Exploring leadership competencies in established and aspiring physician leaders: an interview-based study.
Academic health care institutions have become interested in understanding and supporting current leaders and preparing leaders for the future. We designed this exploratory study to better understand specific perceived leadership needs of physicians from the perspective of "aspiring" and "established" leaders within our institution. A qualitative, inductive, structured interview-based design was used to examine the study questions. A purposeful sample of current and aspiring leaders was obtained, sampling across specialties and levels of leadership. All participants were interviewed by the same investigator (CT). Five open-ended questions were developed as prompts. Two of the investigators independently analyzed the transcripts, using an open coding method to identify themes within the narratives. Inter-observer comparisons were made and discrepancies were resolved through discussion. Four themes emerged from analyzing the responses to our questions. Aspiring and established leaders agreed that "knowledge", "people skills" or emotional intelligence, and "vision" were all characteristics of effective leaders and critical to the success of aspiring leaders. Established leaders in our sample added a characteristic of "organizational orientation" that extended the description of "leaders" to include an understanding of the institution as well as dedication to its success (a trait we have called "organizational altruism"). Our findings validate others' regarding leadership competencies while extending these findings to the specific context of health care and physicians. Important implications for curricular design include: inclusion of emotional intelligence competencies and reducing formal didactics in favor of programs that are both interactive and problem-based.


The Value of Second-Opinion Consultation in Nongynecologic Cytopathology.
The value of consultation in pathology has been well documented in surgical pathology, but there are few comprehensive studies of consultation cases in cytopathology. Here we report our experience with cytopathology consultation cases at a large academic center. A review of consultation cases at our institution was performed by searching our laboratory information system. The contributing institution's diagnosis was compared with that rendered by the reviewing cytopathologist to assess major and/or minor diagnostic discrepancies. In total, 928 cases were reviewed with the following distribution: fine-needle aspiration (FNA, 79.4%), exfoliative nongynecologic cytology (18.3%), and cases with both FNA and nongynecologic cytology (2.3%). There were 379 (40.8%) true consults and 549 (59.2%) confirming consults. A total of 586 (63.1%) cases were in agreement with the outside pathologist, 78 (8.4%) cases had major discrepancies, and 264 (28.4%) cases had minor discrepancies. Major discrepancies were most common for pancreas (38.5%), lymph node (11.5%), and soft tissue sites (9.0%). Of the cases, 8.4% had major diagnostic discrepancies between the original diagnosis and the consultation diagnosis, which is consistent with reported values in surgical pathology consultation studies. The findings support the importance of second-opinion consultation in cytopathology to guide patient care.


IMMUNOHISTOCHEMICAL AND BIOCHEMICAL ANALYSIS OF MAMMARY GLAND TUMOURS OF DIFFERENT AGE PATIENTS.
Immunohistochemical and biochemical study of infiltrative ductal breast carcinoma and tissue adjacent to the tumour revealed a particular molecular profile and characteristics of the oxidant-antioxidant status neoplasms depending on the age of the patients and the presence of metastases in regional lymph nodes. Some causes of high aggressiveness and low hormone sensitivity of tumours in premenopausal women, as well as stability and high metastatic potential of tumours in postmenopausal women have been found.


Clinical Implications of Preinterventional Thrombus Migration in Patients with Emergent Large Vessel Occlusion.
In patients treated with thrombectomy, thrombus migration (TM) to distal arterial segments is occasionally observed. We investigated the incidence of TM, factors associated with TM, and association between TM and clinical outcomes. The study population consisted of 164 patients with anterior circulation stroke who underwent pretreatment brain computed tomography angiography and digital subtraction angiography before undergoing thrombectomy. TM was defined as a thrombus shift to a more distal arterial segment observed on digital subtraction angiography than that on computed tomography angiography. Successful and complete recanalization was defined as cerebral infarction perfusion scale scores of 2b-3 and 3, respectively. Good functional outcomes were defined as scores of ≤2 on the modified Rankin Scale at 3 months. The results are presented as adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Thirty-two patients (19.5%) had TM. Intravenous thrombolysis (IVT) (OR, 5.238; 95% CI, 1.653-16.603) and female sex (OR, 2.874; 95% CI, 1.135-7.277) were associated with TM. IVT-related TM was not significantly associated with thrombus inaccessibility (P = 0.304). In addition, TM was not associated with successful (P = 0.960) or complete (P = 0.612) recanalization. However, TM (OR, 2.777; 95% CI, 1.019-7.569), together with IVT (OR, 2.982; 95% CI, 1.332-6.676), a low National Institutes of Health Stroke Scale score (OR, 0.906; 95% CI, 0.845-0.972), and successful recanalization (OR, 4.878; 95% CI, 1.940-12.266), were independently associated with good functional outcomes. TM is common, particularly after IVT. In addition, TM is associated with better functional outcomes, irrespective of the angiographic outcomes.


Commercial IgG immunoglobulin preparations exhibit IgG and IgA autoantibody reactivity at pharmacologic but not at physiologic concentrations.
IgG immunoglobulin preparations have been increasingly utilized to treat a variety of diseases. Since disease response to this form of therapy in patients with abnormal autoimmune function is often evaluated through the subsequent investigation of autoantibody levels, it is possible that autoantibody positivities reflect autoantibody reactivity of circulating immunoglobulin preparations and not of the patient's inherent B-cell activity. We therefore investigated three commercially available IgG immunoglobulin preparations separately for IgG, IgM and IgA autoantibody reactivity to six phospholipid antigens, total histone and four histone subfractions, and four polynucleotides. Universally, all three preparations demonstrated considerable IgG antiphospholipid and antihistone reactivity at dilutions of up to 1:10(3) but not antipolynucleotide reactivity. Although no IgM reactivity was detected in any of the preparations, in all three preparations surprising IgA reactivity, especially with antihistone specificity, was detected. No autoantibody reactivity was detected at dilutions compatible with physiologic conditions in vivo. Identical observations were made for lupus anticoagulant reactivity, which was evaluated by activated partial thromboplastin time (APTT) and tissue thromboplastin inhibition (TTI). Since autoantibody reactivities and prolonged APTT assays are observed only at pharmacologic dilution levels, it is unlikely that the administration of IgG immunoglobulin preparation will affect the evaluation of autoantibody levels in patients undergoing such treatment.


[Variation of the cytoplasm type in sugar beet (Beta vulgaris L.) upon inbreeding. The influence of hybridization].
Hybrid combinations of inbred sugar beet lines that undergo conversion of N-cytoplasm into S-state were screened for the marker mitochondrial genes atpA and atp6. The involvement of nuclear factors into cytoplasm conversion and possible identity of these factors in different lines have been studied. The cytoplasm conversion factor was localized to nucleus. In different lines with cytoplasm conversion, the nuclear conversion factors are not identical. The state of the mitochondrial genome is normalized after outcrosses with plants having the stable cytoplasm.


Inhibition of human placental aromatase in a perfusion model. Comparison with kinetic, cell-free experiments.
In vitro perfusion of human placenta was evaluated for characterization of aromatase inhibitors. The results were compared with those in kinetic experiments in cell-free system. Inhibition constants (Ki) were determined by measuring the release of tritiated water during coincubation of human placenta microsomes with varying amounts of [1 beta,2 beta 3H]androstenedione and inhibitor in the presence of NADPH-generating system. Irreversible inactivation constants (Kinact) were determined in a similar manner following preincubation of the microsomes with different amounts of inhibitor for varying times. Lineweaver-Burk plots indicated a competitive type of inhibition with Ki values of 37 nM for 4-hydroxy-androstenedione, 3,700 nM for testolactone, 15 nM for 1-methyl-androsta-1,4-diene-3,17-dione, and 7.5 nM for 19-azido-androstenedione. Additionally, irreversible enzyme inactivation by all four substances could be demonstrated with Kinact values of 3.64 x 10(-3), 0.57 x 10(-3), 0.34 x 10(-3), and 0.69 x 10(-3)sec-1, respectively. Perfusion of a single cotyledon of human term placenta was performed by infusing medium through catheters placed in a fetal artery and in the maternal intervillous space. Perfused medium was collected from a cannulated fetal vein and from the maternal basal plate. The medium was supplemented with [3H]androstenedione (4.2 nM) and inhibitor. The perfusates were analyzed for their [3H]estrone and estradiol content following phenolic partition and Sephadex-LH 20 chromatography. The main results were, (1) the recovery of labelled steroids increased rapidly after perfusion started and reached a plateau within 60 min, when 55 and 30% (mean values) of the infused radioactivity were recovered in the fetal and maternal perfusates, respectively, (2) similar amounts of estrone and estradiol were found in both effluates, whereas androgens (mainly androstenedione and lower amounts of 5 alpha-androstane-3,17-dione) were found nearly exclusively in the fetal perfusate, (3) formation of estrogens (estrone + estradiol) reached a plateau within 20 min of perfusion. (4) The percentage of estrogens formed was not changed by increasing androstenedione concentration in the perfusion medium unless this concentration exceeded 3.5 microM indicating limited capacity of aromatase. (5) The four aromatase inhibitors reduced estrogen formation by 50% at concentrations about 100-fold of their Ki determined in the cell-free system, (6) irreversible aromatase inhibition could not be demonstrated in the perfusion model. It was concluded that the human placenta perfusion model can be successfully used to evaluate aromatase inhibitors.


Intestinal absorption of palmitate and 2-aminoisobutyric acid in piglets infected with Strongyloides ransomi.
Piglets were infected with 5000 or 15,000 third stage larvae of Strongyloides ransomi/kg of body weight. On the 15th day post infection absorption of the amino acid 14C alpha-amino-isobutyric acid (AIB) and the fatty acid 3H palmitic acid were studied. It was found that the onset of absorption of amino and fatty acids was delayed in the infected animals. Defective absorption of the amino acid was found in heavily infected piglets, whereas in moderate infection there was no failure of absorption from the entire small intestine. There was no difference in the rates of absorption of 3H-palmitic acid between infected and control piglets.


[Processed EEG for personalized dosing of anesthetics during general anesthesia].
Electroencephalogram (EEG)-guided anesthesia is indispensable in modern operating rooms and has become established as the standard form of monitoring. Many anesthesiologists rely on processed EEG indices in the hope of averting anesthesia-related complications, such as intraoperative awareness, postoperative delirium and other cognitive complications in their patients. This educational review aims to provide information on the five most prevalent monitors used to guide depth of sedation during general anesthesia. This article elucidates the principles underpinning the application of these monitors where known, which are generally based on power in various EEG frequency bands and on the burst suppression pattern. Convinced that EEG-guided anesthesia has the potential of benefitting many surgical patients, it is felt that many basic principles and shortcomings of processed EEG indices need to be better understood in the clinical practice. After discussing the different monitors and clinically relevant data from the literature, the article gives a short practical guidance on how to critically interpret processed EEG information and troubleshooting of confounded indices in the context of clinical situations.


Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations.
Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. Interferon beta-1b at the dosage of 8 million international units every other day. Number and duration (in months) of newly formed BHs. Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi2(1) = 2.47, P = .12). Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.


[Can the scattering of differences from the target refraction be avoided?].
We wanted to check how the stochastic error is affected by two lens formulae. The power of the intraocular lens was calculated using the SRK-II formula and the Haigis formula after eye length measurement with ultrasound and the IOL Master. Both lens formulae were partially derived and Gauss error analysis was used for examination of the propagated error. 61 patients with a mean age of 73.8 years were analysed. The postoperative refraction differed from the calculated refraction after ultrasound biometry using the SRK-II formula by 0.05 D (-1.56 to + 1.31, S. D.: 0.59 D; 92 % within +/- 1.0 D), after IOL Master biometry using the SRK-II formula by -0.15 D (-1.18 to + 1.25, S. D.: 0.52 D; 97 % within +/- 1.0 D), and after IOL Master biometry using the Haigis formula by -0.11 D (-1.14 to + 1.14, S. D.: 0.48 D; 95 % within +/- 1.0 D). The results did not differ from one another. The propagated error of the Haigis formula can be calculated according to DeltaP = square root (deltaL x (-4.206))(2) + (deltaVK x 0.9496)(2) + (DeltaDC x (-1.4950))(2). (DeltaL: error measuring axial length, DeltaVK error measuring anterior chamber depth, DeltaDC error measuring corneal power), the propagated error of the SRK-II formula according to DeltaP = square root (DeltaL x (-2.5))(2) + (DeltaDC x (-0.9))(2). The propagated error of the Haigis formula is always larger than the propagated error of the SRK-II formula. Scattering of the postoperative difference from the expected refraction cannot be avoided completely. It is possible to limit the systematic error by developing complicated formulae like the Haigis formula. However, increasing the number of parameters which need to be measured increases the dispersion of the calculated postoperative refraction. A compromise has to be found, and therefore the SRK-II formula is not outdated.


Zonal hierarchy of differentiation markers and nestin expression during oval cell mediated rat liver regeneration.
Oval cells constitute a heterogeneous population of proliferating progenitors found in rat livers following carcinogenic treatment (2-acetylaminofluorene and 70% hepatectomy). The aim of this study was to investigate the cellular pattern of various differentiation and cell type markers in this model of liver regeneration. Immunophenotypic characterisation revealed at least two subtypes emerging from the portal field. First, a population of oval cells formed duct-like structures and expressed bile duct (CD49f) as well as hepatocytic markers (alpha-foetoprotein, CD26). Second, a population of non-ductular oval cells was detected between and distally from the ductules expressing the neural marker nestin and the haematopoietic marker Thy1. Following oval cell isolation, a subset of the nestin-positive cells was shown to co-express hepatocytic and epithelial markers (albumin, CD26, pancytokeratin) and could be clearly distinguished from anti-desmin reactive hepatic stellate cells. The gene expression profiles (RT-PCR) of isolated oval cells and oval cell liver tissue were found to be similar to foetal liver (ED14). The present results suggest that the two oval cell populations are organised in a zonal hierarchy with a marker gradient from the inner (displaying hepatocytic and biliary markers) to the outer zone (showing hepatocytic and extrahepatic progenitor markers) of the proliferating progeny clusters.


Massive atelectasis by mucoid impaction in an asthma patient during treatment with anti-interleukin-5 receptor antibody.
Benralizumab is an interleukin-5 (IL-5) receptor α-directed cytolytic monoclonal antibody that reduces rapid and nearly complete depletion of eosinophils by enhancing antibody-dependent cell-mediated cytotoxicity. The depletion of eosinophilic inflammation is expected to reduce mucus hypersecretion and mucoid impaction. A 75-year-old non-smoking female had been treated for uncontrolled bronchial asthma with multiple drugs. Treatment with benralizumab was initiated after the asthma attack; however, four months later, she developed massive atelectasis in the left lung leading to the tracheal deviation, to the extent that nasal high-flow therapy was required. The laboratory data showed elevated neutrophil count, whereas blood eosinophils were almost completely depleted. The thick mucus was removed by bronchofiberscopy and the atelectasis was completely resolved. No exacerbation has been observed for nine months after discontinuation of benralizumab and initiation of erythromycin. This is the first documented case that developed atelectasis by mucoid impaction during treatment with anti-IL-5 receptor antibody.


A peer-training model for instruction of basic cardiac life support.
This study evaluates a peer-training model for cardiopulmonary resuscitation (CPR) instruction for laypersons. Forty-one Norwegian factory employees were trained in CPR and given instructor training. These first trainees then trained 311 co-workers. These employees then trained 873 family members and associates at home. The reference group consists of employees in a Massachusetts commercial hotel trained in seven American Red Cross (ARC): Adult CPR classes. The Norwegian home trainees learned CPR using a cardboard training manikin and were trained by Norwegian factory employees who had learned CPR from co-workers. Trainees were evaluated using skill sheets and a Laerdal Skillmeter manikin. The performance of the Norwegians trained at home by peers did not differ from that of the ARC: Adult CPR trainees in six skills of the initial sequence of CPR. The home trainees outperformed the ARC: Adult CPR trainees in the proportion of compressions delivered correctly (P = 0.032) and ventilations delivered correctly (P = 0.015). Peer training may provide CPR instruction comparable to training in CPR classes at lower cost and with potential to reach new population segments.


A B3LYP and MP2(full) theoretical investigation into explosive sensitivity upon the formation of the molecule-cation interaction between the nitro group of 3,4-dinitropyrazole and H+, Li+, Na+, Be2+ or Mg2+.
The explosive sensitivity upon the formation of molecule-cation interaction between the nitro group of 3,4-dinitropyrazole (DNP) and H(+), Li(+), Na(+), Be(2+) or Mg(2+) has been investigated using the B3LYP and MP2(full) methods with the 6-311++G** and 6-311++G(2df,2p) basis sets. The bond dissociation energy (BDE) of the C3-N7 trigger bond has also been discussed for the DNP monomer and the corresponding complex. The interaction between the oxygen atom of nitro group and H(+) in DNP…H(+) is partly covalent in nature. The molecule-cation interaction and bond dissociation energy of the C3-N7 trigger bond follow the order of DNP…Be(2+) > DNP…Mg(2+) > DNP…Li(+) > DNP…Na(+). Except for DNP…H(+), the increment of the trigger bond dissociation energy in comparison with the DNP monomer correlates well with the molecule-cation interaction energy, natural charge of the nitro group, electron density ρ(BCP(C3-N7)), delocalization energy E(2) and NBO charge transfer. The analyses of atoms in molecules (AIM), natural bond orbital (NBO) and electron density shifts have shown that the electron density of the nitro group shifts toward the C3-N7 trigger bond upon the formation of the molecule-cation interaction. Thus, the trigger bond is strengthened and the sensitivity of DNP is reduced.


A Rare Case of Elevated Transaminases With Incomplete Abortion Due to Cytomegalovirus Infection: An Experience From a Resource-Limited Setting.
Cytomegalovirus (CMV) infection during pregnancy may cause spontaneous abortion, stillbirth, and death of newborns. CMV is the most common congenital infection in newborns. It generally has a benign course in immunocompetent individuals, while the severe disease is usually seen in immunocompromised patients. Most of the published studies about CMV infection describe congenital abnormalities in newborns. Only a handful of case reports mention CMV infection associated with elevated transaminases during pregnancy. Here, we present a case of incomplete abortion with elevated liver enzymes in a 26-year-old female caused by CMV infection. Our case report illustrates the importance of considering CMV infection as a differential in an incomplete abortion associated with elevated liver enzymes.


Hepatitis B virus markers in the population of Dar es Salaam, Tanzania.
A total of 542 serum samples from healthy adults (medical students and medical staff, blood donors and pregnant women) residing in or near the city of Dar es Salaam, Tanzania were examined for markers of hepatitis B virus (HBV) infection. Of these samples, 95 (17.5%) were not found to contain any HBV marker when examined by enzyme-linked immunoassay for hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc). HBsAg was demonstrated in 52 (9.6%) samples of which 7 (13.5%) were positive for hepatitis Be antigen (HBeAg) and 17 (32.7%) were positive for anti-HBc IgM. None of 9 HBsAg positive pregnant women were carriers of HBeAg. These results show that hepatitis B infection is very common in this country. The relatively low prevalence of HBeAg among HBsAg carriers may indicate that transmission of hepatitis B at birth is not of major importance.


[Model of intraluminal perfusion of the guinea pig ileum in vitro in the study of the antidiarrheal properties of the guava (Psidium guajava)].
An experimental in vitro model was developed for the study of plant extracts reported by traditional medicines in the treatment of diarrhea. The guinea-pig isolated ileum is perfused with the plant extract using an intraluminal approach. The peristaltic reflex is induced by electrical stimulation while the plant extract is perfused. The spasmolytic effects of Psidium guajava leaf methanol, hexane and water extracts were demonstrated suggesting the existence of two different types of active components. The results obtained allow to propose this in vitro method as a useful model to reproduce some of the characteristics of the oral way of administration of plant extracts.


An evaluation of the response to neoadjuvant chemotherapy for osteosarcoma of extremities: PERCIST versus RECIST 1.1 criteria after long-term follow-up.
The aim of this study was to compare the recent Positron emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for evaluating the response of osteosarcoma to neoadjuvant chemotherapy of the extremities. We retrospectively reviewed patients with osteosarcoma of the extremities who received neoadjuvant chemotherapy and then surgical resection at Peking University People's Hospital. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (MRI) were performed prior to chemotherapy and before surgical resection. Therapeutic response was assessed separately by the PERCIST and RECIST 1.1 criteria. The association between the data acquired by the PERCIST and RECIST 1.1 criteria was then analyzed by Wilcoxon's signed-rank test. The association between the PERCIST criteria and the pathological necrosis rate was analyzed by Fisher's exact test. Finally, the impact of a range of clinicopathological factors on overall survival (OS) and event-free survival (EFS) was analyzed by Cox proportional hazards regression. We recruited 68 patients with a median follow-up of 74 months (range 45-102 months). The evaluations resulting from the RECIST 1.1 and PERCIST criteria were significantly different (p = 0.000). Only two responders were identified according to the RECIST 1.1 criteria. However, 34 responders were identified by the PERCIST criteria. Data arising from the PERCIST criteria were in accordance with the pathological necrosis rate. Survival analysis showed that metastasis at diagnosis, poor pathological response, and disease progression (according to the RECIST 1.1 or PERCIST criteria) were all associated with a poor prognosis (p < 0.05). Our data indicate that the PERCIST criteria are significantly more sensitive than RECIST 1.1 criteria to identify more responders when evaluating the response of osteosarcoma to neoadjuvant chemotherapy.


A Simple Formula to Estimate Parathyroid Weight on 4D-CT, Predict Pathologic Weight, and Diagnose Parathyroid Adenoma in Patients with Primary Hyperparathyroidism.
Parathyroid gland weight is a clinically relevant parameter used to diagnose parathyroid adenomas intraoperatively. We evaluated the accuracy of a formula to estimate parathyroid weight on preoperative 4D-CT. A single-institution retrospective study was performed in patients with primary hyperparathyroidism who underwent 4D-CT between January 2013 and December 2014 with subsequent parathyroidectomy and surgical cure. All patients had correct localization of a solitary parathyroid adenoma. The longest 3 dimensions of all identified parathyroid glands were measured on CT, and weight was estimated using the formula: weight4D-CT (mg) = 1 mg/mm3 × Length (mm) × Width (mm) × Height (mm) × π/6. We correlated weight4D-CT with pathology specimen weight (weightpathology). Using receiver operating characteristic analysis, we estimated the performance of weight4D-CT to discriminate a parathyroid adenoma from normal glands on 4D-CT and determined the optimal threshold based on the Youden index. One hundred sixteen patients (85 women, 31 men) were evaluated. Weight4D-CT was shown to be strongly correlated with weightpathology as demonstrated by Spearman ρ = 0.73 (P < .01), concordance correlation coefficient = 0.92 (95% CI, 0.89-0.94), and Cronbach α = 0.96. The performance of weight4D-CT for the diagnosis of parathyroid adenoma was excellent, with an area under the curve of 0.955 (95% CI, 0.925-0.985; P < .001). Based on the Youden index, the optimal threshold was >50 mg, with a sensitivity of 96.7% and a specificity of 95.7%. Radiologists can accurately estimate parathyroid adenoma weight on 4D-CT. This metric is highly correlated with pathologic weight, and a threshold cutoff of >50 mg can be used to distinguish parathyroid adenoma from normal glands.


Physiochemical characterization of cardiovascular calcified deposits. I. Isolation, purification and instrumental analysis.
Calcified human aortic atherosclerotic deposits and calf ventricular assist device bioprosthetic deposits were isolated and deproteinated by hydrazine treatment. Detailed chemical and instrumental analyses were applied to gain comprehensive physicochemical information which makes possible establishing compositional and structural similarities between the 2 types of pathologic mineral deposits which form on different host surfaces. These microcrystalline deposit materials are morphologically very heterogeneous and can be represented chemically as carbonate substituted apatite which, in some of its properties, significantly differs from hydroxyapatite. It is indicated that the mechanism for the formation of cardiovascular deposits proceeds through hydrolysis of octacalcium phosphate precursor.


Differential effects of a combination of Hibiscus sabdariffa and Lippia citriodora polyphenols in overweight/obese subjects: A randomized controlled trial.
Plant-polyphenols have shown the capacity to ameliorate obesity-induced metabolic disturbances, both in cell and animal models, where most therapeutic approaches have failed. On the basis of previous research, a dietary supplement containing 500 mg of a combination of polyphenolic extracts from Lippia citriodora L. and Hibiscus sabdariffa L. (LC-HS), in the context of an equilibrated isocaloric diet, was evaluated in a double blind, placebo-controlled and randomized trial in 56 obese/overweight subjects for two months. Compared to controls, the consumption of the LC-HS polyphenols showed significant improvements in body weight, abdominal circumference of overweight subjects (-6.79 ± 0.80 cm in overweight LC-HS group vs -1.85 ± 0.83 cm in controls, p < 0.001) and body fat % (-1.33 ± 0.15% in overweight LC-HS group vs -0.66 ± 0.17% in controls, p < 0.05). Heart rate and systolic blood pressure also presented significant improvements in overweight LC-HS participants. However, changes were more modest in obese subjects. Further, LC-HS extract significantly reduced lipid content and increased AMPK activity in a hypertrophied adipocyte cell model. Therefore, consumption of 500 mg/day of LC-HS extracts enriched in polyphenols for two months in the context of an isocaloric diet by overweight subjects decreased symptoms associated to obesity-related diseases. Modulation of fat metabolism in adipose tissue, probably mediated by AMPK activation, is proposed as a molecular target to be explored in future research.


Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy.
Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.


Synthesis of gelatin-containing PHBV nanofiber mats for biomedical application.
Electrospinning is one of the fabrication method to form ultra-fine fiber in a nano-scale made of synthetic and natural extracellular matrix components for tissue-engineering applications. In this study, a nanofibrous scaffold was obtained by co-electrospinning poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and gelatin in 2,2,2-trifluoroethanol (TFE) at a ratio of 50/50. The resulting fiber diameters were in the range of 400-1,000 nm without any beads. The nanofiber surfaces were characterized by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), electron spectroscopy for chemical analysis (ESCA), and atomic force microscopy. It was found, from cell culture experiments, that NIH 3T3 cells on the PHBV/gelatin nanofibrous scaffold more proliferated than on the PHBV nanofibrous scaffold.


Measuring what matters: Why and how to include patient reported outcomes in clinical care and research on inborn errors of metabolism.
Patient reported outcomes (PROs) are generally defined as 'any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else'. A broader definition of PRO also includes 'any information on the outcomes of health care obtained directly from patients without modification by clinicians or other health care professionals'. Following this approach, PROs encompass subjective perceptions of patients on how they function or feel not only in relation to a health condition but also to its treatment as well as concepts such as health-related quality of life (HrQoL), information on the functional status of a patient, signs and symptoms and symptom burden. PRO measurement instruments (PROMs) are mostly questionnaires and inform about what patients can do and how they feel. PROs and PROMs have not yet found unconditional acceptance and wide use in the field of inborn errors of metabolism. This review summarises the importance and usefulness of PROs in research, drug legislation and clinical care and informs about quality standards, development, and potential methodological shortfalls of PROMs. Inclusion of PROs measured with high-quality, well-selected PROMs into clinical care, drug legislation, and research helps to identify unmet needs, improve quality of care, and define outcomes that are meaningful to patients. The field of IEM should open to new methodological approaches such as the definition of core sets of variables including PROs to be systematically assessed in specific metabolic conditions and new collaborations with PRO experts, such as psychologists to facilitate the systematic collection of meaningful data.


The effect of the protein matrix on glycoprotein processing by oviduct Golgi enzymes.
Using the avidin-biotinyl glycan system reported previously (Shao, M.-C., and Wold, F. (1987) J. Biol. Chem. 267, 2968-2972), we have compared the processing efficiency of oviduct enzymes acting on different glycan-(biotinyl)Asn and glycan-(6-biotinamidohexanoyl)Asn derivatives when they are free and bound to avidin. The glycans were selected to permit exploration of the individual processing steps, and the two different groups of derivatives were used to assess both the close (biotinyl) and more distal (biotinamidohexanoyl) display of the glycan relative to the avidin surface. The direct comparison of the free and avidin-bound glycans demonstrated that mannosidase I is strongly inhibited by avidin in both the close and distal complexes, whereas GlcNAc transferase I and mannosidase II are strongly inhibited only in the close complex. GlcNAc transferases III, IV, and V, which could only be assessed individually by indirect means using different substrates, did not appear to be affected in any major way by the protein matrix; the data suggest that transferase III is inhibited only to a minor extent in the close complex. Gal transferase activity showed a minor effect of the avidin matrix for both complexes in the hybrid processing pathways. The most significant consequence of the avidin effect on Gal transferase was the apparent abolishment of the incorporation of a 2nd Gal residue in the two avidin complexes. This survey of the protein matrix effects on glycan processing by oviduct enzymes appears to provide reasonable clues to the origin of the very different glycan structures observed in oviduct-processed glycoproteins. Thus, ovalbumin and avidin itself, containing a mixture of oligomannose and hybrid glycans at their single glycosylation sites, may well present they glycans to the processing enzymes in a display very similar to that of the avidin close complex observed here. The inhibition of mannosidase I and GlcNAc transferase I lead to preservation of oligomannose structures, whereas the strong inhibition of mannosidase II favors the incorporation of the bisecting GlcNAc by GlcNAc transferase III to yield hybrid structures as the most processed products. Ovomucoid, which contains multiantennary complex structures at all glycosylation sites, may on the other hand display its glycans, unencumbered by the protein surface, in conformations similar to either the free glycans or the distal complexes observed in this work.


Obesity and the risk of cholangiocarcinoma: a meta-analysis.
A number of studies have shown that obesity is implicated in the susceptibility to several cancers. However, the association between obesity and cholangiocarcinoma remains unclear. This meta-analysis aimed to quantitatively assess the association between overweight or obesity and the incidence of cholangiocarcinoma. A literature search was performed for cohort and case-control studies published from 1996 to 2013 using PubMed, Cochrane, and EMBASE databases. Studies were included if they reported odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) of cholangiocarcinoma with respect to obesity or overweight. Normal weight, overweight, and obesity were defined when the body mass index (BMI) was 18.5-24.9, 25-29.9, and ≥ 30 kg/m(2), respectively. Excess body weight was defined as BMI ≥ 25 kg/m(2). Ten studies met the inclusion criteria, which included five cohort and five case-control studies. Compared with normal weight, being overweight (pooled OR 1.30, 95 % CI 1.13-1.49), obesity (pooled OR 1.52, 95 % CI 1.13-1.89), and excess body weight (pooled OR 1.37, 95 %CI 1.22-1.55) were significantly associated with cholangiocarcinoma. The funnel plot revealed no evidence for publication bias. Obesity is associated with the increased risk of cholangiocarcinoma, which needs to be confirmed by long-term cohort studies.


Immunoreactive substance P in the tubero-hypophyseal system of the rat: selective decrease in the neural lobe after dehydration and sodium loading.
In the tubero-hypophyseal system of the rat the approximate concentrations of immunoreactive substance P (I-SP), expressed as fmol/mg tissue, were 100 in the medial basal hypothalamus (MBH), 20 in the anterior lobe (AL), 20 in the neural lobe (NL) and 4 in the intermediate lobe of the hypophysis. These values were not altered by treatment with capsaicin on day 2 after birth. In rats in which the secretion of neurohormones from the NL was increased by dehydration followed by sodium loading there was a fall by 70% in the I-SP concentration of the NL; no change occurred in the AL or the MBH.


Continuous leg dyskinesia assessment in Parkinson's disease -clinical validity and ecological effect.
Dyskinesias in Parkinson's disease (PD) patients are a common side effect of long-term dopaminergic therapy and are associated with motor dysfunctions, including gait and balance deficits. Although promising compounds have been developed to treat these symptoms, clinical trials have failed. This failure may, at least partly, be explained by the lack of objective and continuous assessment strategies. This study tested the clinical validity and ecological effect of an algorithm that detects and quantifies dyskinesias of the legs using a single ankle-worn sensor. Twenty-three PD patients (seven with leg dyskinesias) and 13 control subjects were investigated in the lab. Participants performed purposeful daily activity-like tasks while being video-taped. Clinical evaluation was performed using the leg dyskinesia item of the Unified Dyskinesia Rating Scale. The ecological effect of the developed algorithm was investigated in a multi-center, 12-week, home-based sub-study that included three patients with and seven without dyskinesias. In the lab-based sub-study, the sensor-based algorithm exhibited a specificity of 98%, a sensitivity of 85%, and an accuracy of 0.96 for the detection of dyskinesias and a correlation level of 0.61 (p < 0.001) with the clinical severity score. In the home-based sub-study, all patients could be correctly classified regarding the presence or absence of leg dyskinesias, supporting the ecological relevance of the algorithm. This study provides evidence of clinical validity and ecological effect of an algorithm derived from a single sensor on the ankle for detecting leg dyskinesias in PD patients. These results should motivate the investigation of leg dyskinesias in larger studies using wearable sensors.


Distribution of plastic debris pollution and it is implications on mangrove vegetation.
Plastic pollution in mangroves located in small islands was not well documented. This study found that mangrove ecosystem in small island was polluted by plastic debris (mainly film: 63% and fiber: 31%). Density of plastic debris in mangrove area was ranging from 10 ± 4 items m-2 to 230 ± 75 items m-2, mean density was 92 ± 28 items m-2. Landward was the most polluted zone mangrove (mean density: 155 ± 58 items m-2) or about 61% of plastic debris was distributed in this zone. This is corresponds to the sources of plastic waste was from land such as households and markets. Mean density of plastic debris was significantly correlated with mangrove health (r2 = 0.59, p = 0.00). This indicated that plastic debris negatively affected mangrove ecosystem directly and indirectly. Effective land-based plastic waste management and actions such as regular beach cleanup are essential to reduce plastic pollution and to ensure mangrove conservation.


Immunological barrier of the central nervous system in neurosurgical diseases.
The immunoelectrophoresis in cerebral tumours, craniocerebral injuries and cerebral haemorrhages showed antibodies against the pathologically changed cerebral tissue, especially in the case of severe traumata and malignant cerebral tumours. Serum and cerebrospinal fluid of 85 patients were examined. Eight of them showed positive results with antibodies (4 gliomas, 1 craniopharyngioma, 3 severe cerebral contusions with disturbance of consciousness).


Fungal melanonychia.
Fungal melanonychia is a relatively rare nail disorder caused by nail infection that produces brown-to-black pigmentation of the nail unit. The number of organisms implicated as etiologic agents of fungal melanonychia is increasing, and the list currently tops 21 species of dematiaceous fungi and at least 8 species of nondematiaceous fungi. These superficial infections may clinically mimic subungual melanoma and are often not responsive to traditional antifungal therapy. This article reviews the literature on fungal melanonychia and the role of fungal melanin in infection.


The projection from the motor cortex to the inferior olive in the cat. An experimental study using axonal transport techniques.
The cortico-olivary projection has been investigated in the cat with the methods of retrograde transport of horseradish peroxidase and wheat-germ agglutinin conjugated with horseradish peroxidase as well as autoradiographic techniques using tritium-labelled amino acids. The projection arises from cells in cortical layer V and terminates mainly ipsilaterally and less densely contralaterally. The strongest termination site is in the caudal medial accessory olive adjacent to subnucleus beta. Projections to that area originate in the medial portions of areas 4 and 6 rostral to the cruciate sulcus. Regions of the motor cortex related to axial back and neck, proximal forelimb and face musculature plus the frontal eye field are represented in largely overlapping areas of the caudal medial accessory olive. A second zone of termination is present in the rostral olive at the junction of the ventral lamella of the principal olive and the medial border of the dorsal accessory olive. Projections to that area arise from a central portion of area 4 at the border between the anterior sigmoid gyrus and the presylvian gyrus. This area contains portions of the representation of the muscle groups controlling the neck and proximal forelimb (shoulder and elbow) only. The frontal eye field, which in the cat influences both extraocular and neck musculature, is also an important direct source of input to this portion of the inferior olive. Contralateral terminations are distributed symmetrically. Combining this information with the olivocerebellar distribution, cerebellar cortical areas corresponding to this direct cortical input are defined. Taking into account that the cortico-olivary fibers appear to arise only from those portions of the motor cortex involved in the control of axial and proximal forelimb muscles, it is suggested that the cortico-olivo-cerebellar projections play a preponderant role in the cerebellar control of posture.


In vitro evaluation of targeted antisense 177Lu radiotherapy.
The BCL2 proto-oncogene in non-Hodgkin's lymphoma is a dominant inhibitor of apoptosis. The goal of this work was to develop a (177)Lu-labeled anti-BCL2-peptide nucleic acid (PNA) conjugate designed for dual modality NHL therapy, i.e., simultaneous down-regulation of BCL2-mediated resistance to apoptosis and delivery of cytotoxic internally emitted radiation. The effect of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetra-acetic acid (DOTA)-anti-BCL2-Tyr(3)-octreotate was evaluated by uptake, efflux, proliferation, and viability assays, using Mec-1 lymphoma cells. In vitro dosimetry was modeled with a Monte Carlo projection. Cellular efflux indicated moderate retention of radioactivity in the Mec-1 cells. Viability studies using the (177)Lu-labeled PNA conjugate indicated a mass-dose dependence and strongly additive statistical effect in reducing cellular viability. These studies demonstrate the ability of a BCL2 antisense PNA conjugate to specifically target, be retained in, and reduce cellular viability in Mec-1 NHL cells. The results also hold promise for the development of a therapeutic radiopharmaceutical with potential dual modality function.


A novel class of oxazepine-based anti-cancer agents induces cell death in primary human CLL cells and efficiently reduces tumor growth in Eμ-TCL1 mice through the JNK/STAT4/p66Shc axis.
Survival and expansion of malignant B cells in chronic lymphocytic leukemia (CLL) are highly dependent both on intrinsic defects in the apoptotic machinery and on the interactions with cells and soluble factors in the lymphoid microenvironment. The adaptor protein p66Shc is a negative regulator of antigen receptor signaling, chemotaxis and apoptosis whose loss in CLL B cells contributes to their extended survival and poor prognosis. Hence, the identification of compounds that restore p66Shc expression and function in malignant B cells may pave the way to a new therapeutic approach for CLL. Here we show that a novel oxazepine-based compound (OBC-1) restores p66Shc expression in primary human CLL cells by promoting JNK-dependent STAT4 activation without affecting normal B cells. Moreover, we demonstrate that the potent pro-apoptotic activity of OBC-1 in human leukemic cells directly correlates with p66Shc expression levels and is abrogated when p66Shc is genetically deleted. Preclinical testing of OBC-1 and the novel analogue OBC-2 in Eμ-TCL1 tumor-bearing mice resulted in a significantly longer overall survival and a reduction of the tumor burden in the spleen and peritoneum. Interestingly, OBCs promote leukemic cell mobilization from the spleen to the blood, which correlates with upregulation of sphingosine-1-phosphate receptor expression. In summary, our work identifies OBCs as a promising class of compounds that, by boosting p66Shc expression through the activation of the JNK/STAT4 pathway, display dual therapeutic effects for CLL intervention, namely the ability to mobilize cells from secondary lymphoid organs and a potent pro-apoptotic activity against circulating leukemic cells.


A ventral glomerular deficit in Parkinson's disease revealed by whole olfactory bulb reconstruction.
Olfactory dysfunction is common in Parkinson's disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson's disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson's disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson's disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson's disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson's disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson's disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson's disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson's disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson's disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson's disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson's disease.


HIF-1 versus HIF-2--is one more important than the other?
Hypoxia is a state where oxygen availability/delivery is below the level necessary to maintain physiological oxygen tension for a particular tissue. It is well-established that when tissue demand exceeds its oxygen supply, a cascade of intracellular events is activated, with the elevation of the expression of hypoxia-inducible factors (HIFs). As a consequence, the extensive transcriptional response regulating angiogenesis, glucose metabolism, cell growth, metastasis and others processes is induced. The discovery of differences between HIF isoforms has provided new insights into HIFs biology. Importantly, the opposite effects can be exerted by HIF-1 and HIF-2 on the regulation of angiogenic response. Although both isoforms may upregulate the expression of pro-angiogenic vascular endothelial growth factor (VEGF), HIF-1 diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor whereas HIF-2 augmented expression of IL-8 in an Nrf2-independent way but via upregulation of SP-1 activity. Moreover, the opposite regulation of c-Myc transcription factor by both HIF isoforms may influence IL-8 regulation. Complexity of effects exerted by both HIF isoforms resulting from the cooperation with other transcription factors should be subjected to intensive investigation especially in the context of pro-and anti-angiogenic therapies.


Comparison between diagnostic performance of intestinal Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli in 5-fluorouracil resistance to colorectal cancer: A meta‑analysis.
Intestinal Fusobacterium nucleatum (F. nucleatum) infection has been implicated into the progression of colorectal cancer (CRC). However, F. nucleatum as a biomarker in 5-fluorouracil (5-FU) resistance of CRC has not been fully analyzed by comparing with other types of gut microbiota. In order to further reduce the random error and bias of individual research, this meta‑analysis aimed to compare the diagnostic performance of intestinal Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli in 5-FU resistance to colorectal cancer and provide evidence‑based data to clinical practice. Comprehensive searches of PubMed, Embase, Cochrane Library and Web of Science databases were conducted. A total of 11 studies were selected according to the preestablished inclusion and exclusion criteria and analyzed by Review Manager 5.4 software, which included mapping of forest plots, heterogeneity tests, meta‑regression, sensitivity analysis and publication bias. Overall sensitivity and specificity of F. nucleatum detection in 5-FU resistance of CRC were 0.65 (95% CI:0.60-0.69) and 0.70 (95% CI:0.59-0.87), respectively. Its positive likelihood ratio (PLR) and negative likelihood ratio (NLR) in detecting colorectal cancer were 2.57 (95% CI:1.47-3.21) and 0.52 (95% CI:0.43-0.63). The diagnostic odds ratio (DOR) was 4.92 (95% CI:2.23-7.33), which significantly exceeds the performance of B. fragilis (DOR: 0.53, 95% CI:0.31-0.82) and E. coli (DOR: 0.63, 95% CI: 0.57-0.76) for indicating 5-FU resistance of CRC. Compared with intestinal B. fragilis and intestinal E. coli, intestinal F. nucleatum is more reflective of 5-FU resistance to colorectal cancer.


Neurochemical and histochemical characterization of neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurones in the mouse.
Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a rapid and long-lasting reduction of both 3,4-dihydroxyphenylalanine (dopamine, DA) and noradrenaline (NA) in mouse brain, as observed histo- and neurochemically. The depleting effects were more pronounced after repeated MPTP administration and the most marked reductions were observed after 2 X 50 mg MPTP/kg s.c., when DA in striatum and NA in frontal cortex were reduced by greater than 90% 1 week after MPTP. Mice with such catecholamine depletions were markedly sedated and almost completely immobilized. The behavioural syndrome after MPTP resembled that seen after reserpine, a monoamine-depleting drug. MPTP also caused a long-lasting reduction of catecholamine uptake in striatal DA and cortical NA nerve terminals and reduced tyrosine hydroxylase activity in these regions. There was no evidence that MPTP caused any marked DA and NA cell body death. MPTP given acutely transiently elevated serotonin levels. The results are compatible with a neurotoxic action of MPTP on both DA and NA nerve terminals. The nigro-striatal DA and the locus coeruleus NA neurone systems appeared to be most susceptible. Synthesis and utilization of residual striatal DA and cortical NA were increased, as often observed in partially denervated monoamine-innervated brain regions. Both DA and NA showed a gradual recovery, which took months to become complete and may have been related to a regrowth of catecholamine nerve terminals.


Exploring Sick Leave in Integrative Care-Retrospective Observations and Future Study Recommendations.
To describe and contrast the prevalence and trends of sick leave in patients with pain or stress disorders referred to inpatient care that integrates conventional and complementary therapies, that is, integrative care (IC). County council and social insurance data were used to retrospectively observe cross-sectional sick leave prevalence at four time points: 1 year before the first registered inpatient visit with the target diagnosis, after referral at index, and at 1 and 2 years after index. To contrast the IC findings, observations of patients with similar background characteristics referred to conventional care (CC) were used. The sick leave prevalence of IC pain patients and IC stress patients increased from the preceding year to peak at index, where after it decreased back toward preindex levels over 2 years. Overall sick leave prevalence was higher in IC than in CC, where analogous but lower prevalence trends of sick leave changes were observed. Observed sick leave prevalences, which were higher in IC than in CC, gradually decreased over time following IC or CC referral. While natural recovery or other reasons for change of sick leave cannot be excluded, future prospective and randomized clinical trials are recommended.


Impact of Smoking and Smoking Cessation Medications in Aviators.
To (1) compare the effects of cigarette smoking, nicotine withdrawal, and smoking cessation medications in US civilian and military aviators and (2) review the regulations in place regarding the use of smoking cessation medications for US aviators. Cigarette smoking and associated cessation attempts are associated with multiple hazards in flight to aviators including effects from nicotine intoxication, nicotine withdrawal, carbon monoxide intoxication, and side effects related to smoking cessation medications. Current civilian and military regulations place significant restrictions on the use of smoking cessation medications to aviators; however, recent research suggests that the hazards associated with these medications might be lower than the risk-associated unassisted nicotine withdrawal. An evidence-based approach to smoking cessation may require changing restrictions against smoking cessation medication use in US civilian and military aviators. Use and cessation of smokeless tobacco and e-cigarettes require additional attention and research in this population.


Atomic force microscope observation on biomembrane before and after peroxidation.
Atomic force microscope (AFM) has been used to visualize the morphological change on the surface of erythrocyte membrane before and after oxidation. A smooth surface of intact erythrocyte cell was observed, while treatment by ferrous ion and ascorbate induced hemolysis of intact erythrocytes, generated many holes with average size of 146.6 +/- 33.2 nm in diameter (n=28) on membrane surface as seen by AFM. Ghost membrane and its inside-out vesicles were also used for the experiment. Skeleton structure and protein vesicles could be observed on the surface of an intact erythrocyte membrane before oxidation. Sendai virus induced fusion of inside-out vesicles seemed suppress peroxidation, while no such effect was observed in ghost membrane and erythrocyte systems.


Automated correction angle calculation in high tibial osteotomy planning.
High tibial osteotomy correction angle calculation is a process that is usually performed manually or in a semi-automated way. The process, according to the Miniaci method, is divided into several stages to find specific points: the center of the femoral head, the edges of the tibial plateau, the Fujisawa point, the center of the ankle joint, and the Hinge point. In this paper, we proposed an end-to-end approach that consists of different techniques for finding each point. We used YOLOv4 to detect regions of interest. To identify the center of the femoral head, we used the YOLOv4 and the Hough transform. For the other points, we used a combined method of YOLOv4 with the ASM/AAM algorithm and YOLOv4 with image processing algorithms. Our fully-automated method achieved a mean error rate of 0.5[Formula: see text] (0[Formula: see text]-2.76[Formula: see text]) ICC 0.99 (0.98-0.99) 95% CI on our own dataset of standing long-leg Anterior Posterior view X-rays. This might be the first method that automatically calculates the correction angle of high tibial osteotomy.


What's new in pediatric oncology? Epidemiology, treatment principles and prognosis in childhood malignancies.
The proportion of malignancies in children differs from that in adults: Leukemias and malignant lymphomas predominate with a total of 50%, followed by tumors of the nervous system, of the kidneys, and of connective and supportive tissue. Most of these diseases respond well to cytostatic therapy. Therefore chemotherapy occupies a major role in the curative concepts for nearly all childhood malignancies. Its objective is the destruction of micrometastases as well as the reduction of primary tumor mass in inoperable cases, and it often helps to limit the extent of radical surgery. Radiotherapy, too, can be reduced under the influence of cytostatic therapy. In nearly all childhood cancers, prognosis has improved substantially over the past 10 to 15 years. Today, our aim is not the mere limited survival, but a definitive cure. Modern strategies have raised the cure rates of Hodgkin's disease to 90%, of Wilms' tumor, acute lymphoblastic leukemia and non- Hodgkin lymphomas to 70-75%, of soft tissue sarcomas and osteosarcomas to about 50%, and of acute myelogenous leukemia, neuroblastoma and medulloblastoma to 30-35%. Centralized management of childhood cancers in specially staffed hospitals is mandatory on account of their relative low frequency, the risks of chemotherapy, and the high staff workload.


Volume-Rendered Optical Coherence Tomography of Retinal Vein Occlusion Pilot Study.
To investigate the retinal vascular findings and associated cystoid edema in the central macula of eyes with retinal vein occlusion using volume-rendered angiographic and structural optical coherence tomography. Observational case series. In this retrospective study 12 eyes of 12 consecutive patients, 3 with branch and 9 with central retinal vein occlusion, were imaged in 27 sessions with optical coherence tomography (OCT) using split-spectrum amplitude decorrelation. The structural OCT data were segmented for cystoid spaces and integrated into the angiographic data for subsequent volume rendering. The inner and deep vascular plexus were analyzed in relation to cystoid macular edema with retention of depth information. Retinal vascular flow abnormalities were demonstrated by flow voids with abnormal vascular morphology in the inner vascular layer and varying flow loss in the deep vascular plexus. Areas of cystoid edema were associated with topographically co-localizing flow voids in the deep vascular layer. Treatment with intravitreous anti-vascular endothelial growth factor injections resulted in resolution of edema but no change in flow patterns in either the inner or deep plexus. Recurrence of edema happened in the same areas of altered inner and absent deep vascular plexus flow signal. Cystoid macular edema in retinal vein occlusion occurred in relation to altered inner plexus and absent deep vascular plexus flow. This pattern of cystoid fluid accumulation is similar to that seen in diabetic retinopathy and may represent an important underlying pathophysiologic foundation for cystoid macular edema in retinal vascular diseases.


Non-traumatic rhabdomyolysis with gluteal ulcer.
The case is presented of a 34-year-old woman with rhabdomyolysis due to massive intake of nimetazepam, a benzodiazepine hypnotic. On admission, the patient had numerous blisters all over the body. One of the blisters in the gluteal region developed into a deep ulcer accompanied by muscle necrosis although it was not at a pressure point. The ulcer needed surgical intervention. Rhabdomyolysis is caused by the lysis and necrosis of muscle due to direct or indirect injury, high fever, ischaemia, hypoxia or enzyme defects. Release of myocyte components into the circulation then may induce major problems, especially acute renal failure associated with hypermyoglobinaemia. However, there have been few reports of cutaneous ulcer formation in non-traumatic rhabdomyolysis.


Nur77: a potential therapeutic target in cancer.
The orphan nuclear receptor Nur77 (also known as NR4A1, NGFIB, TR3, TIS1, NAK-1, or N10) is a unique transcription factor encoded by an immediate early gene. Nur77 signaling is deregulated in many cancers and constitutes an important molecule for drug targeting. Nur77 as a versatile transcription factor that displays distinct dual roles in cell proliferation and apoptosis. In addition, several recent insights into Nur77's non-genomic signaling through its physical interactions with various signaling proteins and its phosphorylation-dependent regulation will be highlighted. The possible mechanisms by which Nur77 supports carcinogenesis and specific examples in different human cancers will be summarized. Different approaches to target Nur77 using mimetics, natural products, and synthetic compounds are also described. These latest findings shed light on the novel roles of Nur77 as an exploitable target for new cancer therapeutics. Further work which focuses on a more complete understanding of the Nur77 interactome as well as how the different networks of Nur77 functional interactions are orchestrated in a stimulus or context-specific way will aid the development of more selective, non-toxic approaches for targeting Nur77 in future.


Three lactation-related hormones: Regulation of hypothalamus-pituitary axis and function on lactation.
The endocrine system plays a central role in many aspects of lactation, including mammogenesis (mammary gland development), lactogenesis (onset of lactation), and galactopoiesis (maintenance of milk secretion). Many hormones of the endocrine system directly or indirectly regulate lactation process. The secretion of prolactin (PRL), one of the most important lactation-related hormones, is inhibited by hypothalamus-pituitary dopaminergic system and stimulated by hypothalamus-pituitary oxytocinergic system. This hormone is essential in all stages of lactation. The growth hormone (GH) regulates metabolism and the distribution of nutrients between tissues mammary glands, and stimulates the production of IGF-I from the liver which binds to IGF-IR of mammary epithelial cells (MECs) to indirectly promote lactation. The synthesis and secretion of estrogen (E) are affected by the hypothalamus-pituitary axis. The hormone regulates duct morphogenesis and MECs proliferation. It also modulates the synthesis and secretion of PRL and GH, which together regulate the lactation in female animals. In this article, we reviewed the three main lactation-related hormones (PRL, GH, and E), summarize their regulation by the hypothalamus-pituitary axis and how they influence lactation.


Blood flow distribution in infant pigs subjected to surface cooling, deep hypothermia, and circulatory arrest. Deleterious effects in pigs with left-to-right shunts.
Surface cooling, deep hypothermia and circulatory arrest have been used effectively for correction of congenital heart defects in infancy. Which patients are best suited for this technique has not been addressed. The addition of surface cooling to deep hypothermia and circulatory arrest provides homogeneous cooling and avoids swelling due to reperfusion injury after circulatory arrest. However, surface cooling in patients with large left-to-right shunts causes increased peripheral resistance and increased shunting which can result in decreased perfusion of vital organs. The purpose of this study is to measure the effect of a large left-to-right shunt on total organ blood flow distribution in infant piglets during surface cooling, deep hypothermia, and circulatory arrest. Eleven 2-week-old piglets had surface cooling, deep hypothermia, and circulatory arrest for 45 minutes, followed by rewarming and weaning from cardiopulmonary bypass. Microspheres (15 mu) were injected before surface cooling, at 28 degrees C, at 15 degrees C, and after weaning from cardiopulmonary bypass. Group I (five piglets) was the control. Group II (six piglets) had a large (6 mm) left-to-right aortopulmonary shunt established before microsphere injection. Cardiac outputs in both Groups I and II decreased with surface cooling. The distribution of cardiac output in Group I did not change with surface cooling; however, Group II pigs showed marked change in distribution of cardiac output, resulting in decreased renal, visceral, and pulmonary flow (p less than 0.05). Amylase determinations before and after surface cooling, deep hypothermia, and circulatory arrest were unchanged in Group I but elevated in Group II (p less than 0.05). These observations suggest altered cellular metabolism in visceral organs during the period of surface cooling which may be compounded by circulatory arrest and rewarming.


Impact of the changing landscape of induction therapy prior to autologous stem cell transplantation in 540 newly diagnosed myeloma patients: a retrospective real-world study.
Autologous stem cell transplantation (ASCT) is the standard treatment for younger patients with newly diagnosed multiple myeloma (MM). However, due to restrictive exclusion criteria, more than half of eligible patients are usually excluded from transplant studies. This retrospective monocentric analysis included 540 patients with MM who received an ASCT between 1996 and 2019. Up to 2005, induction therapy consisted mainly of conventional chemotherapies, e.g. vincristine/doxorubicin/dexamethasone (VAD). In the following years, the triple-combinations based on bortezomib coupled with doxorubicin/dexamethasone (PAD), melphalan/prednisolone (VMP), cyclophposphamide/dexamethasone (VCD) or bendamustine/prednisolone (BPV) became the most popular treatment options. A progressive improvement in PFS was observed in patients treated with the two current induction therapies BPV (47 months) or VCD (54 months) compared to VAD (35 months, p < 0.03), PAD (39 months, p < 0.01 and VMP (36 months, p < 0.01). However, there was no significant difference in median OS (VAD 78, PAD 74, VMP 72, BPV 80 months and VCD not reached). In our analysis, we also included 139 patients who do fulfill at least one of the exclusion criteria for most phase 3 transplant studies (POEMS/amyloidosis/plasma cell leukemia, eGFR < 40 mL/min, severe cardiac dysfunction or poor general condition). Outcome for these patients was not significantly inferior compared to patients who met the inclusion criteria for most of the transplant studies with PFS of 36 vs 41 months (p = 0.78) and OS of 78 vs 79 months (p = 0.34). Our real-world data in unselected pts also stress the substantial value of ASCT during the first-line treatment of younger MM pts.


Clinical comparison between two different splint designs for temporomandibular disorder therapy.
To compare splint therapy in temporomandibular disorder (TMD) patients using two splint designs. In a double-blind randomized parallel trial, 40 consenting patients were selected from the dental faculty pool of TMD patients. Two splint designs were produced: an ordinary stabilization (Michigan type) and a NTI (Nociceptiv trigeminal inhibition). The differences in splint design were not described to the patients. All patients were treated by one operator. A separate, blinded, examiner assessed joint and muscle tenderness by palpation and jaw opening prior to splint therapy, and after 2 and 6 weeks' and 3 months' splint use during night-time. The patients reported headache and TMD-related pain on a visual analog scale before and after splint use, and were asked to describe the comfort of the splint and invited to comment. Thirty-eight patients with mainly myogenic problems were observed over 3 months. A reduction of muscle tenderness upon palpation and self-reported TMD-related pain and headache and an improved jaw opening was seen in both splint groups (p < 0.05; paired t-test and Wilcoxon signed-ranks tests). There were no changes for TM joint tenderness upon palpation. No differences were noted between the two splint designs after 3 months for the chosen criteria of treatment efficacy (p > 0.05; Mann-Whitney U-test). No differences in treatment efficacy were noted between the Michigan and the NTI splint types when compared over 3 months.


Oral styletted intubation under video control in a patient with a large mobile glottic tumour and a difficult airway.
With fibreoptic intubation, advancement of the endotracheal tube (ETT) through the glottis is blind. Thus, in patients with a laryngeal tumour, there is a potential for damage to the tumour. Previously, we proposed the use of a fibreoptic bronchoscope (FOB)-video camera system to permit visualization of tube passage. We used this technique successfully in a patient with a known difficult airway and a large glottic tumour. A 61-yr-old man with a known history of difficult laryngoscopic intubation underwent laryngeal microsurgery for recurrence of a glottic tumour. As preoperative indirect laryngoscopy revealed a large, mobile, and pedunculated glottic lesion obstructing the glottic opening, we planned a conventional awake fibreoptic intubation. Endoscopy showed that the tumour partially obstructed the glottis and the space between the tumour and the glottic opening was very narrow. To avoid damage to the tumour, we changed to an alternative fibreoptic intubation technique. The FOB attached to a video camera was passed nasally and a jaw thrust manoeuver was applied, providing an excellent view of the larynx. An anesthesiologist inserted the ETT with a curved stylet orally, and carefully advanced the tube tip into the space between the tumour and the glottic opening under video control. Absence of damage to the tumour and passage of the tube between the cords were confirmed visually. This alternative intubation technique, providing a view of the tube passage into the glottis, was a reasonable method to avoid potential damage to the glottic tumour by blind tube passage during conventional fibreoptic intubation.


Validation of Italian version of Brace Questionnaire (BrQ).
Brace questionnaire (BrQ) is a tool used to evaluate Health Quality of Life (HRQoL) in patients with Adolescent Idiopathic Scoliosis (AIS) that undergo bracing treatment. The BrQ has not been translated and validated for Italian-speaking patients with AIS. The aim of the study was to perform a trans-cultural validation of BrQ to be used in an Italian speaking population. Translation into Italian (I-BrQ) and back translation to the original Greek (G-BrQ) was performed. The final I-BrQ was then analyzed for Italian cultural characteristics and no inconsistencies were found. After that, construct validity was measured analyzing the I-BrQ relationship with 1) Scoliosis Research Society-22 patient Questionnaire (SRS-22), in order to evaluate the relationship with another patient-oriented questionnaire not focused on brace therapy; 2) Cobb degree scale, in order to evaluate the relationship with the magnitude of the curve. Reproducibility was also tested. Translation of the G-BrQ into Italian was successful and back-translation to Greek corresponded well with the original Greek version.Global I-BrQ correlated strongly with SRS-22 (r = 0.826; p < 0.001). Almost all sub scores from each I-BrQ domain strongly correlated with the single domain scores of SRS-22. Only two I-BrQ sub scores weakly inversely correlated with Cobb degree value.Reproducibility was good (Spearman-Brown coefficient value was 0.943; p < 0.05). Trans-cultural validation in Italian language showed the validity and reliability of the I-BrQ.


A comparison of health parameters in two different canine populations. Part II: Chemical pathology data.
Blood samples were collected on a random basis from 2 canine populations. A selection of serum enzymes, serum electrolytes, serum protein fractions and serum concentrations of iron, creatinine and urea were investigated in a population of kennelled dogs and a population of dogs from a rural township in a developing country. Significant differences between the 2 populations were found for 16 of the 26 constituents evaluated, although differences in variance and distribution made comparisons difficult for some of the tests. The dogs from the rural township had a low mean serum iron, a very low mean serum albumin and a very high mean serum gammaglobulin concentration compared to that of the kennelled dogs. It is postulated that these differences were caused by environmental factors of a biological, physical and social nature.


Detection of circulating trophoblast particles in maternal blood using density gradient centrifugation in preeclampsia and in normotensive pregnancies.
Preeclampsia (PE) is a frequent pregnancy-related disease and a major cause of maternal and fetal morbidity and mortality. Despite that, exact mechanisms of its pathophysiology remain largely unknown. In pregnancies complicated by PE, changes in the regulation of apoptosis seem to result in increased apoptotic shedding of trophoblast particles (TPs) into maternal circulation. Since the number of TP in peripheral blood is low, their detection necessitates pre-analytical enrichment. In this prospective multicenter pilot study we aimed to analyze TP in peripheral blood of 29 women with PE and of 13 unaffected controls using the OncoQuick®plus system for cell enrichment. Using immunocytochemistry, slides were evaluated microscopically for TP. Statistical analyses were performed using Welch's t-test or Fisher's exact test. TP were detected in 10 (34.5%) women with PE and in two (15.4%) of unaffected controls. More than one TP were only found in PE. Comparing the mean counts of TP between groups, we detected significantly more TP in PE (p = 0.046). The OncoQuick®plus system can be applied to detect TP in both women with PE and in normotensive pregnancies. Longitudinal studies investigating the role of TP as a screening method for patients at risk for PE are warranted.


Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study.
Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85). The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs.


Changes in elastin in human atherosclerotic aorta: carbon-13 magic angle sample-spinning NMR studies.
The dipolar-decoupled, natural abundance Fourier transform and cross polarization [13C] NMR spectra of human elastin isolated from atherosclerotic aorta and aortas free of atherosclerotic lesions, bovine insoluble elastin and bovine kappa-elastin were obtained at 75 MHz, with 5-7 kHz magic angle sample spinning. Spin-lattice rotating frame relaxation parameters were measured for protons (T1pH) and for carbons (T1pC) at room temperature. Proton relaxation times were shorter for bovine kappa-elastin (T1pH = 1.7 ms) than for bovine elastin (T1pH) = 3.5 ms). Calculation of T1pH showed no differences between human normal and atherosclerotic elastins. T1pC were shorter for bovine kappa-elastin than for bovine elastin. While alpha-carbons of human atherosclerotic elastin had shorter T1pC than normal elastin alpha carbons, carbons from hydrophobic amino acid side chains had longer T1pC for atherosclerotic then for normal elastin. Biochemical studies of aortic wall and purified elastin showed significantly increased content of lipids (atherosclerotic 67.7 mmol/g elastin, control 54.7 mmol/g elastin) and calcium (atherosclerotic 38.3 mmol/g elastin, control 19.6 mmol/g elastin). Changes in relaxation parameter values may be caused by the structural and biochemical changes in human elastin. Increased mobility of polypeptide chains as based on the model kappa-elastin studies is caused by the action of elastase. Restriction of mobility is expected to be caused by the accumulation of lipids and calcium.


Chelatable metal ions are not required for aryl hydrocarbon receptor transformation to a DNA binding form: phenanthrolines are possible competitive antagonists of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
The aryl hydrocarbon receptor (AhR) mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds by binding DNA and altering gene transcription. We determined whether AhR transformation to a DNA binding form requires chelatable metal ions. The chelator 1,10-phenanthroline and its nonchelating isomers 1,7- and 4,7-phenanthroline blocked, in a concentration-dependent manner, TCDD-elicited transformation of the AhR in rat hepatic cytosol to a form which bound a dioxin-response element (DRE; upstream of the structural gene for cytochrome P4501A1). This was found to be due to the ability of these compounds to competitively inhibit [3H]TCDD specific binding to the AhR under conditions in vitro. EDTA (20 mM) failed to inhibit DRE binding of the transformed AhR, but pretreatment of cytosol with EDTA prior to transformation inhibited DRE binding up to 60%. However, removal of EDTA from the cytosol by gel filtration prior to incubation with TCDD resulted in the same DRE binding as filtered control cytosol without the added divalent metal ions. Both chelators, oxalic acid and iminodiacetic acid, failed to inhibit DRE binding when added prior to AhR transformation. Together these data indicate that chelatable metal ions are not required for AhR transformation to the DNA binding form.


Effects of plasma on PGI2 release from prolonged perfused canine veins.
Prostacyclin release from endothelial cells in culture appears increased by the presence of plasma, but occurrence of a similar phenomenon in intact vessels has not been established. In the present investigation release of 6-keto-PGF1 alpha, the stable breakdown product of prostacyclin, was quantitated from canine veins perfused ex vivo for 15 minute periods, using three different perfusates: 1) Hank's balanced salt solution (HBSS), 2) 20% platelet poor plasma (PPP) derived from heparinized blood, in HBSS, and 3) 20% PPP in HBSS with added arachidonic acid (AA). No differences in initial 6-keto-PGF1 alpha release existed among the three perfusates. However, PPP and PPP + AA solutions were associated with lesser declines in release, than occurred with HBSS alone, these differences being statistically significant after 60 min of perfusion (p less than 0.05). When PPP derived from heparinized and citrated blood rather than from only heparinized blood was used, there was a significantly lower release of prostacyclin (p less than 0.05). The latter may be due to citrate binding of calcium. These data indicate that autologous plasma does not alter initial prostacyclin release from freshly harvested canine veins, but that it weakens the decline in release usually following prolonged periods of perfusion.


Effectiveness and adherence to closed face shields in the prevention of COVID-19 transmission: a non-inferiority randomized controlled trial in a middle-income setting (COVPROSHIELD).
The use of respiratory devices can mitigate the spread of diseases such as COVID-19 in community settings. We aimed to determine the effectiveness of closed face shields with surgical face masks to prevent SARS-CoV-2 transmission in working adults during the COVID-19 pandemic in Bogotá, Colombia. An open-label non-inferiority randomized controlled trial that randomly assigned participants to one of two groups: the intervention group was instructed to wear closed face shields with surgical face masks, and the active control group was instructed to wear only surgical face masks. The primary outcome was a positive reverse transcription polymerase chain reaction test, IgG/IgM antibody test for SARS-CoV-2 detection, or both during and at the end of the follow-up period of 21 days. The non-inferiority limit was established at - 5%. A total of 316 participants were randomized, 160 participants were assigned to the intervention group and 156 to the active control group. In total, 141 (88.1%) participants in the intervention group and 142 (91.0%) in the active control group completed the follow-up. a positive SARS-CoV-2 test result was identified in one (0.71%) participant in the intervention group and three (2.1%) in the active control group. In the intention-to-treat analysis, the absolute risk difference was - 1.40% (95% CI [- 4.14%, 1.33%]), and in the per-protocol analysis, the risk difference was - 1.40% (95% CI [- 4.20, 1.40]), indicating non-inferiority of the closed face shield plus face mask (did not cross the non-inferiority limit). The use of closed face shields and surgical face masks was non-inferior to the surgical face mask alone in the prevention of SARS-CoV-2 infection in highly exposed groups. Settings with highly active viral transmission and conditions such as poor ventilation, crowding, and high mobility due to occupation may benefit from the combined use of masks and closed face shields to mitigate SARS-CoV-2 transmission. ClinicalTrials.gov NCT04647305 . Registered on November 30, 2020.


Two distinct arginine kinases in Neocaridina denticulate: psychrophilic and mesophilic enzymes.
The small shrimp Neocaridina denticulata has two types of arginine kinases (AKs): AK1 and AK2. We determined the full kinetic parameters for the forward reaction of the AKs at temperatures between 15 and 35°C. The catalytic efficiencies, determined by kcat/(Ka(ATP)·Kia(ARG)), of the two enzymes showed a marked difference in temperature dependence. The efficiency of AK2 decreased markedly with decreasing temperature, while that of AK1 did not decrease with decreasing temperature, suggesting that AK1 is a cold-adapted enzyme. This unusual characteristic of AK1 was attributable to the remarkable decrease in Kia(ARG) with decreasing temperature, which enlarges its catalytic efficiency. Criterion with the values of Δ(ΔH(o‡))p-m and Δ(TΔS(o‡))p-m also indicate that AK1 is a psychrophilic enzyme and AK2 is mesophilic.


Yi Qi Chu Tan Formula (YQCTF) inhibited the progress of lung cancer via regulating tumor-associated neutrophil: An integrated study of network pharmacology, proteomics and pharmacodynamics.
Yi Qi Chu Tan Formula (YQCTF), a prescription consisting of eight traditional Chinese medicine for treating lung cancer, has been clinically proven to be effective in improving the life quality and prolonging the survival time of non-small cell lung cancer (NSCLC) patients. This study aimed to evaluate the therapeutic efficacy of YQCTF on NSCLC mice model and further explore its therapeutic targets by using network pharmacology, proteomics and pharmacodynamic methodologies. The network pharmacology analysis was firstly conducted to screen out the potential active ingredients and therapeutic targets of YQCTF against NSCLC. Three kinds of extracts, i.e. the water extract (WE), water extraction-alcohol precipitation (WEAP) and alcohol extract (AE) of YQCTF were prepared, which chemical compositions were subsequently analyzed by using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS), and which anti-neoplastic efficacy was examined on NSCLC mice model. Mice tumor tissues were collected for proteomics analysis, and the immunomodulatory effects of YQCTF extracts on the tumor microenvironment (TME) were further validated by using flow cytometry, immunofluorescence, ELISA and Western blot. Network pharmacology identified 60 conjunct genes and ample cancer-related signaling pathways as potential therapeutic targets of YQCTF. Protein-protein interaction (PPI), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that YQCTF might negatively regulate cancer-related inflammation. UPLC-MS/MS analysis showed that the main components of YQCTF include at least ginsenosides, solasodine, solamargine, solasonine, peimisine, peiminine, peimine and sipeimine-3β-D-glucosihde. All kinds of YQCTF extracts significantly inhibited the growth of lung cancer allograft and regulated the ratio of immune cells in tumor tissues, i.e. upregulated the fractions of T cells, promoted the maturation of dendritic cells (DCs), increased the M1/M2 ratio of tumor-related macrophages, but reduced the number of Tregs and immunosuppressive neutrophils. Proteomics identified neutrophils to be the most prominently enriched target linked to NETs formation in mice tumor tissue, which is verified by the downregulation of neutrophil recruiting factors involving IL-6, HIF-1α and IL-8, as well as the decreases of NETs-related biomarkers including H3cit, MPO, CD18, MMP9 and ICAM-1 in immunofluorescence, ELISA and Western blot analysis. YQCTF inhibited the progress of mice NSCLC allograft, suppressed the pro-tumorigenic tumor-associated neutrophils and improved the tumor immune microenvironment (TIME).


The passage of cells can improve the detection rate of avian leukosis virus to facilitate the elimination of avian leukosis in chickens.
Avian leukosis (AL) is one of the most harmful diseases to the poultry industry in China. The detection of the avian leukosis virus (ALV) p27 antigen plays a decisive role in the elimination of avian leukosis. To explore the influence of passaging cells on the detection rate of the ALV p27 antigen, 21 aseptic anticoagulated blood samples were collected from 21 chickens for which the cloacal swabs were positive for the p27 antigen to inoculate two sets of cell culture plates containing DF1 cells. The cells were cultured for 4 d, one set was passaged, and the other set was not. After the DF1 cells had been cultured for 9 d, the ALV p27 antigen in the supernatants of the two sets was detected by ELISA. The results showed that the p27 antigen-positive rate for the passaged cells was 71.43% (15/21), higher than that of the cells that were directly cultured, which was 42.86%. There was a strong correlation, as high as 0.928, with respect to the S/P value of the p27 antigen in the supernatant between the two sets. In conclusion, there was a strong correlation between the results for the passaged and unpassaged cells, and the passage of cells greatly improved the detection of the p27 antigen.


Malnutrition among Hospitalized Children in the United States: A 2012-2019 Update of Annual Trends.
Malnutrition is associated with adverse clinical outcomes and increased health care utilization for hospitalized children. Yet pediatric malnutrition often goes undiagnosed and national prevalence research in this population is scarce. The aim was to assess change in the coded diagnosis of malnutrition (CDM) among US hospitalized children given increased awareness of the need for improved recognition and standardized diagnosis. Retrospective, cross-sectional analysis using nationally representative data from the Nationwide Inpatient Sample. Our sample was 13.2 million hospitalizations from 2012 to 2019 among pediatric patients between age 1 month and 17 years. CDM using International Classification of Diseases Ninth and 10th Revision-Clinical Modification diagnosis codes. Descriptive statistics and sampling weights were used to estimate the national frequency and prevalence of CDM. Temporal trends in CDM overall and stratified by age, race/ethnicity, and hospital type were analyzed using joinpoint regression. CDM prevalence increased from 3.9% in 2012 to 6.4% in 2019. During this period, failure to thrive decreased from 40.6% to 23.3% of all cases with concomitant increases in the diagnosis of protein-calorie malnutrition and children identified with more than one malnutrition subtype. Differences in CDM diagnoses are evident by hospital type, race/ethnicity, and age of the patient. Although pediatric malnutrition continues to be underdiagnosed in hospital settings, this study demonstrates improvement over time. There continues to be a need for continued professional education regarding best practices for diagnosis to improve health care provider knowledge and self-efficacy on this topic, especially in nonteaching hospitals.


Structural anomalies of the peripheral olfactory system in psychosis high-risk subjects.
Olfactory impairments are prominent in both schizophrenia and the preceding at-risk state. Their presence prior to illness predicts poor functional outcome. In schizophrenia, these impairments reflect peripheral olfactory structural abnormalities, which are hypothesized to arise during early embryonic development. If this is correct, then similar structural anomalies should be apparent among clinical high-risk subjects. Thirty-nine clinical high-risk (CR) subjects (24M/15F) were compared to 36 low-risk (LR) subjects (19M/17F). Olfactory measures derived from 3T MRI scans included olfactory bulb volume, primary olfactory cortical gray matter volume, and the depth of the olfactory sulcus overlying the bulb. Additionally, nasal cavity volumes were assessed with acoustic rhinometry. Male CR subjects exhibited bilateral reductions in olfactory bulb volume and abnormal asymmetries of the posterior nasal cavities and olfactory sulci (left reduced relative to right). Post-hoc contrasts also indicated reduced left, but not right, olfactory cortical gray matter volume. Female CRs had no significant abnormalities, although they exhibited similar trend effects. Left olfactory bulb volume correlated, across all CR subjects, with negative, but not positive, symptoms. In a classification analysis, with 80% target specificity, olfactory measurements distinguished male CR from male LR subjects with 93% sensitivity. Among females, the comparable sensitivity was 69%. Psychosis-risk youths exhibit an array of sexually dimorphic and laterally asymmetric anomalies of the peripheral olfactory system. These are consistent with a developmental disruption primarily affecting male fetuses. These structural biomarkers may enhance the identification of at-risk subjects with poor prognosis, before their clinical trajectory is apparent.