), and tools (51 %). Twenty-two percent of gastroenterologists do not currently use SDM tools. Gastroenterologists lack the systematic approaches and tools for implementing SDM within their IBD practices. These data offer a foundation for future research in developing and testing SDM programs for gastroenterologists and their IBD patients.


Heme sulfuric anhydrides as soybean leghemoglobin structure probes.
Mesoheme monosulfuric anhydride reacts at three distinct sites in soybean apoleghemoglobin a, at lysine-6, lysine-19 and lysine-57, the last one being the major site of reaction. The heme peptides obtained from thermolytic and pronase hydrolysates of the anhydride-leghemoglobin a were purified and correlated with the known amino acid sequence of the protein. Mesoheme bissulfuric anhydride also reacts with soybean apoleghemoglobin a giving a complex mixture of hemepeptides after hydrolysis with pronase. The visible spectrum of anhydride leghemoglobin is that of low spin heme. This suggests that anhydride leghemoglobin has a conformation with a covalent attachment via propionic acid side chain to lysine-57 and the sixth coordination position of the heme iron occupied by the distal histidine at position 61. Native leghemoglobin is assumed to exist in a similar type of configuration at low temperature, but with the heme propionate side chain being involved in a salt bridge with lysine-57.


Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.
Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression are considered.


Comparison of the diagnostic quality of aspiration and core-biopsy needles for transjugular liver biopsy.
Liver biopsy remains essential for the diagnostic work-up of patients with liver disease. To evaluate aspiration vs. core-biopsy needles for transjugular liver biopsy (TJLB) in patients undergoing hepatic venous pressure gradient (HVPG) measurements. 84 patients undergoing TJLB between 06/2017 and 12/2018 were prospectively included. Liver biopsy specimens were systematically evaluated for quantitative and qualitative criteria such as number of portal tracts, sample length and fragmentation. In direct comparison of paired TJLB specimens (n=35), core-biopsy samples were significantly longer (median 12 vs. 9mm, p=0.012), tended to contain more portal tracts (median 8 vs. 6, p=0.064) and were less fragmented (p<0.001), which resulted in better confidence for liver fibrosis assessment (p=0.035). However, a superior quality in terms of less fragmentation of core-biopsy specimens (p<0.05) was only confirmed in patients with HVPG ≥10mmHg or liver stiffness measurement >40kPa. In contrast, the aspiration needle provided significantly longer samples in patients with HVPG <10mmHg (median 21 vs. 12mm, p=0.007) or with liver stiffness measurement <20kPa (median 21 vs. 11mm, p=0.025). In patients with HVPG ≥10mmHg, we recommend to performed TJLB using core-biopsy needles, while the aspiration needle provides high quality liver biopsy specimens in patients with HVPG <10mmHg.


A mice resting-state functional magnetic resonance imaging dataset on the effects of medetomidine dosages and prior-stimulation on functional connectivity.
Nine 8 C57Bl6 mice (9 ± 0.5 months) were utilised for this dataset. Each animal was scanned twice on a 9.4T Bruker Magnetic Resonance Imaging (MRI) scanner using a cryogenically cooled coil with 0.1 mg/kg body weight/h (low) or 0.3 mg/kg body weight/h (high) medetomidine doses; 0.5% isoflurane was used in conjunction with both doses. The scans were one week apart, and the first session's dose was decided randomly. In each session, the animal had a pre-stimulation resting-state functional Magnetic Resonance Imaging (rs-fMRI) scan followed by 10 min where mild, constant electrical stimulation to the forepaw was applied, and a post-stimulation rs-fMRI scan. Each fMRI scan lasted 10 min, and there was 5 min break between fMRI scans. The dataset included, for each animal, a pair of forward-phase and reverse-phase gradient echo Echo-Planar-Imaging (EPI) images for EPI distortion correction purpose and three (unprocessed) functional MRI images acquired using the same EPI sequence: prior, during, and post-stimulation. The MRI data was saved in compressed NIFTI format converted from Bruker DICOMs. The dataset also included the pre-processed functional MRI images, with the following pre-processing steps: slice-timing correction, temporal despiking, motion correction, distortion correction, band-pass filtration at 0.01-0.2 Hz, and spatial normalisation. This dataset adds to the publicly available collection of resting-state functional MRI in the mice and facilitates reproducibility and validation of functional imaging and its analysis.


Characterization of the Sounds Produced by Temperate and Tropical Sea Urchins During Feeding (Diadematidae and Echinometridae).
Despite the abundance and ecological importance of sea urchins in eastern Australia, it is not known how they may contribute to ambient noise. The sounds of feeding of two temperate and two tropical species were recorded in captivity. Most sound was produced between 2.3 and 9.2 kHz, but there were differences between species and substrate types.


Dopamine or norepinephrine infusion during thoracic epidural anesthesia? Differences in hemodynamic effects and plasma catecholamine levels.
During thoracic epidural anesthesia, an intravenous dopamine infusion augments the systemic pressure response and modifies plasma catecholamine levels. If such an altered response occurs when norepinephrine is infused is not clear. Therefore, dopamine and norepinephrine induced circulatory and catecholamine responses were studied before and during thoracic epidural anesthesia. Nine chloralose-anesthetized dogs were equipped with thoracic epidural catheters. Dopamine (5, 10, and 20 microg kg(-1) min(-1)), and norepinephrine (0.1, 0.25, and 0.5 microg kg(-1) min(-1)) were infused before and during epidural anesthesia, while cardiovascular performance and plasma catecholamine changes were studied. Thoracic epidural anesthesia decreased arterial pressure, and cardiac contractility. The systemic pressure response induced by dopamine was augmented during epidural anesthesia. Norepinephrine did not increase arterial pressure and myocardial contractility as markedly as dopamine, and cardiac output was not altered. Thoracic epidural anesthesia attenuated the plasma norepinephrine level. Plasma dopamine levels were augmented by the dopamine infusion during epidural anesthesia, while plasma norepinephrine levels were attenuated. In contrast, norepinephrine augmented the plasma norepinephrine levels during epidural anesthesia. In general, plasma norepinephrine levels were three to six times higher during a norepinephrine infusion compared to a dopamine infusion. The cardiovascular response to a graded dopamine infusion is augmented during thoracic epidural anesthesia, while norepinephrine-induced effects are unaltered. The modified plasma catecholamine levels may contribute to the hemodynamic differences between dopamine and norepinephrine infusions during thoracic epidural anesthesia.


Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability.
The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.


The genetic basis of urate control and gout: Insights into molecular pathogenesis from follow-up study of genome-wide association study loci.
This review focuses on the post-genome-wide association study (GWAS) era in gout, i.e., the translation of GWAS genetic association signals into biologically informative knowledge. Analytical and experimental follow-up of individual loci, based on the identification of causal genetic variants, reveals molecular pathogenic pathways. We summarize in detail the largest GWAS in urate to date, then we review follow-up studies and molecular insights from ABCG2, HNF4A, PDZK1, MAF, GCKR, ALDH2, ALDH16A1, SLC22A12, SLC2A9, ABCC4, and SLC22A13, including the role of insulin signaling. One common factor in these pathways is the importance of transcriptional control, including the HNF4α transcription factor. The new molecular knowledge reveals new targets for intervention to manage urate levels and prevent gout.


Ichthyosis Prematurity Syndrome: A Rare Form but Easily Recognizable Ichthyosis.
Ichthyosis prematurity syndrome is a rare autosomal recessive genodermatosis that is associated with mutations in the SLC27A4 gene. Its onset occurs in early childhood and presents with the clinical triad of premature birth, thick caseous desquamating epidermis, and neonatal asphyxia. Here, we describe a prematurely born baby patient (33 weeks of gestation) with a homozygous variant at the initiation codon site (c.1 A> G, p.Met1Val) in the SLC27A4 gene to raise awareness of this rare syndrome despite its distinctive features as we believe it is still underdiagnosed.


Multilevel Analysis of the Effects of Individual- and Community-Level Factors on Childhood Anemia, Severe Anemia, and Hemoglobin Concentration in Malawi.
The purpose of this article was to examine individual- and community-level factors associated with childhood anemia, severe anemia, and hemoglobin (Hb) concentration in Malawi. Using data from the 2010 Malawi demographic and health survey (MDHS), the multilevel regression models were constructed to analyze 2597 children aged 6-59 months living in 849 communities. The results showed that both childhood anemia and severe anemia were negatively associated with child's age, no fever in the previous 2 weeks and height-for-age, and positively associated with residing in poor household. Childhood anemia was negatively associated with community female education. Child's age, no fever in the previous 2 weeks and maternal Hb levels were positively associated with child Hb concentration, while residing in poorest households was negatively associated with children's Hb concentration. Comprehensive public health strategies aimed at reducing childhood anemia need to focus more on the significant characteristics addressed in this study.