Norepinephrine, dopamine and dexamethasone modulate discrete leukocyte subpopulations and cytokine profiles from human PBMC.
The interplay between the immune and neuroendocrine systems is intense, with the cross-talk between these two systems increasing during stress circumstances. Stress events culminate with hormonal pathway activation elevating the plasma levels of glucocorticoids and catecholamines. The majority of the works evaluating the effects of stress hormones on immune cells have utilized in vivo animal models or clinical studies. This work evaluates the effects of norepinephrine, dopamine, dexamethasone, and the combination of norepinephrine and dexamethasone on cellular activation and expression of immunoregulatory cytokines and chemokines by human PBMC in vitro. Norepinephrine and dopamine increased lymphocyte activation accompanied by augmented Th1 and Th2 type cytokine production. Dexamethasone reduced cell activation and decreased frequencies of cytokine producing cells and chemokine production. The action of norepinephrine together with dexamethasone resulted in immunosupression. The observed effects of hormones and neurotransmitters on leukocyte subsets likely underlie their immunomodulatory action in vivo.


A rapid and simple method for the isolation of pure eosinophilic leukocytes from horse blood.
An improved and short method is described for the isolation of intact eosinophilic leukocytes from horse blood with high yield (1--1.5 g/20 l). Viability and purity of the preparations were verified by light and electron microscopy and by the trypan blue exclusion test. Isolated eosinophils were 98--100% pure, intact and viable, and they could be shown to phagocytise immune-complexes.


Opioid receptor mu 1 gene, fat intake and obesity in adolescence.
Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the μ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.


Prognostic analysis of patients with stage IIIC1p cervical cancer treated by surgery.
Cervical cancer (CC) is one of the most common gynaecologic malignancies. The prognosis of stage IIIC1p cervical cancer patients treated by surgery is heterogeneous. Therefore, the aim of this study was to analyse the factors influencing the prognosis in such patients. From January 2012 to December 2017, 102 patients with cervical cancer who underwent surgical treatment in the Department of Gynaecology and Tumours, Changzhou Maternal and Child Health Hospital, and had pelvic lymph node metastasis confirmed by pathology were analysed retrospectively. All patients underwent radical hysterectomy with/without oophorectomy with pelvic lymphadenectomy with/without para-aortic lymphadenectomy. Clinical data was collected including age, surgical method, ovarian status, intraoperative blood loss, perioperative complications, tumour size, pathological type, depth of stromal invasion (DSI), whether the lymphatic vascular space was infiltrated, number of pelvic lymph node metastases, location of pelvic lymph node metastases, total number of lymph nodes resected, lymph node ratio (LNR), nature of vaginal margin, whether parametrium was involved, postoperative adjuvant therapy, preoperative neutrophil-lymphocyte ratio (NLR) and prognostic information of patients. Survival curves for overall survival (OS) and disease-free survival (DFS) were plotted using the Kaplan-Meier method, and the difference between the survival curves was tested using the log-rank test. Univariate and multivariate COX regression models were used to assess the factors associated with overall survival and disease-free survival in patients with stage IIIC1p cervical cancer. Nomogram plots were constructed to predict OS and DFS, and the predictive accuracy of the nomograms was measured by Harrell's C-index and calibration curves. A total of 102 patients with stage IIIC1p cervical cancer were included in the study, and the median follow-up time was 63 months (range from 6 to 130 months). The 5-year OS was 64.7%, and the 5-year DFS was 62.7%. Multivariate analysis showed that no postoperative adjuvant therapy, LNR > 0.3 and NLR > 3.8 were independent risk factors for OS and DFS in patients with stage IIIC1p cervical cancer. Patients with stage IIIC1p cervical cancer have a poor prognosis. Lower OS and DFS were associated with no postoperative adjuvant therapy, LNR > 0.3 and NLR > 3.8.


Low-profile double plating of unstable osteoporotic olecranon fractures: a biomechanical comparative study.
In the treatment of unstable olecranon fractures, anatomically preshaped locking plates exhibit superior biomechanical results compared with tension band wiring. However, posterior plating (PP) still is accompanied by high rates of plate removal because of soft-tissue irritation and discomfort. Meanwhile, low-profile plates precontoured for collateral double plating (DP) are available and enable muscular soft-tissue coverage combined with angular-stable fixation. The goal of this study was to biomechanically compare PP with collateral DP for osteosynthesis of unstable osteoporotic fractures. A comminuted displaced Mayo type IIB fracture was created in 8 osteoporotic pairs of fresh-frozen human cadaveric elbows. Pair-wise angular stable fixation was performed by either collateral DP or PP. Biomechanical testing was conducted as a pulling force to the triceps tendon in 90° of elbow flexion. Cyclical load changes between 10 and 300 N were applied at 4 Hz for 50,000 cycles. Afterward, the maximum load was raised by 0.02 N/cycle until construct failure, which was defined as displacement > 2 mm. Besides failure cycles and failure loads, modes of failure were analyzed. Following DP, a median endurance of 65,370 cycles (range, 2-83,121 cycles) was recorded, which showed no significant difference compared with PP, with 69,311 cycles (range, 150-81,938 cycles) (P = .263). Failure load showed comparable results as well, with 601 N (range, 300-949 N) after DP and 663 N (range, 300-933 N) after PP (P = .237). All PP constructs and 3 of 8 DP constructs failed by proximal fragment cutout, whereas 5 of 8 DP constructs failed by bony triceps avulsion. Angular-stable DP showed comparable biomechanical stability to PP in unstable osteoporotic olecranon fractures under high-cycle loading conditions. Failure due to bony triceps avulsion following DP requires further clinical and biomechanical investigation, for example, on suture augmentation or different screw configurations.


Intraoral occlusal adjustment time and volume required for CAD/CAM crowns fabricated with different virtual mounting methods (A randomized crossover trial).
To measure the required clinical time and volume of occlusal adjustment when the maxillary cast is positioned in a virtual articulator using one of three methods: digitization of a facebow-mounted mechanical articulator (group A), virtual Bonwill triangle (group B) or a 3D face scan (group F). In this randomized, triple-blind, crossover trial; 11 participants were enrolled. Every participant had one molar indicated for a single crown restoration. Three crowns were designed and milled for every participant molar totaling 33 crowns. Each of the three crowns was fabricated with the participant's casts virtually mounted utilizing a different method. An impression was taken of the crown in place before occlusal adjustment. The occlusal adjustment was then performed and timed with the three crowns in the different groups. After the occlusal adjustment, an impression of the adjusted crown was taken. The pre-adjustment and post-adjustment impressions were digitally superimposed and the volume difference was measured. The Kruskal-Wallis test was used to compare the groups. Group A showed the shortest mean adjustment time (3:44.59 ± 3:39.07) followed by group F (4:30.09 ± 2:01.50) and group B (4:35.30 ± 2:32.33). The mean adjustment volume for group A was (28 ± 19.1 mm3) followed by group F (30.5 ± 18.8 mm3) and group B (40.6 ± 29.5 mm3). Different virtual mounting methods had no statistically significant effect on adjustment time (P-value = 0.538) or adjustment volume (P-value = 0.490). A simplified approach in virtual articulator mounting appears to be justified in the construction of a single full-coverage prosthesis. Added labor, time and cost of more elaborate virtual mounting methods seem to be counterproductive.


Reciprocal effects between academic self-concept, self-esteem, achievement, and attainment over seven adolescent years: unidimensional and multidimensional perspectives of self-concept.
In their influential review, Baumeister, Campbell, Krueger, and Vohs (2003) concluded that self-esteem--the global component of self-concept--has no effect on subsequent academic performance. In contrast, Marsh and Craven's (2006) review of reciprocal effects models from an explicitly multidimensional perspective demonstrated that academic self-concept and achievement are both a cause and an effect of each other. Ironically, both reviews cited classic Youth in Transition studies in support of their respective claims. In definitive tests of these counter claims, the authors reanalyze these data-including self-esteem (emphasized by Baumeister et al.), academic self-concept (emphasized by Marsh & Craven), and postsecondary educational attainment-using stronger statistical methods based on five waves of data (grade 10 through 5 years after graduation; N=2,213). Integrating apparently discrepant findings under a common theoretical framework based on a multidimensional perspective, academic self-concept had consistent reciprocal effects with both achievement and educational attainment, whereas self-esteem had almost none.


Shorter leukocyte telomere length is associated with risk of nonobstructive azoospermia.
To determine the association between leukocyte telomere length and the risk of nonobstructive azoospermia (NOA). The mean leukocyte telomere length (LTL) among men with NOA, obstructive azoospermia (OA), and normospermic subjects was determined by quantitative polymerase chain reaction (PCR). We used logistic regression to investigate the association between LTL and the risk of NOA after adjustment for age and body mass index (BMI). Partial correlation analysis was also used to evaluate the relationship of clinical parameters with the mean LTL among men with OA and NOA. Reproductive medicine center. A total of 866 men, including 270 normospermic controls, 247 OA and 349 NOA patients. None. Leukocyte telomere length. The mean relative LTL of men with NOA was significantly shorter than that of those with OA and in normospermic controls (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.64-0.98 vs. OR 0.92, 95% CI 0.70-1.24 vs. OR 0.99, 95% CI 0.83-1.22), respectively). Subjects with shorter telomeres (lowest tertile) had a significantly higher risk of NOA than those with longer telomeres (highest tertile). Interestingly, we also found that a low relative LTL was associated with poor efficiency of spermatogenesis using the Johnsen score after testis biopsy and histopathology in azoospermic patients, after adjusting for patient age and BMI. This is the first report that short LTL is associated with NOA, shedding light on an important biological pathway involved in the etiology of this form of male factor infertility.


Geophagy, iron status and anaemia among pregnant women on the coast of Kenya.
In a cross sectional survey based in an antenatal clinic at Kilifi District Hospital, Coast Province, Kenya, 154 of 275 pregnant women (56%) reported eating soil regularly. Geophagous women had lower haemoglobin and serum ferritin concentrations than non-geophagous women (mean haemoglobin level 9.1 vs. 10.0 g/dL, P < 0.001; median ferritin level 4.5 vs. 9.0 micrograms/L, P < 0.001). In multiple linear regression analyses, geophagy was a significant predictor of haemoglobin (beta = -6.4, P = 0.01) and serum ferritin concentrations (beta = -6.6, P = 0.002), while controlling for gestational age and malaria and hookworm infection. Another 38 pregnant women, who reported eating soil regularly, participated in focus group discussions and were interviewed on geophagy. The most commonly eaten soil was from the walls of houses. The median estimated daily intake was 41.5 g (range 2.5-219.0 g). Twenty-seven of these women assisted in the collection of soil samples which were then analysed for their content of iron, zinc and aluminium after extraction with 0.1 M HC1. The average daily soil intake supplied the geophagous women with 4.3 mg of iron, corresponding to 14% of the recommended dietary allowance of iron for pregnant women. The study revealed a strong negative association between geophagy and both haemoglobin and ferritin status. At the same time it demonstrated the potential of soil as a source of dietary iron for geophagous women. These seemingly contradictory results might be due to other components in the soil interfering with iron uptake or metabolism. Alternatively, it may be that the geophagous women had extremely depleted iron stores before starting to eat soil. From these cross-sectional data, no inference about causality could be made.


Comparison of ozone and HO· induced conversion of effluent organic matter (EfOM) using ozonation and UV/H2O2 treatment.
This study experimentally examined the impact of oxidation on the properties of effluent organic matter (EfOM) using two different oxidation techniques: ozonation and UV/H2O2 treatment. Multiple surrogates for EfOM related to its spectral properties, molecular size, concentration, polarity and biodegradability were used to study the oxidant induced conversions. Spectral calculations as differential absorbance spectra (DAS) and absorbance slope index (ASI) were applied for the first time to describe EfOM oxidation and proved to be useful to unravel differences in working mechanism between ozone and hydroxyl radical (HO) induced transformation of EfOM. Effluent ozonation inherently led to significant HO production as a result of electron transfers between ozone and electron rich moieties of EfOM. HO production increased as function of ozone dose and was strongly correlated to UV absorption at 254 nm (UV254). During the UV moderated process, pseudo steady-state behaviour of the HO concentration was observed. Ozone decomposition was extremely sensitive to EfOM reactivity. Most likely, the degree of dissociation of EfOM controlled its reactivity towards ozone. The pH effect was quantified by calculating the pseudo-first order decay constant for ozone as function of reaction time and pH. Treatment with both processes led to more oxygen rich, less hydrophobic and more biodegradable EfOM.


The power of the weak: When altruism is the equilibrium.
A rational economic analysis complements Grossmann's fearful ape hypothesis. Two examples of mixed-motive games with strong inter-dependence (i.e., weak chirping nestling, boxed pigs) demonstrate that signaling weakness is a dominant strategy. Weakness elicits cooperative, caring response, comprising the equilibrium of the game. In extensive form, a reliable reputation of weakness elicits caring as a sequential equilibrium.


Impact of post-implantation time on bioresorbable vascular scaffold outcomes for type C versus non-type C coronary lesions: A longer-term study.
We have demonstrated that bioresorbable vascular scaffold (BVS) for ACC/AHA type C lesions was associated with higher risks of long-term target lesion revascularization (TLR) and target lesion failure (TLF). We determined the specific time after which higher risks of BVS for type C lesions are reduced in a longer-term follow-up. We analyzed data of 457 patients (59 ± 12 years, 87% male) with 714 BVS implanted for 529 lesions and a median follow-up of 56.4 (48.6-62.6) months. Patients with BVS for at least one type C lesion (N = 177) at index intervention and all non-type C lesions (N = 280) were compared for TLF (cardiac death, target vessel myocardial infarction, TLR). We specified the interactions between the non-type C versus type C group and the event-free survival times dichotomized at 24, 30, 32, 33, 36, and 39 months respectively. The type C group had more multivessel disease (86% versus 65%, p < 0.001), left anterior descending artery treated (68% versus 53%, p = 0.002), intravascular imaging used (48% vs. 25%, p < 0.001), and BVS (2.3 ± 0.9 vs. 1.1 ± 0.3, p < 0.001) implanted with a longer total length (57 ± 21 vs. 29 ± 8 mm, p < 0.001). The TLR or TLF was higher (both log-rank p < 0.05) in the type C than in the non-type C group. However, the risks of TLR (hazard ratio: 3.6, 95% CI = 1.1-11.6) and TLF (hazard ratio: 3.8, 95% CI = 1.2-12.1) for type C lesions only remained higher until 24 months post-BVS implantation. BVS provides a longer-term advantage, particularly for type C lesions with the majority requiring long stenting.


A Case of Pulmonary Pleomorphic Carcinoma With Renal Metastasis.
A 62-year-old man was referred to our hospital for an axillary mass. Computed tomography (CT) revealed a right axillary tumor and a left renal tumor. Needle biopsies of lung tumor and renal tumor were performed, but a definite diagnosis was impossible. Because his performance status worsened and the lung tumor grew day by day, chemotherapy with gemcitabine and cisplatin was started without definite diagnosis. However, the chemotherapy could not be continued because of interstitial pneumonia and the patient died because of the progression of disease. The final histopathologic diagnosis was pulmonary pleomorphic carcinoma based on immunohistochemical staining.


Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects.
Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.


Detection of moisture content in salted sea cucumbers by hyperspectral and low field nuclear magnetic resonance based on deep learning network framework.
The accurate control of moisture content (MC) during the processing of sea cucumber is beneficial to improve the taste of sea cucumber and maintain its nutritional value, which is directly related to the quality and shelf life of sea cucumber. The purpose of this study is to explore the feasibility using deep learning (DL) to realize rapid nondestructive detection of MC in salted sea cucumbers based on hyperspectral imaging (HSI) and low field nuclear magnetic resonance (LF-NMR) data. Firstly, three Cuckoo Search (CS) dimensionality reduction algorithms (Traditional-CS, Binary-CS and Chaotic-CS) were combined with DL framework respectively using HSI and LF-NMR data to establish prediction models, which proved the feasibility of DL framework in predicting the MC of sea cucumbers, and Chaotic-CS algorithm was selected as the optimal dimensionality reduction algorithm. Then, the MC visualization based on HSI and LF-NMR data was realized respectively to detect the migration and decrease of MC. Finally, using both HSI and LF-NMR data, the advantages of the models based on Fusion-net DL (FDL) framework were discussed, which showed better performance than the single-data models, with RC2 of 0.9929, RMSEC of 0.0016, RP2 of 0.9936 and RPD of 12.5041. In summary, the rapid nondestructive detection of MC in salted sea cucumbers could be realized by HSI and LF-NMR data based on DL framework, and the advantage of data fusion detection based on FDL framework was verified.


Women receiving 17-alpha-hydroxyprogesterone caproate hospitalized for preterm labor at less than 34 weeks benefit from daily perinatal nursing surveillance.
The objective of the study was to compare pregnancy outcomes of women receiving 17-alpha-hydroxyprogesterone caproate (17P) prophylaxis for the prevention of recurrent spontaneous preterm delivery (SPTD) hospitalized for preterm labor (PTL) less than 34 weeks' gestation prescribed daily vs weekly perinatal nursing surveillance. Singleton gestations with prior SPTD enrolled for outpatient 17P administration at less than 27 weeks' gestation were eligible. Women hospitalized for PTL at less than 34 weeks (n = 379) were identified. Women receiving daily perinatal nursing surveillance (dPNS) (n = 99) following PTL were matched by Medicaid status and gestational age at onset of PTL to women receiving weekly surveillance (n = 280), yielding 83 matched pairs. Among patients receiving 17P who were hospitalized for PTL, the addition of dPNS following hospitalization resulted in lower rates of SPTD less than 32 weeks (odds ratio [OR], 0.29, 95% confidence interval [CI], 0.21-0.38) and less than 35 weeks (OR, 0.25, 95% CI, 0.17-0.33), whereas the rates of SPTD less than 37 weeks were similar. Women receiving prophylactic 17P hospitalized for PTL before 34 weeks benefit from the addition of daily perinatal nursing surveillance.


Lowest enthalpy polymorph of cold-compressed graphite phase.
Based on an ab initio evolutionary algorithm, a novel carbon polymorph with an orthorhombic Cmcm symmetry is predicted, named as C carbon, which has the lowest enthalpy among the previously proposed cold-compressed graphite phases.


Physiology of ileal pouch-anal anastomosis. Current concepts.
Increasing experience with ileal pouch-anal anastomosis (IPAA) associated with increasing knowledge about anorectal physiology has lead to a large number of publications. The purpose of this review is to evaluate the current understanding of fecal continence as revealed by the evolution of the ileoanal procedure. Review of the literature covering the most important physiologic parameters involved in fecal continence was undertaken. Rectoanal inhibitory reflex is probably absent after IPAA but is preserved when distal anorectal mucosa is spared. Anal resting pressure decreases but is less affected when the internal anal sphincter is less traumatized. Squeeze pressure is not importantly affected, and the importance of reservoir function as a determinant of stool frequency is emphasized. IPAA does not affect the coordination between pouch and anal canal motility in the majority of cases. Normal continence is preserved, even during the night, by preserving a gradient of pressure between the pouch and anal canal. Physiologic concepts are well established, but controversies about the continence mechanism related to IPAA remain. The IPAA procedure has allowed discrimination of details about the function of multiple structures involved in fecal continence.


A faulty interaction between SOD1 and hCCS in neurodegenerative disease.
A proportion of Amyotrophic lateral sclerosis (ALS) cases result from impaired mutant superoxide dismutase-1 (SOD1) maturation. The copper chaperone for SOD1 (hCCS) forms a transient complex with SOD1 and catalyses the final stages of its maturation. We find that a neurodegenerative disease-associated hCCS mutation abrogates the interaction with SOD1 by inhibiting hCCS zinc binding. Analogously, SOD1 zinc loss has a detrimental effect on the formation, structure and disassociation of the hCCS-SOD1 heterodimer. This suggests that hCCS functionality is impaired by ALS mutations that reduce SOD1 zinc affinity. Furthermore, stabilization of wild-type SOD1 by chemical modification including cisplatination, inhibits complex formation. We hypothesize that drug molecules designed to stabilize ALS SOD1 mutants that also target the wild-type form will lead to characteristics common in SOD1 knock-outs. Our work demonstrates the applicability of chromatographic SAXS when studying biomolecules predisposed to aggregation or dissociation; attributes frequently reported for complexes involved in neurodegenerative disease.


Hepatitis B virus X protein up-regulates tumor necrosis factor-α expression in cultured mesangial cells via ERKs and NF-κB pathways.
To investigate the effects of hepatitis B virus (HBV) X protein (HBx) on the expression of tumor necrosis factor-α (TNF-α) in glomerular mesangial cells (GMCs) and the underlying intracellular signal pathways. The plasmid pCI-neo-X that carries the X gene of hepatitis B virus was transfected into cultured GMCs. HBx expression in the transfected GMCs was assessed by Western-blot. TNF-α protein and mRNA were assessed by ELISA and semi-quantitative RT-PCR, respectively. Three kinase inhibitors-U0126, an inhibitor of extracellular signal-regulated kinases (ERKs); lactacystin, an inhibitor of nuclear factor-κB (NF-κB); and SB203580, a selective inhibitor of p38 MAP kinase (p38 MAPK) were used to determine which intracellular signal pathways may underlie the action of HBx on TNF-α expression in transfected GMCs. A significant increase in HBx expression in pCI-neo-X transfected GMCs was detected at 36 h and 48 h, which was not affected by any of those kinase inhibitors mentioned above. A similar increase in the expression of both TNF-α protein and mRNA was also observed at 36 h and 48 h, which was significantly decreased in the presence of U0126 or lactacytin, but not SB203580. HBx upregulates TNF-α expression in cultured GMCs, possibly through ERKs and NF-κB pathway, but not p38 MAPK pathway.


Effects of pyrantel pamoate on adult and preadult Toxocara canis worms: an electron microscope and autoradiography study.
Adult as well as preadult Toxocara canis isolated from the intestine of a beagle were incubated for 2, 4, and 14 h in medium containing either different concentrations of pyrantel pamoate (23.6, 236, and 2360 micrograms/ml medium) or tritiated pyrantel pamoate (2.36 micrograms/ml medium). These incubations were performed to study the effects of pyrantel pamoate on the morphology of the parasitic nematodes and to obtain information concerning the mode of uptake, the distribution, and the total amount of pyrantel pamoate ingested by T. canis. The results of the ultrastructure studies indicate that the intestine, hypodermis, and muscle cells are the organs that are predominantly affected by the drug. Additionally, it turned out that the duration of the treatment, i.e., the incubation time, was more important in determining the efficacy of pyrantel pamoate against T. canis than was the concentration itself. Autoradiography studies revealed that the adult worms ingest the drug orally, whereas preadults absorb pyrantel pamoate mainly through the whole body surface. Finally, measurements of the total amount of pyrantel pamoate taken up by T. canis indicated that adult worms can limit or even reduce the ingestion of pyrantel for more than 4 h, but then ingest large amounts of the drug. Preadult worms, however, absorb the drug more or less continuously during the first 14 h through the cuticula, albeit in lower concentrations than the adults. The different experiments elucidate differences in the uptake of pyrantel pamoate as well as in the total amount of drug ingested or absorbed by adult or preadult worms, leading to the assumption that repeated treatment with lower concentrations will be more effective than high concentrations given only once.


New anticoagulants in the treatment of patients with cancer-associated venous thromboembolism.
Venous thromboembolism (VTE) represents a common source of morbidity and mortality among patients with malignant disease. In this specific setting, the treatment of VTE is challenging as cancer patients display a high tendency to develop recurrent VTE, as well as anticoagulant-related bleeding complications. Low-molecular-weight heparins have been demonstrated to be more effective in the long-term prevention of recurrent VTE in cancer patients compared with conventional treatment with vitamin K antagonists. A limitation of this therapeutic approach includes the long-term requirement of daily subcutaneous injections, which may be burdensome to patients. Over the past decade, several novel oral anticoagulants have emerged, which can be administered in fixed doses without the need for monitoring. Clinical trials evaluating these agents for treatment in the general VTE population yielded promising results. This review summarizes the current management of cancer-associated VTE, overviews the trials that investigated the novel anticoagulant drugs for the treatment of acute VTE and discusses the potential of these novel agents for use in cancer patients.


A family of brevinin-2 peptides with potent activity against Pseudomonas aeruginosa from the skin of the Hokkaido frog, Rana pirica.
Nine peptides displaying varying degrees of antimicrobial activity were extracted from the skin of the Hokkaido frog, Rana pirica. Five structurally related peptides were identified as members of the brevinin-2 family. These peptides were active against reference strains of Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella pneumoniae) and Gram-positive (Staphlococcus aureus) bacteria but displayed relatively low hemolytic activity. The most abundant peptide, brevinin-2PRa (680 nmol/g weight of dry skin) showed high potency [minimal inhibitory concentration (MIC) values between 6 and 12 microM] against a range of clinical isolates of P. aeruginosa. In addition, activity was unaffected by NaCl concentrations up to 200 mM. Cladistic analysis based on the primary structures of brevinin-2 peptides supports a close phylogenetic relationship between R. pirica and Japanese mountain brown frog Rana ornativentris. One peptide of the ranatuerin-2 family and one strongly hemolytic peptide of the brevinin-1 family were also isolated from the extract along with two members of the temporin family, temporin-1PRa (ILPILGNLLNGLL.NH(2)) and temporin-1PRb (ILPILGNLLNSLL.NH(2)) that atypically lacked basic amino acid residues and showed only very weak antimicrobial and hemolytic activity.


Comparing Real-World Healthcare Costs Associated with Single-Tablet Regimens for HIV-1: The 2-Drug Regimen Dolutegravir/Lamivudine vs. Standard 3- or 4-Drug Regimens.
Dolutegravir/lamivudine (DTG/3TC) is a 2-drug regimen for HIV-1 treatment with long-term efficacy and good tolerability comparable to 3- or 4-drug regimens. This study evaluated DTG/3TC cost versus other standard single-tablet regimens during its first year of approval. This retrospective study analyzed US claims data from adults with HIV-1. Eligibility criteria included ≥ 1 dispensing of DTG/3TC, DTG/abacavir (ABC)/3TC, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF, and darunavir (DRV)/COBI/FTC/TAF (index date was first dispensing) and ≥ 6 months of continuous eligibility before index date (baseline period). All-cause and HIV-related healthcare costs were evaluated during the observation period (index date until earliest of end of continuous eligibility or data availability). Adjusted cost differences and adjusted cost ratios were estimated using multivariable regression models controlling for differences in baseline characteristics between cohorts. Overall, 22,061 individuals with HIV-1 and dispensed treatment with DTG/3TC (n = 590), DTG/ABC/3TC (n = 4355), BIC/FTC/TAF (n = 9068), EVG/COBI/FTC/TAF (n = 7081), or DRV/COBI/FTC/TAF (n = 967) were included. Most claims data were from men (mean age ~ 46 years). Mean unadjusted all-cause total healthcare costs per patient per month were significantly lower for DTG/3TC versus BIC/FTC/TAF and DRV/COBI/FTC/TAF, and mean unadjusted HIV-related healthcare costs per patient per month were significantly lower for DTG/3TC versus DRV/COBI/FTC/TAF. Cost differences were primarily driven by significantly lower pharmacy costs for DTG/3TC versus other regimens (P < 0.001), while medical costs were similar across cohorts. Results were similar among treatment-naive and treatment-experienced individuals. After adjusting for baseline covariates, significant adjusted cost differences were generally consistent with unadjusted findings. Adjusted cost ratios generally favored DTG/3TC for all-cause healthcare and HIV-related costs, with all pharmacy cost ratios favoring DTG/3TC (P < 0.001). Dolutegravir/lamivudine had the lowest healthcare costs of BIC/FTC/TAF, EVG/COBI/FTC/TAF, and DRV/COBI/FTC/TAF, and the lowest pharmacy costs of all regimens, in unadjusted and adjusted analyses and by treatment experience, supporting the economic benefits of DTG/3TC as an initial or switch regimen for HIV-1.


[Age-related aspects in neurourology].
This review highlights age-related aspects of neurogenic lower urinary tract dysfunction. The changing needs and requirements of elderly long-term paraplegics and of elderly people affected from acute spinal cord injury or neurological diseases are discussed. Complications and delayed damage in the urinary tract must be recognized in time to be treated successfully. For uro-oncological early recognition examinations and the assessment of screening parameters, disease and paralysis-associated aspects as well as the individual social situation must be considered. Urologists involved in the long-term treatment of elderly paraplegic patients should take the increased cardiovascular morbidity and mortality into consideration. If paraplegia or a neurodegenerative disease occurs in elderly persons, constellations are often present which stretch the established neurourological concepts of diagnostics, therapy and long-term care to their limits. Knowledge compiled over decades of neurourological care of younger paraplegic patients can be adapted to the needs of elderly patients and new approaches can sometimes be tried.


Salmonella enterica serotype Enteritidis phage types 4, 7, 6, 8, 13a, 29 and 34: a comparative analysis of genomic fingerprints from geographically distant isolates.
To evaluate genetic heterogeneity in the most common phage types of Salmonella enterica serovar Enteritidis. A total of 233 isolates of Salm. Enteritidis from England, Northern Ireland, Spain, Hong Kong and the USA belonging to phage types (PT) 4 (n=88), PT7 (n=12), PT6 (n=72), PT8 (n=14), PT13a (n=29), PT29 (n=14) and PT34 (n=4) were characterized by PstI-SphI (PS) ribotyping and pulsed-field gel electrophoresis after digestion of DNA with XbaI. PS ribotyping differentiated the isolates into 53 different PS types and PFGE showed 14 different macrorestriction profiles; with the combination of both methods, 73 combined types were identified. Some of these clones appeared to be present within several countries. Movement of foodstuffs, animals or people may have been involved in the spread of these strains. On the other hand, some clones were only found in specific locations. Several well defined clonal lines seem to co-exist within the different phage types included in this study, and a combined typing approach may constitute a useful tool for epidemiological investigations. Clustering analysis of ribotypes and PFGE types agree with previous studies and suggest that phage types that share receptor binding properties can be distinguished as two families: the PT4 family including PT7 and PT6, and the PT8 family including PT13a. The other phage types are difficult to place in a family unless the geographical site of isolation is known. This paper reports on an extensive assessment of the use of molecular tools for the study of the epidemiology of the enteric pathogen Salm. Enteritidis. It also gives new information regarding relationships among some common phage types.


C-erbB2 expression predicts response to preoperative chemotherapy for locally advanced breast cancer.
Previous work suggests that the presence of c-erbB2 oncoprotein immunostaining and the proliferation rate of tumours, may be relevant to chemo-sensitivity in breast cancer. To investigate this we assessed pretreatment biopsies from 50 patients with locally advanced breast cancer for expression of c-erbB2 and MIB1 (proliferative marker) in relation to clinical response after 3 months preoperative chemotherapy. Objective response was significantly more likely (22/30, 73%) for tumours negative for c-erbB2 membrane staining, compared to positively staining tumours (6/20, 30%, p = 0.0025). The percentage of cells staining positively for MIB1 was not predictive of response (p = 0.56). This study has shown an increased likelihood of response to preoperative chemotherapy for breast cancers negative for c-erbB2 staining. Previous studies have shown that c-erbB2 immunostaining can correlate with either chemo-resistance or chemo-response. We postulate that this conflict may be due to differences in the type of chemotherapy administered. This raises the possibility of biological markers being use to assist in the selection of the type of chemotherapy regimen administered to particular tumour biological phenotype.


A novel suction-based lung-stabilizing device in single-port video-assisted thoracoscopic surgical procedures.
Single-port video-assisted thoracoscopic surgery (SPVATS) has become a subject of interest for thoracic surgeons in recent years; however, it has not been fully accepted partly because the procedure is technically demanding. We speculate that the most critical problem of SPVATS is that significant interferences of the instruments may occur during the procedure because all the instruments share only a single incisional port. The purpose of this study was to evaluate the usability of a new suction-based lung-stabilizing device during SPVATS procedure. We developed a novel suction-based lung-stabilizing device equipped with three hemispheric silicon suction cups. Ten cases of canine's lower lobectomies were performed. Five cases were performed without this device and designated as the control cases. The remaining cases were performed using this device and were designated as the experimental cases. A significantly fewer number of interruption times were noted in the novel lung-stabilizing device group than in the control group (average, 0.4 vs. 4.4; P = 0.0031). Although the differences did not reach statistical significance, the device tended to demonstrate better performance compared with the control group regarding the operation time, organ damage, and accomplishment of SPVATS. Our study indicates that the novel lung-stabilizing device has potentially useful applications in SPVATS procedures.


Diagnostic performance of cone-beam computed tomography on detection of mechanically-created artificial secondary caries.
The aim of this study was to compare the diagnostic accuracy of cone-beam computed tomography (CBCT) images and bitewing images in detection of secondary caries. One hundred and twenty proximal slots of Class II cavities were randomly prepared on human premolar and molar teeth, and restored with amalgam (n=60) and composite resin (n=60). Then, artificial secondary caries lesions were randomly created using round steel No. 4 bur. The teeth were radiographed with a conventional bitewing technique and two CBCT systems; Pax-500ECT and Promax 3D. All images were evaluated by five observers. The area under the receiver operating characteristic (ROC) curve (A(z)) was used to evaluate the diagnostic accuracy. Significant difference was tested using the Friedman test (p value<0.05). The mean A(z) values for bitewing, Pax-500ECT, and Promax 3D imaging systems were 0.882, 0.995, and 0.978, respectively. Significant differences were found between the two CBCT systems and film (p=0.007). For CBCT systems, the axial plane showed the greatest A(z) value. Based on the design of this study, CBCT images were better than bitewing radiographs in detection of secondary caries.


Periorbital Necrotizing Fasciitis Induced by Streptococcus pyogenes: A Case Report and Clarification.
Periorbital necrotizing fasciitis (PONF) is a rare condition of the face. PONF can lead to blindness, functional and esthetic sequelae, multiple-organ failure, and death. The aim of this report is to raise the awareness of this severe condition in maxillofacial surgeons. This report describes the case of a 30-year-old woman who presented with a bilateral palpebral edema and pain 3 days after a jugal wound was sutured. Necrosis of the skin of the left palpebral unit was extending rapidly. The patient had signs of sepsis. Surgical debridement was performed promptly and intravenous broad-spectrum empiric antibiotics were administered. The patient recovered slowly with no complication other than a residual skin defect of the 2 eyelids that was later corrected by full-thickness skin grafting. Special attention should be paid to signs of preseptal cellulitis because it can, in some cases, rapidly develop into PONF. Early diagnosis and treatment are the keys to a favorable outcome.


Fermentation strategies for 1,3-propanediol production from glycerol using a genetically engineered Klebsiella pneumoniae strain to eliminate by-product formation.
We generated a genetically engineered Klebsiella pneumoniae strain (AK-VOT) to eliminate by-product formation during production of 1,3-propanediol (1,3-PD) from glycerol. In the present study, the glycerol-metabolizing properties of the recombinant strain were examined during fermentation in a 5 L bioreactor. As expected, by-product formation was completely absent (except for acetate) when the AK-VOT strain fermented glycerol. However, 1,3-PD productivity was severely reduced owing to a delay in cell growth attributable to a low rate of glycerol consumption. This problem was solved by establishing a two-stage process separating cell growth from 1,3-PD production. In addition, nutrient co-supplementation, especially with starch, significantly increased 1,3-PD production from glycerol during fed-batch fermentation by AK-VOT in the absence of by-product formation.


Integration of MicroRNA databases to study MicroRNAs associated with multiple sclerosis.
MicroRNAs (miRNAs) are small non-coding RNAs which regulate many genes post-transcriptionally. In various contexts of medical science, miRNAs gained increasing attention over the last few years. Analyzing the functions, interactions and cellular effects of miRNAs is a very complex and challenging task. Many miRNA databases with diverse data contents have been developed. Here, we demonstrate how to integrate their information in a reasonable way on a set of miRNAs that were found to be dysregulated in the blood of patients with multiple sclerosis (MS). Using the miR2Disease database, we retrieved 16 miRNAs associated with MS according to four different studies. We studied the predicted and experimentally validated target genes of these miRNAs, their expression profiles in different blood cell types and brain tissues, the pathways and biological processes affected by these miRNAs as well as their regulation by transcription factors. Only miRNA-mRNA interactions that were predicted by at least seven different prediction algorithms were considered. This resulted in a network of 1,498 target genes. In this network, the MS-associated miRNAs hsa-miR-20a-5p and hsa-miR-20b-5p occurred as central hubs regulating about 500 genes each. Strikingly, many of the putative target genes play a role in T cell activation and signaling, and many have transcription factor activity. The latter suggests that miRNAs often act as regulators of regulators with many secondary effects on gene expression. Our present work provides a guideline on how information of different databases can be integrated in the analysis of miRNAs. Future investigations of miRNAs shall help to better understand the mechanisms underlying different diseases and their treatments.


Clinical use of low-dose parenteral anticoagulation, incidence of major bleeding and mortality: a multi-centre cohort study using the French national health data system.
Low-dose parenteral anticoagulation has demonstrated its efficacy for venous thromboembolism prophylaxis in randomized trials. However, current practice is not widely documented. In ambulatory settings, we aimed to provide an overview of the clinical use of low-dose parenteral anticoagulation in France and to assess the incidence of major bleeding and death rates. A population-based prospective cohort study using the French national health data system (SNIIRAM) identified 142,815 adults living in five well-defined geographical areas who had a course of low-dose parenteral anticoagulants (a total of 150,389 courses) in the period 2013-2015. The main outcome measures were the types of low-dose parenteral anticoagulant, the duration and the clinical context. Adjusted incidence rate ratios (IRR) were derived from Poisson models. Enoxaparin was the most frequently prescribed anticoagulant (58.9%) followed by tinzaparin (27.3%) and fondaparinux (10.9%). Patients receiving unfractionated heparin (N = 766, 0.53%) were older, more frequently had renal disease (48.75%) and had a higher modified HAS-B(L)ED score (≥ 3 in 61.6%) than patients receiving low-molecular weight heparin (LMWH). Surgical thrombo-prophylaxis was the most frequent indication (47.6%), followed by medical prophylaxis (29.9%). Course durations were in line with regulatory agency specifications. Only 43 (0.028%) major bleeding events and 478 (0.32%) deaths were observed. Adjusted IRRs for major bleeding or death were not significantly different for dalteparin/nadroparin, tinzaparin or fondaparinux compared to enoxaparin. Very low incidence rates of major bleeding and all-cause mortality were observed. Our study confirms the safety of LMWHs and fondaparinux in thrombo-prophylaxis in ambulatory settings. ClinicalTrials.gov identifier: NCT02886533.


Giant cystic parathyroid adenoma with thrombosis of internal jugular vein seen on CT and Tc-99m methoxy isobutyl isonitrile parathyroid scan.
Primary hyper-parathyroidism is attributed by a solitary parathyroid adenoma in 80-85% cases and mostly are non-palpable and needs imaging for localization. Cystic degeneration of parathyroid adenoma is rarely seen in primary hyperparathyroidism. We are presenting a case of giant cystic functioning parathyroid adenoma with associated localized co-morbids.


How often is total laryngectomy necessary for the treatment of T1 failures after radiotherapy or cordectomy?
Between 1992 and 1998, 547 patients (pts) with laryngeal SCC were diagnosed and treated in our department, 145 (27%) of whom presented with glottic tumors T1N0M0 (125 T1a and 20 T1b). Seventy-eight (54%) were treated surgically with cordectomy and 67 (46%) with radiotherapy. After a median follow-up time of 43 months, 22 (15.2%) of the 145 pts presented with recurrent disease. In more detail, 16 (13%) of the 125 T1a pts and 6 (30%) of the 20 T1b pts had recurrences. Among the 78 surgically treated patients only 4 (5%) had recurrence, while 18 (27%) of the radiotherapy group relapsed. The difference is statistically significant (log rank test, P = 0.0001 < 0.05). After salvage treatment, of the 67 pts of the radiotherapy group 57 (85%) remain disease-free, 49 (73%) retaining their larynx intact and 1 only having undergone cordectomy. Among the cordectomy group 75 (96%) pts remain disease-free with only 1 having had a total laryngectomy. Using the Kaplan-Meier method and calculating the disease-free survival regardless of salvage treatment, there is no doubt that surgical treatment statistically is more successful than radiotherapy (log rank test, P = 0.01 < 0.05). Analysis of parameters such as tumor differentiation and T1a or T1b staging, which indeed influence the overall recurrence rate, did not alter the favorable outcome after surgical treatment.


Multiscale analysis of biological systems.
It is argued that multiscale approaches are necessary for an explanatory modeling of biological systems. A first step, besides common to the multiscale modeling of physical and living systems, is a bottom-up integration based on the notions of effective parameters and minimal models. Top-down effects can be accounted for in terms of effective constraints and inputs. Biological systems are essentially characterized by an entanglement of bottom-up and top-down influences following from their evolutionary history. A self-consistent multiscale scheme is proposed to capture the ensuing circular causality. Its differences with standard mean-field self-consistent equations and slow-fast decompositions are discussed. As such, this scheme offers a way to unravel the multilevel architecture of living systems and their regulation. Two examples, genome functions and biofilms, are detailed.


Transforming growth factor betas and their receptors in human liver cirrhosis.
Transforming growth factor betas (TGF-betas) are a group of homologous polypeptides that exert pleiotropic effects on various cell types and stimulate the formation of extracellular matrix and fibrosis. To evaluate whether TGF-beta isoforms (TGF-beta1, TGF-beta2 and TGF-beta3) and their receptors (types I-III) are also of importance in the pathophysiology of liver cirrhosis, we analysed their concomitant expression and localization in human liver cirrhosis. Cirrhotic liver tissue samples were obtained from 17 patients (four women, 13 men) with a median age of 41 years (range 22-67). Normal liver tissues from ten patients (seven women, three men) with a median age of 55 years (range 45-75) served as controls. The tissues were fixed in Bouin's solution and paraffin-embedded for histological analysis. For RNA analysis, freshly obtained tissue samples were snap-frozen in liquid nitrogen and stored at -80 degrees C until analysed. Northern blot analysis was used to examine the expression of TGF-beta1, beta2 and beta3 and their receptors, type I (TbetaR-I), type II (TbetaR-II) and type III (TbetaR-III). Immunohistochemistry was performed to determine the localization of the corresponding proteins in the normal and the cirrhotic liver. Northern blot analysis revealed enhanced expression (P < 0.05) of TGF-beta1 (twofold increase), TGF-beta2 (threefold increase) and TGF-beta3 (8.5-fold increase) and of TbetaR-II (threefold increase) mRNA in liver cirrhosis in comparison with normal controls. In contrast, TbetaR-I (ALK-5) and TbetaR-III mRNA expression showed no significant changes. No TGF-beta isoform immunoreactivity was present in hepatocytes in either normal livers or in liver cirrhosis. However, in liver cirrhosis, intense TGF-beta1 immunoreactivity was present in bile duct and ductular epithelial cells (including ductular proliferations) and in inflammatory cells. In a few sinusoidal lining cells, faint TGF-beta1 and moderate TGF-beta2 immunoreactivity was present. TGF-beta3 immunostaining was present in bile duct and ductular epithelial cells, in inflammatory cells and in fibroblast-like spindle cells in liver cirrhosis. For TbetaR-I and TbetaR-II, the immunoreactivity was localized in hepatocytes and biliary cells in normal and cirrhotic liver tissues, with higher intensity for TbetaR-II in the cirrhotic liver. Enhanced expression of all three TGF-bea isoforms and of TbetaR-II in liver cirrhosis suggests their involvement in this fibrotic disorder. The higher immunoreactivity of the three TGF-beta isoforms in the bile duct epithelial cells in cirrhotic tissues suggests a possible role of these cells in the pathogenesis of liver cirrhosis.


A new use for sodium hyaluronate (Healon) in penetrating keratoplasty.
Sodium hyaluronate (Healon) is injected into the well of a disposable corneal trephine to facilitate earlier protection of the donor endothelium during corneal transplantation.


A simplified method for reading hemagglutinations on a flat-bottom microtitration plate in the mouse H-2 assay.
Kaliss' method for determining hemagglutination titer of mouse alloantiserum was modified to a simpler form. It became possible to read the hemagglutination directly on a flat-bottom microtitration plate using an inverted type microscope. Sensitivity of the modified method was almost the same as that of the original one. This method seems to be useful especially for the larger scale assay of H-2 specificities.


Distinguishing between contact lens warpage and ectasia: Usefulness of optical coherence tomography epithelial thickness mapping.
To distinguish between corneal ectasia and contact lens-related warpage by characteristic patterns on corneal topography and optical coherence tomography (OCT) epithelial thickness maps. Casey Eye Institute, Portland, Oregon, USA. Prospective and retrospective case series. Axial and mean power maps were obtained on corneal topography systems. Epithelial thickness maps were generated using RTVue OCT. A sector divider was applied to all maps. The locations of the minimum epithelial thickness, maximum epithelial thickness, maximum axial power, and maximum mean power were determined based on sector averages. Agreement was defined as the extremums occurring in the same or adjacent sectors. Twenty-one eyes with keratoconus, 6 eyes with forme fruste keratoconus (better eye of asymmetric keratoconus), and 15 eyes with contact lens-related warpage were identified. The keratoconus and forme fruste keratoconus eyes had coincident topographic steepening with epithelial thinning. The locations of minimum epithelial thickness and maximum axial power agreed in 90% of the keratoconic eyes, while the minimum epithelial thickness and maximum mean power agreed in 95% of them. Conversely, the warpage eyes had coincident topographic steepening with epithelial thickening and normal pachymetry maps. The locations of maximum epithelial thickness and maximum axial power agreed in 93% of the warpage eyes, while the maximum epithelial thickness and maximum mean power agreed in all warpage eyes. Results show that epithelial thickness maps and corneal topographic maps are powerful synergistic tools in evaluating eyes with abnormal topography and can help differentiate between keratoconus and nonectatic conditions.


Doxorubicin induces the persistent activation of intracellular transglutaminase 2 that protects from cell death.
The activation of transglutaminase 2 (TG2), an enzyme that catalyzes post-translational modifications of proteins, has been implicated in apoptosis, cell adhesion and inflammatory responses. We previously reported that intracellular TG2 is activated under oxidative stress conditions, such as ultraviolet irradiation, ischemia-reperfusion, and hypoxia. In this study, we examined the effect of genotoxic stress on the intracellular activity of TG2 using doxorubicin which generates reactive oxygen species that lead to double-strand breakage of DNA. We demonstrated that doxorubicin elicits the persistent activation of TG2. Doxorubicin-induced TG2 activity was suppressed by treatment with caffeine at the early phase, N-acetylcysteine at the mid-phase, and EGTA at the late phase. However, treatment with a blocking antibody against TGFβ or toll-like receptor 2 showed no effect on TG2 activity, indicating that at least three different signaling pathways may be involved in the process of TG2 activation. In addition, using MEF cells defective for TG2 and cells overexpressing an activesite mutant of TG2, we revealed that doxorubicin-induced cell death is inversely correlated with TG2 activity. Our findings indicate that the persistent activation of TG2 by doxorubicin contributes to cell survival, suggesting that the mechanism-based inhibition of TG2 may be a novel strategy to prevent drug-resistance in doxorubicin treatment.


High yield of biologically active recombinant human amelogenin using the baculovirus expression system.
The amelogenins are secreted by the ameloblast cells of developing teeth; they constitute about 90% of the enamel matrix proteins and play an important role in enamel biomineralization. Recent evidence suggests that amelogenin may also be involved in the regeneration of the periodontal tissues and that different isoforms may have cell-signalling effects. During enamel development and mineralization, the amelogenins are lost from the tissue due to sequential degradation by specific proteases, making isolation of substantial purified quantities of full-length amelogenin challenging. The aim of the present study was to express and characterize a recombinant human amelogenin protein in the eukaryotic baculovirus system in quantities sufficient for structural and functional studies. Human cDNA coding for a 175 amino acid amelogenin protein was subcloned into the pFastBac HTb vector (Invitrogen), this system adds a hexa-histidine tag and an rTEV protease cleavage site to the amino terminus of the expressed protein, enabling effective one-step purification by Ni2+-NTA affinity chromatography. The recombinant protein was expressed in Spodoptera frugiperda (Sf9) insect cells and the yield of purified his-tagged human amelogenin (rHAM+) was up to 10 mg/L culture. Recombinant human amelogenin (rHAM+) was characterized by SDS-PAGE, Western blot, ESI-TOF spectrometry, peptide mapping, and MS/MS sequencing. Production of significant amounts of pure, full-length amelogenin opened up the possibility to investigate novel functions of amelogenin. Our recent in vivo regeneration studies reveal that the rHAM+ alone could bring about regeneration of the periodontal tissues; cementum, periodontal ligament, and bone.


Monitoring carbon dioxide tension and arterial oxygen saturation by a single earlobe sensor in patients with critical illness or sleep apnea.
The purpose of the study was to evaluate a novel, combined sensor for transcutaneous monitoring of arterial oxygen saturation and carbon dioxide tension. The new monitoring technique was compared to established reference methods. ICU and sleep laboratory of a university hospital. Eighteen critically ill adult patients with acute respiratory failure or heart failure, and 12 patients with sleep apnea (mean [+/- SD] apnea/hypopnea index, 43 +/- 24 events per hour). Continuous measurements were performed over several hours by the novel heated (temperature, 42 degrees C) earlobe sensor (TOSCA; Linde Medical Sensors; Basel, Switzerland), incorporating electrochemical and optical elements for carbon dioxide measurement (PtcCO2) and pulse oximetry (SpO2), respectively. The data were compared to the results of repeated arterial blood gas analyses in critically ill patients and to simultaneous nocturnal pulse oximetry performed with different devices with earlobe or finger sensors in sleep apnea patients. In critically ill patients, the mean difference and limits of agreement (bias +/- 2 SDs) of transcutaneous PtcCO2 vs arterial PaCO2 were 3 +/- 7 mm Hg; the corresponding values for changes in PtcCO2 vs PaCO2 were 1 +/- 6 mm Hg. The bias +/- 2 SDs for pulse oximetric SpO2 vs arterial oxygen saturation (SaO2) were 1 +/- 4%. In sleep apnea patients, the combined earlobe sensor identified more transient oxygen desaturations, and the rate of change in oxygen saturation during events was greater compared to those with other tested pulse oximeters, indicating a faster response. Due to its ability to accurately assess both ventilation and oxygenation by a single transcutaneous sensor, the described noninvasive monitoring technique is a valuable tool for respiratory monitoring with potential applications in critical care and sleep medicine.


Asians with localized prostate cancer treated with 3-dimensional conformal radiation therapy and adjuvant hormonal therapy: comparing Phoenix and American Society of Therapeutic Radiology and Oncology (ASTRO) definitions in an Asian population.
Conformal radiotherapy with adjuvant androgen suppression is used in our center to treat localized prostate cancer. We compare Phoenix as an alternative to American Society of Therapeutic Radiology and Oncology (ASTRO) for defining biochemical failure. Our primary aim was to assess the Phoenix and ASTRO definitions of biochemical failure in a population of mainly Asian men with early localized prostate cancer treated with conformal radiotherapy with and without androgen ablation. We retrospectively analyzed 141 patients who were treated for T1/T2 cancer of the prostate in our center from January 1997 to June 2002 with a mean duration of follow-up of 62 months. Outcomes were analyzed by using both Phoenix and ASTRO definitions of biochemical failure as well as clinical failure. The Phoenix definition of biochemical failure was superior as measured by sensitivity, specificity, positive and negative predictive values, accuracy, and a greater concordance with clinical outcome as measured by Kappa analysis. The ASTRO definition helped to standardize reporting of biochemical failures post-radiotherapy but inadequacies have been identified especially when adjuvant hormone therapy has been given. The Phoenix definition has been noted to be a more accurate and precise description of biochemical failure in international series, and we find this to be true in our Asian population as well.


Quality evaluation of berberine food supplements with high-field and compact 1H NMR spectrometers.
Due to their health benefits, including regulating blood sugar and lowering cholesterol, berberine food supplements (FS) are widely used by consumers. This study aims to evaluate the quality of such products by proposing a new analytical methodology based on low-field NMR. Eighteen berberine FS were analyzed with both conventional (500 MHz) and benchtop (60 MHz) NMR spectrometers. Three quantitative 60 MHz 1H NMR methodologies were performed to determine berberine contents that were compared to those obtained at 500 MHz considered as reference measurements. To make the recording time of the spectra acquired at low field compatible with the requirements of a routine control, the quantification was carried out using a calibration curve established under conditions of incomplete relaxation of BrB protons. This methodology, applied to a test sample of 15 mg of FS, allowed to accurately measure a minimum quantity of berberine of ≈ 10 mg/capsule or tablet in 15 min. Regarding the FS, their labels are often unclear and/or incomplete for the consumer. Moreover, only 56 % of the FS analyzed actually contain the claimed quantity of berberine. The amounts of active they supply per day are extremely variable with only 39 % of the FS delivering a sufficient dose to achieve a hypoglycemic or hypolipidemic effect (1000-1500 mg/day based on literature data). These results show that health authorities should institute much stricter control and regulation over the production, labeling and marketing of berberine-based FS.


Relationship and sexual experiences in women with early-onset oestrogen deficiency: Comparison between women with Turner syndrome and premature ovarian insufficiency.
Age at first date and sexual intercourse have been observed to be delayed in women with Turner syndrome (TS), with delayed puberty being the main factor. We sought to assess relationship and sexual experiences comparing women with TS and premature ovarian insufficiency (POI). Cross-sectional observational study. 302 women with TS and 53 women with karyotypically normal POI (median age 33.0 [15.0-78.4] and 26.3 [17.8-52.3], respectively). A self-reporting questionnaire was used to collect data on relationship and sexual experiences. Women with TS were older than women with POI (P = .002). Compared to women with POI, a smaller proportion of women with TS had ever had vaginal sexual intercourse (VSI) (40 [78.4%] vs 169 [58.1%], respectively, P = .006) and women with TS exhibited a delay in the median age at first relationship and VSI (POI 19.3 ± 0.4 vs TS 22.2 ± 1.1, P = <.001). Start of oestrogen replacement therapy at ≤ 14 years of age compared with > 14 years did not result in earlier relationship and sexual debut. After adjusting for age and diagnosis, induction of puberty, as opposed to spontaneous puberty, was associated with a delay in the median age at first relationship and VSI and a reduced probability of having VSI (Hazard ratio = 0.44 [95% confidence interval: 0.32-0.60], P = <.001). Turner syndrome and induction of puberty are associated with a reduced likelihood and a delay in relationship and sexual experiences. Women needing puberty induction and women with TS more than POI have a delayed mean age at first VSI compared to the general population.


Refinement of the C222(1) crystal form of oxidized uteroglobin at 1.34 A resolution.
The structure of uteroglobin, a progesterone binding protein from rabbit uterine fluid, was determined and refined at 1.34 A resolution to a conventional R-factor of 0.229. The accuracy of the co-ordinates is estimated to be 0.15 A. The isotropic temperature factor of individual atoms was refined and its average value is 11.9 A2 for the 548 non-hydrogen atoms of the protein monomer. A total of 83 water molecules was located in difference electron density maps and refined, first using a constant occupancy factor of 1 and then variable occupancy, the final (Q) being 0.63. The mean temperature factor of the water oxygen atoms is 26.4 A2. Uteroglobin is a dimer and its secondary structure consists of four alpha-helices per monomer that align in an anti-parallel fashion. There is one beta-turn between helix 2 and helix 3 (Lys26 to Glu29); 76% of the residues are part of the alpha-helices. In the core of the dimeric protein molecule, between the two monomers that are held together by two disulfide bridges, we have observed a closed cavity. Its length is 15.6 A and its width is 9 A; 14 water molecules could be positioned inside. In the "bottom" part of the protein, near the C terminus, we have observed a smaller cavity, occupied by two water molecules. The calculation of the molecular surface revealed four surface pockets whose possible functional implications are discussed below.


Interpretation of the effects of anthropogenic chlorine on nitrate formation over northeast Asia during KORUS-AQ 2016.
The Weather Research and Forecasting-Community Multiscale Air Quality (WRF-CMAQ) model, implemented with anthropogenic chlorine (Cl) emissions, was evaluated against ground and NASA DC-8 aircraft measurements during the Korea-United States Air Quality (KORUS-AQ) 2016 campaign. The latest anthropogenic Cl emissions, including gaseous HCl and particulate chloride (pCl-) emissions from the Anthropogenic Chlorine Emissions Inventory of China (ACEIC-2014) (over China) and a global emissions inventory (Zhang et al., 2022) (over outer China), were used to examine the impacts of Cl emissions and the role of nitryl chloride (ClNO2) chemistry in N2O5 heterogeneous reactions on secondary nitrate (NO3-) formation across the Korean Peninsula. The model results against aircraft measurements clearly showed significant Cl- underestimations due mainly to the high gas-particle (G/P) partitioning ratios at aircraft measurement altitudes such as 700-850 hPa, but the ClNO2 simulations were reasonable. Several simulations of CMAQ-based sensitivity experiments against ground measurements indicated that although addition of Cl emission did not significantly alter NO3- formation, the activated ClNO2 chemistry with Cl emissions showed the best model performance with the reduced normalized mean bias (NMB) of 18.7 % compared to a value of 21.1 % for the Cl emissions-free case. In our model evaluation, ClNO2 accumulated during the night but quickly produced Cl radical due to ClNO2 photolysis at sunrise, which modulated other oxidation radicals (e.g., ozone [O3] and hydrogen oxide radicals [HOx]) in the early morning. In the morning hours (0800-1000 LST), the HOx were the dominant oxidants, contributing 86.6 % of the total oxidation capacity (sum of major oxidants such as O3 and HOx species), while oxidability was enhanced by up to ∼6.4 % (increase in 1 h HOx average of 2.89 × 106 molecules·cm-3) in the early morning mainly due to the changes in OH (+7.2 %), hydroperoxyl radical (HO2)(+10.0 %), and O3 (+4.2 %) over the Seoul Metropolitan Area, during the KORUS-AQ campaign. Our results improve understanding of the atmospheric changes in the PM2.5 formation pathway caused by ClNO2 chemistry and Cl emissions over northeast Asia.


Planning of births and childhood undernutrition in Nepal: evidence from a 2016 national survey.
Childhood undernutrition is a significant public health issue in low-and middle-income countries, including Nepal. However, there is limited evidence showing the association between the planning of birth (PoB) and childhood undernutrition (stunting and underweight). We aimed to investigate the relationship between PoB and childhood undernutrition in the current study. We used the Nepal Demographic and Health Survey (NDHS) 2016 data, a nationally representative cross-sectional household survey. We used two anthropometric indicators of childhood undernutrition as the outcome of this study. PoB is the main predictor. We used binary logistic regression with sampling weights to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) to examine the association between the PoB and childhood undernutrition. Unless stated, the significant association between the variables is calculated with p < 0.001. The overall prevalence of stunting was 35.8%, and underweight was 27.1% in children under 5 years of age in Nepal. We found a higher rate of stunting (52.7%) and underweight (41.1%) in children with birth order > 3 and < 2 years of the interval between birth and subsequent birth (IBBSB). The association between the children's birth order and the prevalence of undernutrition had strong statistical significance. Mother's age at marriage (p = 0.001), underweight mother, mother's education, father's education, wealth quintile, no exposure to mass media, children's age, and place of residence(p = 0.001) were significantly associated with childhood undernutrition. The result of the multiple logistic regression showed that children with birth order one and 12-24 months of the interval between marriage and first birth (IBMFB) had significantly decreased odds of stunting than those children with birth order one and < 12 months of IBMFB (OR 0.6, 95% CI 0.4-0.9). The findings of the study demonstrate that PoB has a protective effect on childhood undernutrition. Delaying of childbirth until 12-24 months after marriage was found to be associated with reduced childhood stunting odds. To mitigate childhood undernutrition, Nepal's government needs to promote delayed childbearing after marriage while focusing on uplifting the household economics status and wide coverage of and utilization of mass media.


Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.
To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.


Impact of prescription drug monitoring programs and pill mill laws on high-risk opioid prescribers: A comparative interrupted time series analysis.
Prescription drug monitoring programs (PDMPs) and pill mill laws were implemented to reduce opioid-related injuries/deaths. We evaluated their effects on high-risk prescribers in Florida. We used IMS Health's LRx Lifelink database between July 2010 and September 2012 to identify opioid-prescribing prescribers in Florida (intervention state, N: 38,465) and Georgia (control state, N: 18,566). The pre-intervention, intervention, and post-intervention periods were: July 2010-June 2011, July 2011-September 2011, and October 2011-September 2012. High-risk prescribers were those in the top 5th percentile of opioid volume during four consecutive calendar quarters. We applied comparative interrupted time series models to evaluate policy effects on clinical practices and monthly prescribing measures for low-risk/high-risk prescribers. We identified 1526 (4.0%) high-risk prescribers in Florida, accounting for 67% of total opioid volume and 40% of total opioid prescriptions. Relative to their lower-risk counterparts, they wrote sixteen times more monthly opioid prescriptions (79 vs. 5, p<0.01), and had more prescription-filling patients receiving opioids (47% vs. 19%, p<0.01). Following policy implementation, Florida's high-risk providers experienced large relative reductions in opioid patients and opioid prescriptions (-536 patients/month, 95% confidence intervals [CI] -829 to -243; -847 prescriptions/month, CI -1498 to -197), morphine equivalent dose (-0.88mg/month, CI -1.13 to -0.62), and total opioid volume (-3.88kg/month, CI -5.14 to -2.62). Low-risk providers did not experience statistically significantly relative reductions, nor did policy implementation affect the status of being high- vs. low- risk prescribers. High-risk prescribers are disproportionately responsive to state policies. However, opioids-prescribing remains highly concentrated among high-risk providers.


Gamma-ray, fast neutron and ion shielding characteristics of low-density and high-entropy Mg-Al-Ti-V-Cr-Fe-Zr-Nb alloy systems using Phy-X/PSD and SRIM programs.
This study aimed to assess the radiation shielding properties of ten low-density high-entropy alloys (LWHEAs) using Phy-X/PSD software to analyze various shielding parameters, such as attenuation coefficients (μm and μ), mean free path (λ), effective atomic number (Zeff), and removal cross-section (ΣR), in the energy range of Image 1 to Image 2. A comprehensive evaluation was performed to compare the attenuation outcomes provided by HEAs with a range of shielding materials documented in the literature. The study also calculated the build-up factors (BUFs) of the alloys by using the GP-fitting interpolation method. The stopping power of the alloys against H1/He+2 ions was analyzed using the SRIM Monte Carlo code, considering total stopping power (TSP) and projected range (PR). The results indicated that HEA8 (Al3.88Cr14.95Mo27.58Nb26.71Ti13.76Zr13.11) had the best performance in terms of shielding against γ-rays, fast neutrons, and H1/He+2 ions, as it achieved the highest values of parameters such as μm, μ, Zeff, and ΣR, along with the lowest values of HVL, TVL, λ, BUFs (Image 3 Image 4), TSP, and PR. On the other hand, HEA10 (Mg10.77Al11.96Mn24.35Fe24.75Cu28.17) had the lowest BUFs in both lower (Image 5 Image 4) and higher (Image 6 Image 4) energy regions. The order of μm for the alloys was found to be HEA5<HEA6<HEA9<HEA7<HEA10<HEA4<HEA2<HEA3<HEA1<HEA8. The study concluded that LWHEAs possess superior radiation shielding properties compared to conventional materials, making them a promising new class of materials for radiation shielding applications.


Supraclavicular lymph node: incidence of unsuspected metastatic prostate cancer.
An uncommon presentation of prostate carcinoma to the supraclavicular lymph nodes is herein reviewed. With prompt diagnosis and treatment, patient survival can be extended. A high index of suspicion is necessary to make the diagnosis. The clinical features of four cases involving metastatic prostate carcinoma will be discussed.


Non-destructive evaluation of an internal adaptation of resin composite restoration with swept-source optical coherence tomography and micro-CT.
Swept-source optical coherence tomography (SS-OCT) and micro-CT can be useful non-destructive methods for evaluating internal adaptation. There is no comparative study evaluating the two methods in the assessment of internal adaptation in composite restoration. The purpose of this study was to compare internal adaptation measurements of SS-OCT and micro-CT. Two cylindrical cavities were created on the labial surface of twelve bovine incisors. The 24 cavities were randomly assigned to four groups of dentin adhesives: (1) three-step etch-and-rinse adhesive, (2) two-step etch-and-rinse adhesive, (3) two-step self-etch adhesive, and (4) one-step self-etch adhesive. After application, the cavities were filled with resin composite. All restorations underwent a thermocycling challenge, and then, eight SS-OCT images were taken using a Santec OCT-2000™ (Santec Co., Komaki, Japan). The internal adaptation was also evaluated using micro-CT (Skyscan, Aartselaar, Belgium). The image analysis was used to calculate the percentage of defective spot (%DS) and compare the results. The groups were compared using one-way ANOVA with Duncan analysis at the 95% significance level. The SS-OCT and micro-CT measurements were compared with a paired t-test, and the relationship was analyzed using a Pearson correlation test at the 95% significance level. The %DS results showed that Group 3≤Group 4<Group 1≤Group 2 on both SS-OCT and micro-CT images. The %DSs on micro-CT were lower than SS-OCT (p<0.05) and the Pearson correlation coefficient between SS-OCT and micro-CT was r=0.787 (p<0.05).


Feedback about previous action improves executive functioning in schizophrenia: An analysis of maze solving behaviour.
Disturbances of executive functions (EF) in schizophrenia have received special attention during the past years, but there is still an ongoing debate whether impairment in EF tasks can be linked to deficits of EF themselves or if they rather reflect impairment of other cognitive functions such as working memory processes that are additionally required for task solving. In the present study, we analyzed whether impairments in the maintenance of previous processing assumed to be related to working memory contribute to the impairments in EF tasks seen in schizophrenia. Twenty-five schizophrenic patients treated with atypical antipsychotic agents and 25 healthy controls matched according to age, sex, and education were instructed to solve novel two-dimensional maze tasks by steering a pen through a system of paths. Low demands on maintaining previous actions by giving feedback on preceding movements (visualising the trace of the pen) were contrasted with high demands, i.e. without such a trace of past processing. Without feedback of previous action, task solution was less successful and the control of motor action was deficient in schizophrenic patients. With feedback, both domains of behaviour improved to the level of healthy controls at the costs of higher time demands. The behaviour of healthy controls was not influenced by the experimental manipulation. Lower demands on the maintenance of previous action seem to enable schizophrenic patients to perform executive functions successfully. But data suggest that task solving of schizophrenic patients is characterized by alterations in the coordination of executive functions with other cognitive processes.


Cutting in on a secretase pas de deux.
Two proteolytic enzymes, β- and γ-secretases, work together to produce the amyloid β-peptide of Alzheimer's disease. New evidence suggests that these proteases directly interact and compounds that disrupt this interaction reduce amyloid β-peptide levels without directly blocking either enzyme's solo activity.


Nivolumab-induced contact dermatitis in a patient with advanced lung cancer.
An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.


Oral-ibuprofen-induced acute renal failure in a preterm infant.
The side effects of indomethacin for ductal closure in preterm neonates (e.g. increased incidence of necrotizing enterocolitis, decreased cerebral blood volume and transient renal failure) have led clinicians to seek a safer alternative. Intravenous indomethacin and ibuprofen appear to be equally effective for patent ductus arteriosus closure, but oral ibuprofen remains an experimental option with theoretical advantages yet with potential side effects. We herein report a case of transient but severe acute renal failure developing in a preterm infant in whom oral ibuprofen was used and discuss the safety of this drug in relation to its pharmacokinetics.


Synthesis of fumaramide derived [3]rotaxanes as potential precursors for molecular boxes.
Three new fumaramide-derived [3]rotaxanes have been synthesized, with the aim of macrocycle linking to form a molecular box. In one case, a nine-component templated [3]rotaxane synthesis was accomplished in 40% yield. Rotaxane reduction resulted in an unexpectedly facile de-slipping process.


Incidental FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci.
We report on the incidental finding of a FOXL2 mutated adult granulosa cell tumour of the ovary with thecoma-like foci, a rare entity recently described by Jennifer N. Stall and Robert H. Young in a series of sixteen cases in 2019, displaying features differing from conventional adult granulosa cell tumour. Our aim is to specify the morphologic and molecular particularities of this presumably underrecognized finding, with a short presentation of the typical clinical context. Awareness of this rare and challenging neoplasm with indeterminate clinical course is crucial in routine diagnostics.


Atypical deletion of Williams-Beuren syndrome reveals the mechanism of neurodevelopmental disorders.
Genes associated with specific neurocognitive phenotypes in Williams-Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams-Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams-Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1. However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS.


Adverse events occurring after smallpox vaccination.
We reviewed the literature on adverse events reported to occur after smallpox vaccination. Nearly one-half of the United States population is vaccinia-naïve and may be at risk for development of serious adverse events. We describe the clinical features of postvaccinial central nervous system disease, progressive vaccinia, eczema vaccinatum, accidental implantations, "generalized vaccinia," and the common erythematous and/or urticarial rashes. In the 1960s, death occurred approximately once in every million primary vaccinations, with fatalities resulting from progressive vaccinia, postvaccinial encephalitis, and eczema vaccinatum. Death in revaccinees occurred less commonly and almost entirely from progressive vaccinia. In today's population, death rates might be higher because of the increased prevalence of immune deficiency and atopic dermatitis.


Lidocaine-loaded biodegradable nanospheres. I. Optimization Of the drug incorporation into the polymer matrix.
Spherical nanoparticulate drug carriers made of poly(d,l-lactic acid) with controlled size were designed. A local anesthetic, lidocaine, a small hydrophobic molecule, was incorporated in the core with loadings varying from about 7 to 32% (w/w) and increasing with the particle size. Particles with sizes from about 250 to 820 nm and low polydispersity were prepared with good reproducibility; the polymer concentration (at constant surfactant concentration) governed the particle size. The large particles with a high loading ( approximately 30%) showed under in vitro conditions a slow release over 24-30 h, the medium sized carriers (loading of approximately 13%) released the drug over about 15 h, whereas the small particles with small loading ( approximately 7%) exhibited a rapid release over a couple of hours. It seems that the drug release rate is related to the state (crystallized or dispersed) of the drug incorporated in the polymer matrix.


Body composition and outcome in patients undergoing resection of colorectal liver metastases.
Recent evidence suggests that depletion of skeletal muscle mass (sarcopenia) and an increased amount of intra-abdominal fat (central obesity) influence cancer statistics. This study investigated the impact of sarcopenia and central obesity on survival in patients undergoing liver resection for colorectal liver metastases (CLM). Diagnostic imaging from patients who had hepatic resection for CLM in one centre between 2001 and 2009, and who had assessable perioperative computed tomograms, was analysed retrospectively. Total cross-sectional areas of skeletal muscle and intra-abdominal fat, and their influence on outcome, were analysed. Of the 196 patients included in the study, 38 (19·4 per cent) were classified as having sarcopenia. Five-year disease-free (15 per cent versus 28·5 per cent in patients without sarcopenia; P = 0·002) and overall (20 per cent versus 49·9 per cent respectively; P < 0·001) survival rates were lower for patients with sarcopenia at a median follow-up of 29 (range 1-97) months. Sarcopenia was an independent predictor of worse recurrence-free (hazard ratio (HR) 1·88, 95 per cent confidence interval 1·25 to 2·82; P = 0·002) and overall (HR 2·53, 1·60 to 4·01; P < 0·001) survival. Central obesity was associated with an increased risk of recurrence in men (P = 0·032), but not in women (P = 0·712). Sarcopenia has a negative impact on cancer outcomes following resection of CLM.


Pericardial substitutes: delayed reexploration and findings.
Four patients' experience with two varieties of pericardial substitutes has been evaluated. Two patients received glutaraldehyde-preserved, formalin-fixed bovine bioprosthetic pericardial substitutes. These were associated with dense prosthesis-to-epicardium adhesions and the formation of a thick gelatinous peel. Two other patients received glutaraldehyde-preserved, ethanol-fixed bovine bioprosthetic pericardial substitutes. One patient had minimal prosthesis-to-epicardium adhesions, and the remaining patient demonstrated moderate prosthesis-to-epicardium adhesions with giant-cell and lymphocyte fibrosis. In all patients prosthesis-to-sternum adhesions were minimal. These observations suggest that careful washing is essential in all bioprosthetic implants to eliminate residual preservatives and fixatives. In addition, preservation in ethanol is associated with less prosthesis-epicardium reaction than is formalin preservation. Both products are successful in easing reentry, and no episode of infection has been associated with either prosthesis.


Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation.
Equol, a gut bacterial metabolite of isoflavone daidzein, may improve health through changes in vascular function and in estrogen metabolism. Tibolone, a synthetic steroid alternative for the treatment of postmenopausal symptoms, causes a different estrogenic milieu than estrogen and may affect vascular health. We studied the effects of equol production and soy supplementation on vascular function in postmenopausal women under long-term tibolone use. We screened 110 women using tibolone for 3-60 months for high equol production capacity with a one-week soy challenge. Twenty women with high equol production capacity (4-fold elevation in equol level) and 20 comparable control women without this capacity were treated in a randomized placebo-controlled cross-over trial with a soy drink (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Arterial stiffness and endothelial function were assessed before and after soy and placebo supplementation with pulse-wave analysis. Prior to soy supplementation arterial stiffness, expressed as augmentation index, was lower (p=0.01) in equol producers (25.9+/-1.1%) than non-equol producers (29.6+/-0.9%). Similarly, endothelial function index was better at baseline (p=0.009) in these women (72.3+/-5.3%) compared to women lacking equol production capacity (55.2+/-3.8%). Soy supplementation had no effect on arterial stiffness or endothelial function in either group. In postmenopausal tibolone users, endogenous equol production capability is associated with favorable vascular function. This phenomenon was not affected by soy and thus, equol producing capacity may be an independent vascular health marker, at least in postmenopausal women using tibolone.


Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects.
In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.


Characterization of microcystin-induced apoptosis in HepG2 hepatoma cells.
Microcystins (MCs) are a class of hepatotoxins that are commonly produced by freshwater cyanobacteria. MCs harm liver cells through inhibiting protein phosphatases 1 and 2A (PP1 and PP2A) and can produce dualistic effects, i.e., cell death and uncontrolled cellular proliferation. The induction of programmed cell death, i.e., apoptosis, in MC treated hepatic cells has been described previously; however, its exact pathway remains unclear. To address this, HepG2 human hepatoma cells were exposed to MC-LR, the most prevalent isomer of MCs, and morphological and physiological responses were examined. Microscopy and Alamar Blue assay showed that HepG2 cells responded to MC-LR treatment with apoptosis characteristics, such as clumping and shrinking of cells and detachment from the monolayer culture surface. A fluorescent caspase activation assay further revealed activation of all tested apoptosis-dependent caspases (i.e., caspase-3/7, 8 and 9) after 24 h of MC-LR treatment. Furthermore, caspase-8 was found being activated 4 h after MC-LR treatment, earlier than observed activation of caspase-9 (8 h after MC-LR treatment). These data demonstrated that MC-LR can induce apoptosis of HepG2 cells through both extrinsic and intrinsic pathways and that the extrinsic pathway may be activated before the intrinsic pathway. This indicates that extrinsic pathway is more sensitive than intrinsic pathway in MC induced apoptosis. This knowledge contributes to a better understanding of MC hepatotoxicity and can be further used for developing treatments for MC exposed hepatic cells.


Experimental study on the toxicity of povidone-iodine solution in brain tissues of rabbits.
To determine whether Povidone-iodine was toxic to brain tissues by rinsing the cerebral cortex of New Zealand rabbits with Povidone-iodine Solution of different concentrations. 12 New Zealand rabbits were randomly divided into 4 groups (Group A, B, C and D, 3 rabbits each group). In each group, the left cerebral cortex of rabbits was rinsed with physiological saline after the craniotomy; in Group A and B, the right cerebral cortex of rabbits was also locally rinsed with Povidone-iodine Solution (0.01%), in Group C and D, the right cerebral cortex of rabbits was also locally rinsed with Povidone-iodine Solution (0.05%). In Group A and C, the rabbits were sacrificed at D3 after the operation, and the brain was taken out; and in Group B and D, the rabbits were sacrificed at D7 after the operation, and the brain was taken out. Under the optical and electron microscope, the change in micro-structure of brain tissues was observed in each group. In each group, there was no epilepsy or paralysis during and after the operation. At the treatment side of physiological saline, there was no significant cell damage in the local brain tissues. At the treatment side of Povidone-iodine Solution, there was no cell apoptosis or degeneration in the local brain tissues. The Povidone-iodine Solution (0.05% and 0.01%) was toxic to brain tissues, with a more obvious damage of brain tissues for the former concentration. The histological sign was more serious at D7 than that at D3.


Immunotherapy of B-cell non-Hodgkin lymphoma by targeting the chemokine receptor CXCR5 in a preclinical mouse model.
Bispecific antibodies are promising agents for immunotherapy. Here, we describe a quadroma-based trifunctional bispecific antibody binding the chemokine receptor CXCR5 and the T-cell antigen CD3 that efficiently prevents tumor growth in a mouse B-cell lymphoma model. CXCR5 regulates the tissue homeostasis of mature B cells and is highly expressed on B-cell non-Hodgkin and lymphocyte-predominant Hodgkin lymphoma, as well as on a subset of CD4(+) T cells known as follicular T-helper cells. In vitro, the bispecific CXCR5::CD3 antibody efficiently recruited effector T cells to CXCR5 expressing B cells and induced a co-stimulation-independent activation of CD8(+) and CD4(+) T cells as demonstrated by the de novo expression of CD25 and CD69, and secretion of the cytokines IFN-γ, TNF-α, IL-6 and IL-10 by peripheral blood mononuclear cells. Notably, at low antibody concentrations, CXCR5::CD3 displayed a significantly higher cytotoxic activity against autologous B cells than its parental antibodies or rituximab. In vivo imaging revealed that CXCR5::CD3 and its parental CXCR5 antibody efficiently prevent tumor growth in a xenograft model of B-cell lymphoma in mice and prolong their survival. Taken together, our results identify CXCR5 as a promising target for antibody-based therapies in the treatment of B-cell malignancies.