Endoscopic Training Model for Intranasal Transsphenoidal Hypophysis Surgery Using a Skull Model and Chicken Wings.
To evaluate the feasibility of an experimentally designed model for training on endoscopic intranasal transsphenoidal hypophysis surgery. In this experimental study, a surgical training model for endoscopic transsphenoidal hypophysis surgery was designed to simulate real life surgical challenges, such as drilling through the sella turcica under endoscopic vision. This laboratory experiment was repeated at 1-week intervals and it was observed that surgeons improved their skills. The compatibility of the training model was evaluated as either poor, acceptable or perfect. The results revealed that according to earlier data, greater success occurred in tests conducted after 1 week. Three new specialist neurosurgeons also expressed that their self-confidence increased during the second procedure. This laboratory study will result in improved use of microsurgical instruments and understanding of the threedimensional surgical field, as well as the development of manual dexterity. We believe that this model will contribute to the practical training of endoscopic hypophysis surgery.


Ovarian hyperstimulation inhibits embryo implantation in the mouse.
Embryo implantation is dependent on the synchronous development of the embryo and of the endometrium. Pharmacologic doses of estrogens change endometrial histology and are known to inhibit implantation. During controlled ovarian hyperstimulation, such as occurs during an in vitro fertilization cycle, serum estradiol levels may be elevated to as much as three to six times those found during spontaneous cycles. Serum progesterone levels are also increased and may counteract the elevated estradiol levels. The overall effect of ovarian stimulation on implantation is therefore not known. To study this question, we developed a mouse embryo donation model. Donor embryos were obtained in the late morula to early blastocyst stage from hyperstimulated mated mice. The donated embryos were then transferred to the uteri of two groups of recipient mice. The study group underwent ovarian hyperstimulation with pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) (OHR group), while the controls were allowed to cycle spontaneously (SR group). All recipient mice underwent cervical stimulation to induce a pseudopregnant state. Five embryos were transferred to the left uterine horn of each of nine OHR mice and seven SR mice. A higher implantation rate was noted in the SR group than in the OHR group (50 +/- 12 vs 8 +/- 4%, P less than 0.001). Our data suggest that, in the mouse, ovarian hyperstimulation impedes implantation by causing adverse changes in uterine receptivity.


Gastric cancer cell-originated small extracellular vesicle induces metabolic reprogramming of BM-MSCs through ERK-PPARγ-CPT1A signaling to potentiate lymphatic metastasis.
Tumor microenvironment and metabolic reprogramming are critical for tumor metastasis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely involved in the formation of tumor microenvironment and present oncogenic phenotypes to facilitate lymph node metastasis (LNM) in response to small extracellular vesicles (sEV) released by gastric cancer (GC) cells. However, whether metabolic reprograming mediates transformation of BM-MSCs remains elusive. Herein, we revealed that the capacity of LNM-GC-sEV educating BM-MSCs was positively correlated with the LNM capacity of GC cells themselves. Fatty acid oxidation (FAO) metabolic reprogramming was indispensable for this process. Mechanistically, CD44 was identified as a critical cargo for LNM-GC-sEV enhancing FAO via ERK/PPARγ/CPT1A signaling. ATP was shown to activate STAT3 and NF-κB signaling to induce IL-8 and STC1 secretion by BM-MSCs, thereby in turn facilitating GC cells metastasis and increasing CD44 levels in GC cells and sEV to form a persistent positive feedback loop between GC cells and BM-MSCs. The critical molecules were abnormally expressed in GC tissues, sera and stroma, and correlated with the prognosis and LNM of GC patients. Together, our findings uncover the role of metabolic reprogramming mediated BM-MSCs education by LNM-GC-sEV, which presents a novel insight into the mechanism underlying LNM and provides candidate targets for GC detection and therapy.


Combined lifestyle, mental health, and mortality in US cancer survivors: a national cohort study.
Adopting healthy lifestyles and staying mentally health are two cost-effective modifiable strategies that cancer survivors can implement in self-management. We aimed to evaluate the independent, mediation, interaction, and joint associations of combined lifestyle and mental health with mortality in cancer survivors. We performed a cohort study including 3145 cancer survivors from National Health and Nutrition Examination Survey (2005-2018). A healthy lifestyle score was constructed based on post-diagnosis body mass index, physical activity, diet, smoking, and drinking. Post-diagnosis mental health was assessed by Patient Health Questionnaire (PHQ-9). Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cancer, and non-cancer mortality were computed using Cox proportional hazards regression models. After 20,900 person-years of follow-up (median, 6.3 years), cancer survivors with higher lifestyle score had decreased mortality, independent of mental health. Compared to participants with lower lifestyle score (0-1), HRs (95% CIs) for all-cause and non-cancer mortality among those with higher lifestyle score (3-5) were 0.68 (0.52-0.89) and 0.69 (0.56-0.85), respectively. 6.2-10.3% of the associations were mediated by mental health. Similar trends were observed among participants categorized by mental health, those with better mental health had lower mortality, independent of lifestyle. Participants with better mental health benefited more from adopting healthy lifestyles, and vice versa. Combinations of higher healthy lifestyle score and better mental health were associated with significant decreased mortality, the lowest mortality was seen in participants with highest healthy lifestyle score and concurrently with best mental health. For the first time, in this cohort study with a nationally representative sample of US cancer survivors, we comprehensively explored the complex associations of lifestyle, mental health, and mortality. Evidence derived from this study may give much confidence to cancer survivors and healthcare providers that, changing one's lifestyle and/or staying mentally healthy after cancer diagnosis can improve survival.


Cytogenetic studies of Hodgkin's disease. Analysis of involved lymph nodes from 12 patients.
Cytogenetic studies were performed on 12 involved lymph nodes from Hodgkin's disease patients utilizing conditioned medium from 12-O-tetradecanoylphorbol-13-acetate-staphylococcus enterotoxin A induced mononuclear cells. The majority of cells analyzed had a normal karyotype. An unusually high rate of nonclonal karyotypic abnormalities was noted in most cultures. Clonal abnormalities involving chromosomes 3 and 21 were noted in two patients. Cytogenetic analysis of cultures stimulated with conditioned medium or specific growth factors may lead to a better understanding of the genetic mechanisms involved in Hodgkin's disease.


Pharmacodynamics of immune response biomarkers of interest for evaluation of treatment effects in bacterial infections.
This mini-review discusses the pharmacodynamics of immune-related biomarkers in the area of bacterial infectious diseases that could be of interest from a pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) perspective in the evaluation of treatment effects. The host response to an infection is often poorly defined both in preclinical assessments and in clinical practice when it comes to characterisation of PK and PK/PD relationships. Through population modelling, the time courses and variability of immune response variables can be quantified. Incorporation of such biomarker information into PK and PK/PD models may guide the evaluation of individual response to treatment (right antibiotic, more antibiotic, less antibiotic) and when to stop treatment. Furthermore, translation of results from preclinical systems to clinical scenarios may be improved with the incorporation of biomarker information. Potential biomarkers for these purposes are discussed and a few modelling examples are provided.


Clinical and resistance characterization of carbapenem-resistant Klebsiella pneumoniae isolated from intensive care units in China.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious threat to health, and the detection rate in intensive care units (ICUs) is relatively high. We compared regional differences in the clinical and molecular characteristics of CRKP from three ICUs in different hospitals, to make a reference and contribution for infection control and clinical medication. A total of 150 CRKP strains from Chongqing, Beijing, and Nantong, as well as the clinical data of the infected patients, were collected between 2019 and 2021. The carbapenemase phenotype was determined by CarbaNP test, and the outer membrane porin (OMP) genes (ompK35/ompK36), multi-locus sequence typing (MLST) and resistance genes were identified by polymerase chain reaction (PCR) amplification and sequencing. Patients infected with CRKP were mainly elderly, with comorbidity, and had undergone invasive operation and multiple antibiotic therapy. All strains exhibited high-level resistance to most antibiotics except for polymyxin B and tigecycline. Among the CRKP strains, 100 had the bla KPC-2 gene and 8 had bla NDM-1 gene, which were distributed in all of the hospitals. Nearly all the strains harbored extended-spectrum beta-lactamase (ESBL) genes (bla SHV, bla CTX-M, and bla TEM). Class C carbapenemase genes (bla CIT, bla DHA), and deletion and mutation of ompK35/ompK36 existed in some strains. ST11 was the main MLST type, followed by ST15. There were a few significant differences in the molecular epidemiology and clinical characteristics, but generally the features of CRKP from the three ICUs aligned fairly well, which might have resulted from dissemination through frequent personnel exchanges between regions.


Expression of SMARCA2 and SMARCA4 in gastric adenocarcinoma and construction of a nomogram prognostic model.
Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma. We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it. The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy. The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model.


Laser welding of vas deferens in rodents: initial experience with fluid solders.
This study evaluates the use of sutureless laser welding for vasovasostomy. In 14 rodents, the left vas deferens underwent vasovasostomy using an albumin-based solder applied to the adventitia of the vas deferens. The solder contained the dye, indocyanine green, to allow selective absorption and denaturation by a fiber-coupled 800-nm diode laser. The right vas deferens served as a control, receiving conventional layered microsurgical repair. We used a removable 4/0 nylon stent and microclamps to appose the vas deferens during repair, with no need for stay sutures. The mean time to perform laser solder repair (23.5 min) and conventional repair (23.3 min) were not significantly different (P=0.91). However, examination after 8 weeks showed that granuloma formation (G) and patency (P) rates for the conventional suture technique (G, 14%; P, 93%) were significantly better than observed for the laser solder technique (G, 57%; P, 50%).


High-sensitivity ascorbic acid sensor using graphene sheet/graphene nanoribbon hybrid material as an enhanced electrochemical sensing platform.
A novel electrode material of graphene sheet/graphene nanoribbon (GS/GNR) hybrid material was developed by incorporating graphene nanoribbons into graphene nanosheets through simultaneous chemical reduction of graphene oxide sheets and graphene oxide ribbons. The structure and properties of synthesized GS/GNR were characterized by transmission electron microscope, scanning electron microscope, X-ray diffraction, Brunauer Emmett Teller measurements and Fourier transform infrared spectroscopy. This work compares the electro catalytic performance of the GS/GNR, chemically reduced graphene oxide sheets (CRGOS) and GS/carbon nanotube (CNT) by modifying the glassy carbon electrode (GCE) using ascorbic acid (AA) as analyte. The electrochemical impedance spectroscopy revealed that the charge transfer resistance of GS/GNR modified electrode was less than that of CRGOS modified electrode and bare GCE. The cyclic voltammetric sensing of GS/GNR modified electrode towards AA was negatively shifted (0.08 V) compared to CRGOS, GS/CNT modified electrode and bare GCE (0.222, 0.150 and 0.666 V). This catalytic oxidation allows an amperometric detection of AA with a detection limit of 230 nM and sensitivity of 22 nA μM(-1) cm(-2). GS/GNR modified GCE exhibited a high selectivity for ascorbic acid in the presence of other interferents like dopamine, uric acid and citric acid.


A survey of resident physicians' perceptions of competency-based education in standardized resident training in China: a preliminary study.
Understanding resident physicians' perceptions of competency-based medical education(CBME) may help improve approaches for implementing such education in standardized resident training (SRT). We conducted surveys of residents in China to identify their perceptions of CBME and determine the degree to which such education impacts their career plans. Questionnaire contained a total of 24 questions, which were answered using multiple choice or yes/no, was distributed to residents who were undergoing SRT, regardless of specialty, at 7 accredited training bases located across six provinces of China. The survey aimed to investigate residents' reasons for participating in SRT, perceptions of CBME, interest in receiving CBME-associated courses, and attitudes towards CBME. Overall, 441 residents completed the questionnaire.17.7% (78/441) responded "no clear objective" before the participated in SRT. Only 3.9% (17/441) fully understood the objectives, training contents, and assessment system of the current "competency-based" standardized training program for residents in China. Residents ranked clinical skills and patient care, interpersonal communication, and professionalism, as the three most important competencies. Most were interested in the CBME residency programs. 90.7% felt that implementing CBME could help them clarify their professional direction and improve their career planning. Residents had positive perceptions of the incorporation of CBME into SRT. Administrators, educational leaders, and clinical faculty should seek to further publicize and increase the popularity of CBME.


Gram-negative osteomyelitis following puncture wounds of the foot.
Seven cases of gram-negative osteomyelitis following puncture wounds of the foot are presented. Regardless of age (range, five to thirty-two years) all patients had a similar, typical clinical picture of one to two weeks of improvement after the initial post-traumatic inflammation followed by worsening of the local signs. Two patients were successfully treated with antibiotics alone and five, with antibiotics in combination with curettage.


Relationship of blood groups and bladder cancer. A retrospective study.
A retrospective study to evaluate the relationship of blood groups of 96 patients with transitional cell carcinoma of the bladder in Israeli population, reports that patients with blood group O had higher grade tumors and higher recurrence rates than the other blood groups, without a difference in the mortality rates.


Exploring treatment with Ribociclib alone or in sequence/combination with Everolimus in ER+HER2-Rb wild-type and knock-down in breast cancer cell lines.
Breast cancer (BC) is the second most common type of cancer worldwide. Among targeted therapies for Hormone Receptor-positive (HR+) and Human Epidermal growth factor Receptor 2-negative (HER2-) BC, the Cyclin-Dependent Kinases (CDK4/6) are targeted by inhibitors such as Ribociclib (Rib); however, resistance to CDK4/6 inhibitors frequently develops. The aim of this work is to assess in vitro activity of Rib and Everolimus (Eve) in HR+HER2- MCF-7 and HR-HER2-BT-549 BC cell lines. HR+HER2- MCF-7 and HR-HER2- BT-549 BC cell lines were treated with increasing concentration of Rib and Eve (up to 80 μg/mL) for 48-72 h. Subsequently, HR+HER2- MCF-7 cells were silenced for Retinoblastoma (Rb) gene, and thus, the effect of Rib in sequential or concurrent schedule with Eve for the treatment of both Rb wild type or Rb knock-down MCF-7 in vitro was evaluated. Cell viability of HR+HER2- MCF-7cells treated with sequential and concurrent dosing schedule was analyzed by MTT assay. Moreover, cell cycle phases, cell death and senescence were evaluated by cytofluorimetric analysis after treatment with Rib or Eve alone or in combination. The sequential treatment didn't produce a significant increase of cytotoxicity, compared to Rib alone. Instead, the cotreatment synergized to increase the cytotoxicity compared to Rib alone. The cotreatment reduced the percentage of cells in S and G2/M phases and induced apoptosis. Rib triggered senescence and Eve completely reversed this effect in Rb wild type BC cells. Rib also showed Rb-independent effects as shown by results in Rb knock-down MCF-7. Overall, the Rib/Eve concurrent therapy augmented the in vitro cytotoxic effect, compared to Rib/Eve sequential therapy or single treatments.


Variations in Nutrition Practices in Cystic Fibrosis: A Survey of the DIGEST Program.
Evidence-based management of gastrointestinal (GI) and nutrition manifestations of cystic fibrosis (CF) is limited, and practice variations have not been studied. Thus, a survey was developed with the purpose of evaluating current nutrition practices of CF-focused gastroenterologists, specifically utilizing awardees and mentors of the Cystic Fibrosis Foundation (CFF) Developing Innovative GastroEnterology Specialty Training (DIGEST) Program. Topics included appetite stimulation, tube feeding (TF), and aspects of nutrition assessment, specifically urine sodium and essential fatty acid (EFA) status. The response rate was 61% (22/36). About half (55%; 12/22) of respondents had 5-10 years of experience in GI, and 23% (5/22) had >10 years. In regard to appetite stimulation, the majority used cyproheptadine; however, duration and pattern of prescribing varied. Variation was noted in TF management pertaining to tube placement, formula choice, and prescribing pancreatic enzyme replacement therapy with overnight TF. The majority did not check EFAs or urine sodium. Treatment for deficiencies in EFA or abnormal urine sodium was inconsistent. The survey reveals wide variation in management of some aspects of nutrition-related manifestations of CF among experienced providers. This reflects the need for research to provide evidence-based guidelines.


A Hot Summer Brings More ACA Litigation.
The Supreme Court will hear California v. Texas after the election, and courts issued new Affordable Care Act decisions.


Native CRISPR-Cas-Mediated Genome Editing Enables Dissecting and Sensitizing Clinical Multidrug-Resistant P. aeruginosa.
Despite being fundamentally important and having direct therapeutic implications, the functional genomics of the clinical isolates of multidrug-resistant (MDR) pathogens is often impeded by the lack of genome-editing tools. Here, we report the establishment of a highly efficient, in situ genome-editing technique applicable in clinical and environmental isolates of the prototypic MDR pathogen P. aeruginosa by harnessing the endogenous type I-F CRISPR-Cas systems. Using this approach, we generate various reverse mutations in an epidemic MDR genotype, PA154197, and identify underlying resistance mechanisms that involve the extensive synergy among three different resistance determinants. Screening a series of "ancestor" mutant lines uncovers the remarkable sensitivity of the MDR line PA154197 to a class of small, cationic peptidomimetics, which sensitize PA154197 cells to antibiotics by perturbing outer-membrane permeability. These studies provide a framework for molecular genetics and anti-resistance drug discovery for clinically isolated MDR pathogens.


A new model of subarachnoid hemorrhage in experimental animals with the purpose to examine cerebral vasospasm.
Using 20 rabbits, we tried to establish a new model of experimental subarachnoid hemorrhage (SAH) for examining both acute and chronic cerebral vasospasm. A cranial opening was drilled, and a puncture made on the posterior branch of the middle cerebral artery. A second puncture was made in the superior sagittal sinus for additional withdrawal of subarachnoid blood. The bleeding thus induced resulted in arterial spasm which was studied by using serial electrocorticograms, cerebral blood flow measurement with 133Xe, and videomicroscopy of the small pial vessels at various intervals. After death of the animals, the brains were observed to identify the extention of the bleeding. It was indeed obvious that large amounts of subarachnoid blood clots had accumulated. This investigation showed that the rabbit can be used as a new experimental model of SAH. With a two-puncture method, it is possible to simulate the clinical phenomenon of a ruptured aneurysm, that seems to produce acute and chronic cerebral vasospasm. For the latter, the accumulation of blood clots in the basal surfaces plays an important role. The three methods of observation, videomicroscopy, cerebral blood flow measurements, and electrocorticography appeared to provide useful information in the study of biphasic vasospasm in the rabbit.


Combined hepatocellular-cholangiocarcinoma: a population level analysis of incidence and mortality trends.
The purpose of this study was to explore trends in incidence, incidence-based (IB) mortality, and survival for combined hepatocellular-cholangiocarcinoma (cHCC-CC) utilizing a population-based database to attract people's attention to this disease. The Surveillance, Epidemiology, and End Results (SEER) database was utilized to investigate the incidence and IB mortality for cHCC-CC from 2000 to 2014. Trends in age-adjusted incidence and IB mortality were characterized by the Joinpoint Regression program. The Kaplan-Meier method and log-rank test were utilized to implement survival analyses. Cox regression was utilized to estimate independent predictors of mortality. The incidence of cHCC-CC was 0.26 per 1,000,000 individuals in 2000 and 0.59 per 1,000,000 individuals in 2014, with an annual percent change (APC) (i.e., the extent of increase in incidence) of 3.84% (95% confidence interval [CI] 1.7-6.1; P < 0.05). The IB mortality also displayed a sustained increase (APC was 4.59%, 95% CI 1.9-7.4; P < 0.05). Compared to patients not undergoing surgery, patients undergoing surgical treatment experienced a significant increase in median survival (3 vs. 28 months; P < 0.001). However, the median survival decreased in patients with tumor size > 5 cm (20 vs. 9 months; P < 0.001). Based on univariate Cox regression analysis, African-American race, distant stage, regionalized stage, tumor size ≥ 5 cm, and no surgery were risk factors for death. We identified an overall steady increase in the incidence of cHCC-CC, which indicates that primary prevention strategies for cHCC-CC have not improved much in recent years and that cHCC-CC needs to be taken seriously.


The relationship between serum oestradiol levels and serum triglyceride, cholesterol and phospholipid levels in normal human pregnancy.
Blood samples were obtained for serum lipid and oestradiol measurement from 365 women between 7 to 41 weeks of normal pregnancy. In an additional 21 women serum lipid and oestradiol were measured at 20 to 23 weeks gestation and again at 30 to 33 weeks. Significant correlations were noted between changes in the serum triglyceride and oestradiol levels (P less than 0.001) and between changes in serum cholesterol and oestradiol levels (P less than 0.05). The changes in phospholipid and oestradiol levels were not significantly correlated (P less than 0.1). The serum triglyceride level (mean +/- SEM) was highest at 37 weeks gestation (3.8 +/- 0.3 mmol/l), an increase of 400 per cent over the level at 7 weeks. The serum phospholipid level increased by 108 per cent to its highest levels (5.0 +/- 0.2 mmol/l) at 38 weeks and the cholesterol level increased by 93 per cent to its peak (8.7 +/- 0.3 mmol/l) at 38 weeks.


Intracellular expression of anti-p21ras single chain Fv fragments inhibits meiotic maturation of xenopus oocytes.
The recombinant variable regions of the monoclonal antibody Y13-259, directed against the p21ras protein, have been engineered for expression as intracellular single chain Fv fragments. The activity of the plasmid was confirmed by in vitro and in vivo translation of mRNA showing that the intracellularly expressed single chain fragments are stably and efficiently expressed as cytosolic proteins. The expression of the anti-p21ras single chain antibodies in the cytoplasm of Xenopus laevis oocytes leads to the inhibition of the insulin-induced meiotic maturation. This finding represents the first successful application of the strategy of intracellular antibodies to block a complex biological process in the cytosol of vertebrate cells.


Maternal endothelial soluble cell adhesion molecules with isolated small for gestational age fetuses: comparison with pre-eclampsia.
1. To evaluate the activation profile of the endothelium in pregnancies complicated by small for gestational age fetuses compared with pre-eclampsia and normal pregnancy, by measuring the plasma levels of soluble adhesion molecules soluble E-selectin, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1. 2. To determine whether soluble adhesion molecules were related to the severity of small for gestational age fetuses and pre-eclampsia. Observational study. Sixteen women with small for gestational age fetuses; 15 women with pre-eclampsia and 15 healthy primigravidae were recruited as controls. Plasma levels of soluble E-selectin, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 were measured by ELISA. Compared with the healthy controls, soluble E-selectin was significantly increased in both small for gestational age fetuses and pre-eclampsia, whereas intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 were increased only in pre-eclampsia. In the small for gestational age fetuses group, soluble E-selectin correlated inversely with the ratio between birthweight and the expected normal birthweight (r = -0.4, P = 0.007). In the pre-eclampsia group, a significant correlation was observed between vascular cell adhesion molecule-1 and blood pressure (r = 0.54, P = 0.039). Endothelial activation, reflected by raised levels of soluble E-selectin, is a feature of small for gestational age fetuses and is correlated with the severity of the disease. Differences in the profile of soluble cell adhesion molecules suggest variations in the degrees of endothelial activation between pre-eclampsia and small for gestational age fetuses.


Interleukin 21: a cytokine/cytokine receptor system that has come of age.
Interleukin-21 (IL-21) and its receptor represent the sixth cytokine system whose actions were recognized to require the common cytokine receptor gamma chain. IL-21 is produced by activated CD4+ T cells, natural killer T cells, and follicular T helper cells and has actions on a range of lymphohematopoietic lineages. Among its many effects, IL-21 serves a critical role for immunoglobulin production and terminal B cell differentiation, acts as a T cell comitogen and can drive the expansion of CD8+ T cells, can negatively regulate dendritic cell function and plays an essential role in the differentiation of Th17 cells. Importantly, IL-21 is implicated in the pathogenesis of autoimmunity and exhibits potent actions as an antitumor agent. The ability to regulate and manipulate the actions of IL-21, therefore, has important implications for immunoregulation and the therapy of human disease.


Ultrafast Microwave Nano-manufacturing of Fullerene-Like Metal Chalcogenides.
Metal Chalcogenides (MCs) have emerged as an extremely important class of nanomaterials with applications ranging from lubrication to energy storage devices. Here we report our discovery of a universal, ultrafast (60 seconds), energy-efficient, and facile technique of synthesizing MC nanoparticles and nanostructures, using microwave-assisted heating. A suitable combination of chemicals was selected for reactions on Polypyrrole nanofibers (PPy-NF) in presence of microwave irradiation. The PPy-NF serves as the conducting medium to absorb microwave energy to heat the chemicals that provide the metal and the chalcogenide constituents separately. The MCs are formed as nanoparticles that eventually undergo a size-dependent, multi-stage aggregation process to yield different kinds of MC nanostructures. Most importantly, this is a single-step metal chalcogenide formation process that is much faster and much more energy-efficient than all the other existing methods and can be universally employed to produce different kinds of MCs (e.g., MoS2, and WS2).


Knockdown of HMGB1 inhibits the crosstalk between oral squamous cell carcinoma cells and tumor-associated macrophages.
Tumor-associated macrophages (TAMs), the major component of the tumor microenvironment (TME), play distinctly different roles in different tumors. High mobility group box 1 (HMGB1), a nonhistone protein in the nucleus, can perform functions during inflammation and cancers. However, the role of HMGB1 in the crosstalk between oral squamous cell carcinoma (OSCC) cells and TAMs remains unclear. Here, we established a coculture system of TAMs and OSCC cells to explore the bidirectional effect and potential mechanism of HMGB1 in OSCC cell-TAM interactions. Our results showed that HMGB1 was significantly upregulated in OSCC tissues and positively associated with tumor progression, immune cell infiltration and macrophage polarization. Then, knocking down HMGB1 in OSCC cells inhibited the recruitment and polarization of cocultured TAMs. Moreover, the knockdown of HMGB1 in macrophages not only suppressed polarization, but also inhibited cocultured OSCC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, macrophages secreted higher levels of HMGB1 than OSCC cells, and dampening endogenous HMGB1 reduced HMGB1 secretion. Both OSCC cell-generated and macrophage-endogenous HMGB1 may regulate TAM polarization by promoting receptor TLR4 expression and NF-κB/p65 activation and enhancing IL-10/TGF-β expression. HMGB1 in OSCC cells may regulate macrophage recruitment via IL-6/STAT3. In addition, TAM-derived HMGB1 may affect aggressive phenotypes of cocultured OSCC cells by regulating the immunosuppressive microenvironment through the IL-6/STAT3/PD-L1 and IL-6/NF-κB/MMP-9 pathways. In conclusion, HMGB1 may regulate the crosstalk between OSCC cells and TAMs, including modulating macrophage polarization and attraction, enhancing cytokine secretion, and remodeling and creating an immunosuppressive TME to further affect OSCC progression.


Developmental changes and localization of mouse brain serine proteinase mRNA and protein in mouse brain.
Serine proteases are known to be involved in neural development and various functions in the central nervous system. Mouse brain serine proteinase (mBSP) is expressed almost exclusively in the mouse brain and it has been characterized at the molecular and biochemical levels. In this study, we analyzed the developmental changes and localization of mBSP mRNA and protein in the mouse brain, using reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Expression of mBSP was strong in the white matter and the nerve tracts after postnatal day 30, especially in the cerebellum and the medulla oblongata. These results suggest that mBSP contributes to development and sustaining the functions in the mouse brain.


Mandibular morphology and distraction osteogenesis vectors in patients with Robin sequence.
The aims of this cohort study were to compare the mandibular morphology between patients with Robin sequence (RS) and controls, and to examine the effects of mandibular distraction osteogenesis (MDO) using different vectors. Measurements of the mandibles of 80 patients with RS and 46 controls aged< 90 days were made using computed tomography. The data were compared among isolated RS patients (n = 58), syndromic RS patients (n = 22), and controls. Patients with RS exhibited significantly shorter ramus and body lengths and larger symphyseal angles than controls (all P < 0.001). Patients with isolated RS had shorter body lengths (P < 0.001), while syndromic patients had shorter ramus and body lengths (both P < 0.001) than controls. Seventy RS patients underwent MDO. Pre-MDO (n = 37) and post-MDO (n = 29) mandibular measurements were compared between patients undergoing MDO with a vertical vector and those undergoing MDO with a horizontal vector. Polysomnography data from part of the cohort highlighted the effectiveness of both vectors. MDO with a horizontal vector conferred 11% and 36% increases in ramus and body length, respectively, while these increases were 34% and 27.5%, respectively, with a vertical vector. MDO with a vertical vector was effective in lengthening ramus and body components and should be considered in the presence of ramus hypoplasia.


Intermediate and long-term follow-up of total shoulder arthroplasty for the management of postcapsulorrhaphy arthropathy.
The purpose of this study was to evaluate the subjective and objective outcomes in patients undergoing total shoulder arthroplasty for treatment of postcapsulorrhaphy arthropathy (CA) and compare them with outcomes in patients undergoing total shoulder arthroplasty for primary glenohumeral osteoarthritis (OA). Total shoulder arthroplasty was used to treat 25 consecutive CA patients (25 shoulders) at our institution; of these, 22 patients were available for follow-up. An age-matched cohort of 19 consecutive patients (20 shoulders) who were treated with total shoulder arthroplasty for primary glenohumeral OA was compared with the CA group. Patients were evaluated by physical examination and patient outcome measures (American Shoulder and Elbow Surgeons assessment and Simple Shoulder Test). Complications, reoperations, and subscapularis function was also recorded. Compared with the CA group, the OA group achieved greater forward elevation (165° vs 147°; P = .036) and greater external rotation (56° vs. 45°; P = .04); however, no significant differences were seen in subjective patient scores between the 2 groups for Simple Shoulder Test (P = .90), American Shoulder and Elbow Surgeons assessment (P = .65), and pain scores (P = .80). The difference in the number of revision surgeries in the OA group compared with the CA group (1 vs 4) was not significant (P = .35). A significantly higher number of patients in the CA group had subscapularis insufficiency compared with the OA group (5 CA vs 0 OA; P = .049). Our findings suggest that when compared with patients undergoing total shoulder arthroplasty for primary OA, CA patients experience similar outcomes with respect to revision surgery, pain relief, and subjective self-assessment and have a higher incidence of subscapularis insufficiency.


Molecular phylogenetics and floral evolution of the Cirrhopetalum alliance (Bulbophyllum, Orchidaceae): Evolutionary transitions and phylogenetic signal variation.
The Cirrhopetalum alliance is a loosely circumscribed species-rich group within the mega-diverse genus Bulbophyllum (Orchidaceae). The monophyletic status of the alliance has been challenged by previous studies, although established sectional classifications have yet to be tested in a phylogenetic context. We used maximum likelihood and Bayesian analyses of DNA sequence data (cpDNA: matK and psbA-trnH; nrDNA: ITS and Xdh; 3509 aligned characters; 117 taxa), including all sections putatively associated with the Cirrhopetalum alliance, to reconstruct the phylogeny. We mapped 11 selected categorical floral characters onto the phylogeny to identify synapomorphies and assess potential evolutionary transitions across major clades. Our results unequivocally support the recognition of an amended Cirrhopetalum alliance as a well-supported monophyletic group characterized by clear synapomorphies, following the inclusion of sect. Desmosanthes and the exclusion of five putative Cirrhopetalum-allied sections. Most sections within the Cirrhopetalum alliance are demonstrated to be polyphyletic or paraphyletic, necessitating a new sectional classification. The inclusion of sect. Desmosanthes revolutionizes our understanding of the alliance, with significant evolutionary transitions in floral characters detected. We further investigated six continuously variable characters of the sepals and labellum, and detect phylogenetic conservatism in labellum width and the evolutionary lability of lateral sepal length, which can partly be explained by the different functional roles they play in pollination and pollinator trapping.


The combined effect of breast cancer risk factors.
An extension of the logistic model (Cox, 1970) is applied to the prospective study of breast cancer in Guernsey (Bulbrook and Hayward, 1967). Four important risk factors, age at menarche, family history, age at first birth and etiocholanolone excretion, are identified and shown to have additive effects on a logistic scale for the probability of developing breast cancer. The feasibility of screening a high risk group of women is considered and shown unlikely to be of practical value.


Balancing spatially regulated β-actin translation and dynamin-mediated endocytosis is required to assemble functional epithelial monolayers.
Regulating adherens junction complex assembly/disassembly is critical to maintaining epithelial homeostasis in healthy epithelial tissues. Consequently, adherens junction structure and function is often perturbed in clinically advanced tumors of epithelial origin. Some of the most studied factors driving adherens junction complex perturbation in epithelial cancers are transcriptional and epigenetic down-regulation of E-cadherin expression. However, numerous reports demonstrate that post-translational regulatory mechanisms such as endocytosis also regulate early phases of epithelial-mesenchymal transition and metastatic progression. In already assembled healthy epithelia, E-cadherin endocytosis recycles cadherin-catenin complexes to regulate the number of mature adherens junctions found at cell-cell contact sites. However, following de novo epithelial cell-cell contact, endocytosis negatively regulates adherens junction assembly by removing E-cadherin from the cell surface. By contrast, following de novo epithelial cell-cell contact, spatially localized β-actin translation drives cytoskeletal remodeling and consequently E-cadherin clustering at cell-cell contact sites and therefore positively regulates adherens junction assembly. In this report we demonstrate that dynamin-mediated endocytosis and β-actin translation-dependent cadherin-catenin complex anchoring oppose each other following epithelial cell-cell contact. Consequently, the final extent of adherens junction assembly depends on which of these processes is dominant following epithelial cell-cell contact. We expressed β-actin transcripts impaired in their ability to properly localize monomer synthesis (Δ3'UTR) in MDCK cells to perturb actin filament remodeling and anchoring, and demonstrate the resulting defect in adherens junction structure and function is rescued by inhibiting dynamin mediated endocytosis. Therefore, we demonstrate balancing spatially regulated β-actin translation and dynamin-mediated endocytosis regulates epithelial monolayer structure and barrier function.


Interplay of microRNAs to genetic, epigenetic, copy number variations of cervical cancer related genes.
This study was to analyses the miRNAs role in cervical cancer and possibilities of microRNA-based markers as diagnostic tools. Genome wide analysis was performed for CNV detection using PennCNV and QuantiSNP. The associated mRNA qRT-PCR detection was used to measure quantities of microRNA gene expression. More than 10 CNV regions has a significant relationship with cervical cancer risk for both CNV detection algorithms. A total of 34 CNVs was detected by QuantiSNP while it was 27 in case of PennCNV, among which 22 CNVs was found to be overlapping between these two algorithms. the mRNA was analyzed for its expression on 36 carvical tumor normal tissue pairs of four targets i.e., MAP3K3, RIPK2, DIRAS3 and GAS7. These infers that there was a significant downregulation of all the four genes cervical tumor. Our results showed that miR-182 can modulate the expression of FAM83H, DIRAS3, RIPK2 and MAP3K3 in cervical cancer. Therefore, indicated that miR-182 can acts through these signaling pathway in proliferation of cervical cancer cells. The expression of tumor modulator miRNAs can be controlled by miRNA replacement therapy. Several miRNAs have been used for this purpose. The modulation of various signaling pathway and proteins in cervical cancer cells by miR-182 needs further clarification.


[Hemoptysis in a young man smoking cannabis].
The respiratory toxicity of cannabis is well known today. Along with the classic cannabis 'joint', there are other ways of consuming it, which should be known. Smoking cannabis that has been cut with micro-particles of silicon dioxide may cause hemoptysis. We will describe here the case of a young 16-year-old man who was in the hospital because of hemoptic expectoration. The etiologic investigation was negative, in particular a thoracic scan and a bronchial fiberscope. Questioning the patient afterwards allowed us to discover the inhalation of cannabis 2 h before the hemoptysis, cannabis mixed with micro-particles of silicon dioxide. Stopping inhalation stopped the symptoms. Pediatricians should be familiarized with such practices. Silicon dioxide particles cause ENT problems or bronchial ones (coughing, spitting, hemoptysis, wheezing). Over the long term, the risk of silicosis cannot be excluded, although a longer and more complete exposure is necessary.


Herbal medicine (Gancao Xiexin decoction) for Behcet disease: A systematic review protocol.
Behcet disease (BD) is a systemic vasculitis that causes blood vessel inflammation throughout body and no cure exists. The purpose of this review is to evaluate the safety and efficacy of Gancao Xiexin Decoction (GCXX) in the treatment of BD and provide a clinical reference for the treatment of the refractory disease. First, the researcher will retrieve the following database based on the established search strategy: MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure, Wanfang, VIP (Journal Integration Platform). The quality of the literature will be evaluated according to Cochrane's handbook and review inclusion criteria. Data will be extracted and data of sufficient homogeneity was combined using Review Manager (RevMan) software V5.3.5. This study will provide a high quality synthesis of herbal medicine (Gancao Xiexin decoction) for Behcet disease. The conclusion of our systematic review will provide evidence to judge whether herbal medicine (Gancao Xiexin decoction) for Behcet disease is an effective intervention for patient with menopausal women. PROSPERO CRD 42018104099.


Characteristics of left ventricular diastolic function in patients with systolic heart failure: a Doppler tissue imaging study.
Our aim was to characterize myocardial velocity profiles in different types of diastolic dysfunction for patients with severely decreased left ventricular (LV) systolic function. A total of 126 patients with congestive heart failure and an LV ejection fraction of 35% or less were included. Patients underwent an echocardiographic Doppler examination, with measurement of the transmitral inflow pattern, and Doppler tissue imaging of the mitral annulus. Compared with age-matched control subjects, the patients had decreased systolic (9.5 vs 4.9 cm/s, P < .001) and early diastolic (11.6 vs 5.6 cm/s, P < .001) mitral annular velocities. According to the transmitral inflow pattern, 56 patients had signs of a LV restrictive pattern, 36 had a pseudonormalization pattern, and 34 had an abnormal relaxation pattern. The peak systolic and early diastolic mitral annular velocities were quite similarly reduced in different diastolic groups (systolic velocities of 4.6, 5.0, and 5.3 cm/s, and early diastolic velocities of 5.7, 5.8, and 5.1 cm/s at restrictive, pseudonormal, and abnormal relaxation, respectively). The ratio of the transmitral early wave and mitral annular early velocity, an expression of LV filling pressure, was highest in the restrictive group compared with other groups (17.0, 14.6, and 11.7 in the above 3 groups, respectively, P < .001 among groups). The ratio of the transmitral early wave and mitral annular early velocity was also higher in the pseudonormal group than in a control group of patients with ejection fraction of 35% or more with signs of a normal/pseudonormal pattern (14.6 vs 9.0, P < .001). Doppler tissue imaging may enhance the estimates of diastolic dysfunction in patients with decreased LV systolic function, and help to disclose abnormal diastolic function especially in a pseudonormal group.


WITHDRAWN: Dendritic Spine and Synapse Morphological Alterations Induced by a Neural Cell Adhesion Molecule (NCAM) Mimetic.
The neural cell adhesion molecule (NCAM) is a glycoprotein expressed on the surface of neurons and glial cells. It plays a key role in morphogenesis of the nervous system, regeneration of damaged neural tissue and synaptic plasticity. The extracellular domain of NCAM engages in homophilic interactions (NCAM binding to NCAM) and in heterophilic interactions between NCAM and other proteins such as the fibroblast growth factor (FGF) receptor. It promotes synaptogenesis and activity-dependent remodelling of synapses but less is know of its influence on synaptic and dendritic morphology. Recently, quantitative electron microscopy and 3-dimensional reconstruction (3-D) of ultrathin serial sections has been used to examine the morphology of synapses and dendritic spines in the hippocampus of rats treated with a neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, FGL-peptide (an NCAM mimetic). These data show clearly that the FGL peptide has marked influences on both spine and synaptic form.


Validation of the COPD Assessment Test (CAT) as an Outcome Measure in Bronchiectasis.
Objective assessment of symptoms in bronchiectasis is important for research and in clinical practice. The COPD Assessment Test (CAT) is a short, simple assessment tool widely used in COPD. The items included in the CAT are not specific to COPD and also reflect the dominant symptoms of bronchiectasis. We therefore performed a study to validate the CAT as an outcome measure in bronchiectasis. The CAT was administered to two cohorts of bronchiectasis patients along with other quality of life questionnaires. Patients underwent comprehensive clinical assessment. One cohort had repeated questionnaires collected before-and-after treatment of acute exacerbations. We analyzed convergent validity, repeatability, and responsiveness of the score and calculated the minimum clinically important difference (MCID) using a combination of distribution and anchor-based methods. In both cohorts there were positive correlations between the CAT and the St. George's Respiratory Questionnaire (r = 0.90, P < .0001 and r = 0.87, P < .0001). There was an inverse relationship between CAT and Quality of Life - Bronchiectasis Respiratory Symptoms Scale (r = -0.75, P < .0001) and Leicester Cough Questionnaire score (r = -0.77, P < .0001). Patients with more severe disease, based on the bronchiectasis severity index, had significantly higher CAT scores. CAT also correlated with FEV1 % predicted and 6-min walk distance (6MWD). CAT increased significantly at exacerbation and fell at recovery. The intraclass correlation coefficient for two measurements four-weeks apart while clinically stable was 0.88 (95% CI, 0.73-0.95, P < .0001). An MCID of 4 was most consistent. CAT is a valid, responsive symptom assessment tool in bronchiectasis. The MCID is estimated as 4 points.


Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells.
Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process. Among the 23 tested teratogens and 16 non-teratogens, we identified three retinoids including 13-cis-retinoic acid that completely block the process of cardiomyogenesis in hiPSCs. Moreover, we have identified an early gene signature consisting of 31 genes and associated biological processes that are severely affected by the retinoids. To predict the inhibitory potential of teratogens and non-teratogens in the process of cardiomyogenesis we established the "Developmental Cardiotoxicity Index" (CDI31g) that accurately differentiates teratogens and non-teratogens to do or do not affect the differentiation of hiPSCs to functional cardiomyocytes.


Current uses of large data sets to assess the quality of providers. Construction of risk-adjusted indexes of hospital performance.
This article examines how large data sets can be used for evaluating the effects of health policy changes and for flagging providers with potential quality problems. An example is presented, illustrating how three risk-adjusted measures of hospital performance were developed using patient discharge abstracts. Advantages and disadvantage of this approach are discussed.


Synthesis of nitrodiazirinyl derivatives of neurotoxin II from Naja naja oxiana and their interaction with the Torpedo californica nicotinic acetylcholine receptor.
Five singly modified nitrodiazirine derivatives of neurotoxin II (NT-II) from Naja naja oxiana were obtained after NT-II reaction with N-hydroxysuccinimide ester of (2-nitro-4-[3-(trifluoromethyl)-3H-diazirin-3yl]phenoxy)acet ic acid followed by chromatographic separation of the products. To localize the label positions, each derivative was first UV-irradiated and then subjected to reduction, carboxymethylation, and trypsinolysis. Tryptic digests were separated by reversed phase-HPLC, the labeled peptides being identified by mass spectrometry. The derivatives containing the photolabel at the position Lys 25, Lys 26, Lys 44, or Lys 46 were [125I]iodinated by the chloramine T procedure. Each iodinated derivative was found to form photoinduced cross-links with the membrane-bound nicotinic acetylcholine receptor (AChR) from Torpedo californica. The pattern of labeling the receptor's alpha, beta, gamma, or delta subunits was dependent on the photolabel position in the NT-II molecule and differed from that obtained earlier with an analogous series of p-azidobenzoyl derivatives of NT-II. The results obtained indicate that (i) different sides of the neurotoxin molecule are involved in the AChR binding, and (ii) fragments of the different AChR subunits are located close together at the neurotoxin-binding sites.


Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.
Ovarian cancer is the deadliest of the gynecologic malignancies. Carcinogenic progression is accompanied by upregulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUB) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian cancer. The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian cancer cell lines and primary cells. The anticancer activity of RA-9 and its mechanism of action were evaluated in multiple cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intraperitoneal ES-2 xenograft model of human ovarian cancer. Here, we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of apoptosis in ovarian cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an unfolded protein response as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival, and was well tolerated by the host. Our preclinical studies support further evaluation of RA-9 as an ovarian cancer therapeutic.


Supervision of mental health care in The Netherlands.
In the Netherlands the Inspectorate of Mental Health has to supervise the quality of mental health care that is given to its citizens. A shortage of inspectors hampers effective accomplishment of this task, and government budget cuts have increased this problem. Another obstacle is the absence of standardized methods of supervision and clear norms for medical practice. This paper describes the efforts of the Inspectorate to develop a new technique of supervision to solve this problem, the so-called frames of reference.


Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells.
Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3β protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.


Synthesis and evaluation of protein-based biopolymer in production of silver nanoparticles as bioactive compound versus carbohydrates-based biopolymers.
This overall process deals with evaluating the performance of silver nanoparticles, synthesized from sodium caseinate (SC) as green biological active agent, in comparison with widely produced from carboxymethyl cellulose, other carbohydrates (oxidized nanocellulose fibres (OC) and starch (St)). The TGA, FTIR and TEM, as well as its antimicrobial activities toward pathogenic Gram-positive and Gram-negative bacteria in addition to the yeast strain Candida albicans NRRL Y-477 were examined. In addition, with regard to their anti-tumour activity, the evaluation was studied via many cancer cell lines against RPE1 (normal retina cell line). The results revealed that the SC-Ag(I) and CMC-Ag(I) complexes were formed in six- and five-membered chelate rings, respectively, as nanoparticles, while linear chelation structure was formed in case of OC-Ag(I) and St-Ag(I) complexes. The complexation of SC with Ag(I) ions was recommended as promising stable and antimicrobial agent, with lower free Ag(I) ions and particle size than other Ag-complexes. Moreover, it provided anti-tumour activity of most tested cell lines (in vitro), with the following sequence HCT116 > PC3 > HePG 2 > MCF-7 > A549 with IC50 and IC90 values of 25.8 and 54.73 µg ml-1, 45.1 and 66.7 µg ml-1, 64.3 and 110.7 µgml-1, 71.4 and 114.8 µgml-1 and 80.1 and 127.7 µgml-1, respectively. The promising effect of SC-Ag complex was also clear from its selective index versus RPE1 (normal retina cell line).


DBA/2-like minor histocompatibility antigens on a BALB/c lymphoma. A BALB/c anti-DBA/2 serum which lyses the tumor and blocks BALB/c anti-tumor and anti-DBA/2 effectors.
We have previously shown that BALB/c anti-DBA/2 T cells can lyse the Moloney virus-induced BALB/c lymphoma YC8. In order to determine whether serologically defined minor histocompatibility antigens (MiHA) cross-reacting with those of DBA/2 tissues are present on YC8, we produced an antiserum directed against non-H-2 antigens by immunizing BALB/c mice with DBA/2 Con A and lipopolysaccharide (LPS)-induced lymphoblasts. In a direct complement-dependent cytotoxicity assay, the antiserum (OR-1) lysed DBA/2 and YC8 but not BALB/c lymphocytes and blasts. No reactions against viral antigens were detected in the antisera as shown by the lack of cytotoxicity on a panel of lymphomas expressing a variety of viral antigens. In addition, OR-1 was able to specifically block a cytotoxic T lymphocyte (CTL), H-2-restricted BALB/c anti-DBA/2 cytotoxic response when bound to DBA/2 or to YC8 target cells. These results indicate that antigens cross-reacting between YC8 lymphoma and DBA/2 tissues are serologically defined MiHA of DBA/2 background and that OR-1 serum can block a CTL reaction by binding to target antigen rather than to major histocompatibility complex products.


Immune signatures of prodromal multiple sclerosis in monozygotic twins.
The tremendous heterogeneity of the human population presents a major obstacle in understanding how autoimmune diseases like multiple sclerosis (MS) contribute to variations in human peripheral immune signatures. To minimize heterogeneity, we made use of a unique cohort of 43 monozygotic twin pairs clinically discordant for MS and searched for disease-related peripheral immune signatures in a systems biology approach covering a broad range of adaptive and innate immune populations on the protein level. Despite disease discordance, the immune signatures of MS-affected and unaffected cotwins were remarkably similar. Twinship alone contributed 56% of the immune variation, whereas MS explained 1 to 2% of the immune variance. Notably, distinct traits in CD4+ effector T cell subsets emerged when we focused on a subgroup of twins with signs of subclinical, prodromal MS in the clinically healthy cotwin. Some of these early-disease immune traits were confirmed in a second independent cohort of untreated early relapsing-remitting MS patients. Early involvement of effector T cell subsets thus points to a key role of T cells in MS disease initiation.


Physiologic consequences and complications of vasectomy.
Sterilization of men and women is the most popular method of contraception in Canada. The contraceptive effect of a vasectomy usually occurs within 3 months. The production of sperm, however, is not interrupted, and an increase in pressure proximal to the ligation site may cause rupture of the epididymis or the ductus deferens, with extravasation of spermatozoa and the formation of granulomas or sperm antibodies. Increased pressure may also explain the postvasectomy pain syndrome.


HHV-6 Infection in a 19-Year-Old Liver Transplant Recipient - Much More Than Roseola!
Human herpesvirus 6 (HHV-6) infections, most commonly occurring during childhood, are frequently mild and self-limited. However, immunosuppression due to transplantation may cause reactivation of HHV-6 with manifestations ranging from fever and skin exanthem to pneumonitis, hepatitis, encephalitis, and myelitis. Because these infections may be devastating for liver transplant recipients leading to transplant organ fibrosis and failure, it is imperative that internists recognize the manifestations, establish early diagnosis, institute appropriate therapy, and make timely referrals to transplant specialists. We present a case of a 19-year-old liver transplant recipient with HHV-6 viremia, encephalopathy, and hepatitis. The patient's symptoms improved with ganciclovir and intravenous immunoglobulin treatment, serum HHV-6 copies gradually decreased, and she was discharged with outpatient follow-up. After approximately one month of antiviral therapy, the patient's viral load was undetectable. Early recognition of HHV-6 viremia, appropriate laboratory assessment, and early institution of therapy is important for internal medicine physicians to decrease morbidity and mortality in liver transplant recipients.


Matrix metalloproteinase-3 (MMP3) and MMP9 genes and risk of myocardial infarction, ischemic stroke, and hemorrhagic stroke.
We assessed the association of genetic variation in MMP3 and MMP9 with risk of myocardial infarction and stroke. A case-control study was conducted among members of Group Health (GH), a large-integrated health care delivery system. Case subjects with incident non-fatal myocardial infarction (n=854), ischemic stroke (n=367), and hemorrhagic stroke (n=66) were identified and validated. A matched control group was selected from among GH members without myocardial infarction or stroke (n=2696). Haplotype-tagging sets of single-nucleotide polymorphisms (SNPs) in MMP3 and MMP9 were genotyped. MMP3 haplotype 2 was associated with reduced risk of myocardial infarction (adjusted odds ratio (OR) per copy=0.80, 95% confidence interval 0.66, 0.98) and increased risk of hemorrhagic stroke (OR=1.69, 95% confidence interval 1.05, 2.75). Results for MMP3 haplotype 2 and ischemic stroke resembled those for myocardial infarction but did not achieve statistical significance (OR=0.85, 95% confidence interval 0.64, 1.12). No individual SNP identified MMP3 haplotype 2, and none of the individual MMP3 SNPs were associated with myocardial infarction or stroke. MMP9 haplotypes or SNPs were not associated with myocardial infarction or stroke. MMP3 haplotype may predict both cardiac events and stroke.


Similarities and Differences in the Longitudinal Trajectories of Depressive Symptoms from Mid-Adolescence to Young Adulthood: the Intersectionality of Gender, Race/Ethnicity, and Levels of Depressive Symptoms.
Understanding similarities and differences between groups with intersecting social identities provides key information in research and practice to promote well-being. Building on the intersectionality literature indicating significant gender and racial/ethnic differences in depressive symptoms, the present study used quantile regression to systematically present the diversity in the development of depressive symptoms for individuals with intersecting gender, race/ethnicity, and levels of symptoms. Information from the National Longitudinal Survey of Youth 79: Child and Young Adult study was employed. A detailed picture of depressive symptom trajectories from low to high quantiles was illustrated by depicting 13 quantile-specific trajectories using follow-up data from ages 15 to 40 in six gender-race/ethnicity groups: both genders of Black, Hispanic, and non-Black, non-Hispanic individuals. From low to high quantiles, Black and non-Black, non-Hispanic individuals showed mostly curved, and Hispanic individuals showed mostly flat trajectories. Across the six gender-race/ethnicity groups, the trajectories below 0.50 quantiles were similar in levels and shapes from mid-adolescence to young adulthood. The differences between the six gender-race/ethnicity groups widened, indicated by outspreading trajectories, especially at quantiles above 0.50. Furthermore, non-Black, non-Hispanic males and females showed especially fast-increasing patterns at quantiles above 0.75. Among those without or with only a high school degree, Black females and non-Black, non-Hispanic females tended to report similar levels of depressive symptoms higher than other groups at high quantiles. These unique longitudinal trajectory profiles cannot be captured by the mean trajectories. The intersectionality of gender, race/ethnicity, and quantile of symptoms on the development of depressive symptoms was identified. Further studying the mechanism explaining this diversity can help reduce mental health disparities.


The differences and the relationship between demoralization and depression in Chinese cancer patients.
Both demoralization and depression are common forms of psychological distress in cancer patients. This study aimed to investigate the severity of demoralization in Chinese cancer patients and to explore the factors influencing depression and demoralization and their effects on quality of life to better understand the differences and the relationship between demoralization and depression. Cross-sectional study design, in-patients sequentially recruited from a tertiary-level cancer hospital in Beijing between January 2016 and April 2016 completed Mandarin version of Demoralization Scale (DS-MV), Patient Health Questionnaire-9 (PHQ-9), Revised Life Orientation Test (CLOT-R), Beck Hopelessness Scale (BHS), and the 12-items Short Form Health Survey, version 2 (SF-12 V2) and provided socio-demographic and clinical information. 296/424 (70.0%) of patients completed questionnaires. The mean score of DS is 30.4 (SD = 13.0). There are 28% (83/296) patients who experienced a low level of depression but a high level of demoralization. Resignation medical coping method (b = 0.279, P < .001), hopelessness (b = 0.492, P < .001), positive life orientation (b = -0.170, P < .001), and education level (b = -0.132, P < .001) were found to be predictors of demoralization, while only resignation medical coping method (b = 0.373, P < .001) and hopelessness (b = 0.350, P < .001) were found to be predictors of depression. Depression is a mediator between demoralization and physical aspects of quality of life (γ = -0.1604, LLCI = -0.244, ULCI = -0.080). Demoralization is a prevalent psychiatric problem in Chinese cancer patients, and a large proportion of patients had low depression but high demoralization. Therefore, screening for demoralization in Chinese oncology practice is essential. A positive life orientation was found to be protective against demoralization.


Alterations of hepatic triglyceride in patients before and after jejunoileal bypass for morbid obesity.
The effect of obesity and jejunoileal bypass on the amount and composition of hepatic lipid and the relationship of adipose tissue fatty acids, body weight, and rate of weight reduction to hepatic triglyceride (TG) were investigated in 16 patients before and at various times after jejunoileal bypass. Liver and adipose tissue biopsy sections were taken at surgery and at various times thereafter. Hepatic lipid was measured and the composition of triglyceride fatty acids (TGFA) compared with that of adipose tissue. Liver TG increased by an average of 2.5-fold during the period of rapid weight loss and decreased during the period of stable weight, but remained above control values. There was no relationship between concentration of liver TG and body weight or rate of weight reduction. The hepatic TGFA composition at surgery and during the period of stable weight resembled that of adipose tissue. During the period of rapid weight loss the composition of hepatic TGFA was markedly different, showing an increase in palmitic (16:0, P less than 0.01), palmitoleic (16:1, P less than 0.05), and oleic acids (18:1, P less than 0.05) and a decrease in linoleic acid (18:2, P less than 0.001). These changes could not be accounted for by a preferential absorption or mobilization of 16:0, 16:1, and 18:1, or by an increased utilization of 18:2 by the liver. It is proposed that an increased conversion of carbohydrate to fat occurs during the period of rapid weight loss when a relative excess of carbohydrate to amino acids results from an imbalance in the intestinal absorption of carbohydrate and protein.


Acute Focal Bacterial Nephritis: Two Cases and Review of the Literature.
Acute focal bacterial nephritis (AFBN) has mainly been reported in pediatrics. It may be an underdiagnosed condition in adults because it resembles acute pyelonephritis (APN) in its clinical presentation. Two young women (25 and 27 years old, respectively) presented with complaints compatible with a diagnosis of APN. However in both, fever was of high grade, persistent for several days in spite of antibiotic administration, and there was demonstrated worsening of the inflammatory biomarkers. A contrast-enhanced computed tomography (CECT) led to the diagnosis in both cases. Contrast-enhanced computed tomography reveals the most sensitive and specific images of AFBN. This includes wedge-shaped lesions with decreased enhancement, which may be focal or multifocal. Antibiotic therapy for at least 3 weeks. Resolution of AFBN was obtained after 3 weeks of antibiotics. Our 2 cases illustrate the importance of CECT imaging to confirm the diagnosis of AFBN. Interstitial bacterial inflammation may have a worse prognosis if not diagnosed early and efficiently treated. Unlike APN, the management of AFBN requires at least 3 weeks of antibiotics to prevent the development of renal scarring and renal abscess.


Bone morphogenetic protein (BMP) signaling regulates mitotic checkpoint protein levels in human breast cancer cells.
Aberrant expression of mitotic checkpoint genes compromises mitotic checkpoint, leads to chromosome instability and tumorigenesis. However, the cell signals that control mitotic checkpoint gene expression have not been reported so far. In the present study we show that, in human breast cancer cells, chemical inhibition of Bone morphogenetic proteins (BMPs), but not Transforming Growth Factor-β (TGF-β), abrogates the mitotic arrest induced by nocodazole. Protein expression analysis reveals that inhibition of BMP signaling dramatically down regulates protein levels of mitotic checkpoint components BUB3, Hec1, TTK and MAD2, but inhibition of TGF-β has relatively minor effect on the expression of these proteins. Activation of BMP signaling specifically up regulates BUB3, and activation of Activin A signaling globally down regulates these proteins level. Furthermore, overexpressing MAD2, TTK, BUB3 or Hec1 significantly rescues the mitotic arrest defect caused by BMP inhibition. Our results demonstrated for the first time that TGF-β family cytokines are cellular signals regulating mitotic checkpoint and perturbations in intrinsic BMP signaling could lead to suppression of mitotic checkpoint signaling by downregulating key checkpoint proteins. The results suggest a possible mechanism by which dysregulation of TGF-β signaling causes mitotic checkpoint defects and drives tumorigenesis. The finding also provides a potential and more specific strategy for cancer prevention by targeting BMP and mitotic checkpoint connection.


High-temperature biofilm system based on heterotrophic nitrification and aerobic denitrification treating high-strength ammonia wastewater: Nitrogen removal performances and temperature-regulated metabolic pathways.
Conventional autotrophic nitrification process is difficult to treat high-temperature wastewater with high-strength ammonia. In this study, a high-temperature (50 °C) biofilm system based on heterotrophic nitrification and aerobic denitrification (HNAD) was established. The results showed that the HNAD process was high temperature resistant, and the nitrogen removal performance, pathway and microbial mechanism varied remarkably at different temperatures. The high-temperature system showed excellent nitrogen and COD removal capacities at 50 °C. Ammonia oxidation was mainly undertaken by heterotrophic nitrification, while anoxic and aerobic pathways worked in concert for denitrification. High-throughput sequencing indicated that heterotrophic nitrifying bacteria (8.58%) and denitrifying bacteria (52.88%) were dominant at 50 °C. Metagenomic analysis further suggested that the carbon metabolism was up-regulated in response to the increasing temperature, so more energy was generated, thereby promoting the HNAD-related nitrogen removal pathways. The study revealed the microbial mechanism of HNAD at high temperature and provided new insights into high-temperature biological nitrogen removal.


The global perspective on neurology training: the World Federation of Neurology survey.
This World Federation of Neurology (WFN) study aimed to characterize the status quo of post-graduate neurology training throughout the world and enable a better orientation on global training in neurology. Basic data on training curricula and working conditions of neurology residents and neurologists in 39 countries worldwide were evaluated. Our data show considerable differences in manpower and training, but a continuous improvement within the last 10 years of observation. Worldwide a spread of interim evaluations and final examinations of different types are used. Online resources will undoubtedly profoundly change skill and knowledge acquisition and training practices in Neurology in the coming years.


Choroidal detachment and hypotony following selective laser trabeculoplasty: a case report.
Selective laser trabeculoplasty (SLT) is relatively safe and effective in lowering intraocular pressure (IOP). However, although rare, complications can occur after SLT. This report describes a patient with choroidal detachment due to hypotony following SLT without anterior chamber (AC) inflammation. A 67-year-old man was referred for elevated IOP in his left eye with advanced glaucomatous visual field loss. He had previously been diagnosed with idiopathic uveitic glaucoma in the left eye, for which he underwent laser iridotomy, trabeculectomy, and cataract surgery. At the first visit, the IOP of his left eye measured by Goldmann tonometry was 28 mmHg despite maximally tolerated medical treatment. SLT was performed in his left eye, resulting in an IOP of 7 mmHg 7 days later. At 3 weeks post-procedure, the patient experienced ocular pain and decreased visual acuity in his left eye. Slit-lamp examination revealed deep anterior chamber depth and no inflammation reaction, but the IOP in his left eye was 4 mmHg, and both fundus and B-scan ultrasonography showed serous choroidal detachment. All anti-glaucoma agents were stopped, and the patient was started on treatment with oral prednisolone and cyclopentolate eye drops. Three weeks later, choroidal detachment had resolved and the IOP in his left eye had stabilized at 8 mmHg. Follow-up 3 months later showed that the IOP in his left eye remained stable. Choroidal detachment-related hypotony is a rare complication of SLT. This possible complication following SLT should be informed to the patients and considered when performing the procedure.


Genome-wide Detection of Chimeric Transcripts in Early-stage Non-small Cell Lung Cancer.
Lung cancer remains the main culprit in cancer-related mortality worldwide. Transcript fusions play a critical role in the initiation and progression of multiple cancers. Treatment approaches based on specific targeting of discovered driver events, such as mutations in EGFR, and fusions in NTRK, ROS1, and ALK genes led to profound improvements in clinical outcomes. The formation of chimeric proteins due to genomic rearrangements or at the post-transcriptional level is widespread and plays a critical role in tumor initiation and progression. Yet, the fusion landscape of lung cancer remains underexplored. We used the JAFFA pipeline to discover transcript fusions in early-stage non-small cell lung cancer (NSCLC). The set of detected fusions was further analyzed to identify recurrent events, genes with multiple partners and fusions with high predicted oncogenic potential. Finally, we used a generalized linear model (GLM) to establish statistical associations between fusion occurrences and clinicopathological variables. RNA sequencing was used to discover and characterize transcript fusions in 270 NSCLC samples selected from the Glans-Look specimen repository. The samples were obtained during the early stages of disease prior to the initiation of chemo- or radiotherapy. We identified a set of 792 fusions where 751 were novel, and 33 were recurrent. Four of the 33 recurrent fusions were significantly associated with clinicopathological variables. Several of the fusion partners were represented by well-established oncogenes ERBB4, BRAF, FGFR2, and MET. The data presented in this study allow researchers to identify, select, and validate promising candidates for targeted clinical interventions.


Constructing N-Acyl/N-Sulfonyl Aza-Sulfur Derivatives from Amides/Sulfonamides and Thiophthalimides via Oxidant Regulation.
Here, we have constructed five distinct types of N-acyl or N-sulfonyl aza-sulfur scaffolds using readily available (sulfon)amides and thiophthalimides with precise regulation of oxidants. Our novel methods feature one-pot mild reaction conditions and simple operation, thereby making them highly convenient for the late-stage diversification of various amide drugs, bioactive molecules, and peptides.


Noninvasive techniques for evaluating peripheral vascular and extracranial cerebrovascular diseases.
Five hundred and fifty-eight patients have been evaluated at the peripheral vascularocular pulse blood flow laboratory over a year. The accurate correlations with angiography in the peripheral arterial investigation has been 100%, the cerebrovascular investigation has been 75% and the venous correlation has been 86 2/3%. Even though the results from ocular testing are slightly lower than reported by Kartchner and McRae, we believe that the results emphasize the delicacy of instrumentation and the degree of refinement necessary in reading of the tests. We do think, however, that a 75% accuracy does indicate this method to be of significant benefit as a noninvasive stroke screening procedure.


Testing dental quality measures: Emergency department visits for nontraumatic dental conditions and subsequent follow-up dental visits.
The goal of this study was to test the feasibility, reliability, and validity of the Dental Quality Alliance's adult dental quality measures for system-level implementation for ambulatory care sensitive (ACS) emergency department (ED) visits for nontraumatic dental conditions (NTDCs) in adults and follow-up after ED visits for NTDCs in adults. Medicaid enrollment and claims data from Oregon and Iowa were used for measure testing. Testing included validation of diagnosis codes in claims data through patient record reviews of ED visits and calculations of κ statistic, sensitivity, and specificity. Adult Medicaid enrollees' ACS NTDC ED visits ranged from 209 through 310 per 100,000 member-months. In both states, patients in the age category 25 through 34 years and non-Hispanic Black patients had the highest rates of ACS ED visits for NTDCs. Only one-third of all ED visits were associated with a follow-up dental visit within 30 days, decreasing to approximately one-fifth with a 7-day follow-up. The agreement between the claims data and patient records for identification of ACS ED visits for NTDCs was 93%, κ statistic was 0.85, sensitivity was 92%, and specificity was 94%. Testing revealed the feasibility, reliability, and validity of 2 DQA quality measures. Most beneficiaries did not have a follow-up with a dentist within 30 days of an ED visit. Adoption of quality measures by state Medicaid programs and other integrated care systems will enable active tracking of beneficiaries with ED visits for NTDCs and develop strategies to connect them to dental homes.


Light histories influence the impacts of solar ultraviolet radiation on photosynthesis and growth in a marine diatom, Skeletonema costatum.
Phytoplanktonic species acclimated to high light are known to show less photoinhibition. However, little has been documented on how cells grown under indoor conditions for decades without exposure to UV radiation (UVR, 280-400 nm) would respond differently to solar UVR compared to those in situ grown under natural solar radiation. Here, we have shown the comparative photosynthetic and growth responses to solar UVR in an indoor- (IS) and a naturally grown (WS) Skeletonema costatum type. In short-term experiment (<1 day), Phi(PSII) and photosynthetic carbon fixation rate were more inhibited by UVR in the IS than in the WS cells. The rate of UVR-induced damages of PSII was faster and their repair was significantly slower in IS than in WS. Even under changing solar radiation simulated for vertical mixing, solar UVR-induced higher inhibition of photosynthetic rate in IS than in WS cells. During long-term (10 days) exposures to solar radiation, the specific growth rate was much lower in IS than WS at the beginning, then increased 3 days later to reach an equivalent level as that of WS. UVR-induced inhibition of photosynthetic carbon fixation in the IS was identical with that of WS at the end of the long-term exposure. The photosynthetic acclimation was not accompanied with increased contents of UV-absorbing compounds, indicating that repair processes for UVR-induced damages must have been accelerated or upgraded.


A new technique to adjust the length of artificial chordae during mitral anterior leaflet repair.
Length measurement of artificial chordae remains a critical step during mitral valve repair (MVr). The aim of this study is to assess the effectiveness of a new length measuring technique. All consecutive patients with anterior leaflet prolapse/flail who underwent MVr using the described method between January 2020 and January 2022 at our institution were included in the analysis. Clinical and transesophageal echocardiography data were collected postoperatively and at 1-year follow-up. The primary outcome was freedom from mitral regurgitation (MR). Secondary outcomes were presentation with New York Heart Association (NYHA) class <2 and leaflet coaptation length ≥10 mm. Of 25 patients, 16 (64%) were males. A total of 15 (60%) had isolated anterior leaflet disease, while 10 (40%) had concomitant posterior involvement. Twenty patients with isolated MR (80%) underwent right anterior mini-thoracotomy, while 5 (20%) with associated valvular or coronary disease underwent sternotomy. The median number of chordae implanted was 2 [1-4]. Postrepair intraoperative MR grade was 0 in 23 patients (92%) and 1 in 2 (8%). Thirty-day mortality was 0%. De novo atrial fibrillation was 20%. At follow-up, mortality was 0%. No patients presented with moderate or severe MR. A total of 22 patients (88%) were in NYHA class I, while 3 (12%) in class II. The coaptation length was 11 ± 1 mm. The short-term outcomes of the described technique are good with adequate leaflet coaptation in all treated patients. Long-term results are needed to assess the stability and durability of this repair technique.


The role of glucocorticoids, unstressful labor, and atraumatic delivery in the prevention of respiratory distress syndrome.
A 37 month review of the effects of glucocorticoids and uncompromised labor with atraumatic delivery on the incidence of respiratory distress syndrome (RDS) is presented. The incidence of RDS in the control and study population is not significantly different; however, the incidence of RDS in the control and study groups is markedly lower than the published figures for the same age and weight range. The low incidence of RDS in the control population is attributed to the avoidance of intrapartum hypoxia and stress during an uncompromised labor and atraumatic delivery.


Comprehensive modelling and cost-benefit optimization for joint regulation of algae in urban water system.
Algal blooms in urban water system is an international concern, which especially in China, have become a major obstacle to the urban water environment improvement since the preliminary achievements were made in the treatment of black and odorous water bodies. The complex blooming mechanisms require a joint regulation plan. This study established a framework that consisted of three steps, i.e., simulation, optimization, and verification, to build an optimal joint regulation plan. By taking the urban river network in Suzhou Pingjiang Xincheng as a case study, the cost-benefits of six alternative regulation measures were assessed using an algal bloom mechanism model and the discounted cash flow model based on 70 regulation scenarios. The joint regulation plan was optimized using the marginal-cost-based greedy strategy on the basis of the cost-benefits of different measures. The optimized joint plans, which were verified to be global optima, were more cost-effective than the designed regulation scenarios, and reduced the average chlorophyll-a concentrations by 55.3%-60.1% compared with the status quo. Applying the optimized cost allocation ratios of each measure to adjust the existing regulation scheme of another similar case verified that the optimization results had great generalizability.


Bulimic symptoms and mood predict food relevant Stroop interference in women with troubled eating patterns.
Cognitive processing differences based on attentional biases of words pertaining to eating disorders were investigated to assess people's pathological thoughts. Participants were 165 undergraduate women (mean age=19.2) at a large Midwestern university. This Stroop task that included color identification of three word groups (food-related words, neutral words, and color words) was administered to measure differential speed in cognitive processing of salient words in individuals with and without troubled eating patterns. As predicted by the moderator hypothesis, a statistically significant interaction effect between bulimic symptoms and negative mood was found on food-related reaction time. Post hoc analysis of the interaction showed that women endorsing more bulimic symptoms responded slower to food-related cues than women with fewer bulimic symptoms among individuals who reported negative mood. The study results indicate that women who have problematic eating patterns and experience negative mood are hyperattentive to food-related cues.


Some medicolegal tips.
The purposes for each type of medical record are critical legal determinants for its content. Deposition is the most important single step in the litigation process. The uses for a deposition greatly exceed the mere discovery of fact. The weight given the testimony of witnesses by a jury is affected by many subtle factors, including professional demeanor, attitude, manner of dress, ability to communicate and recollect, and prior inconsistent statements.


An atomistic view on human hemoglobin carbon monoxide migration processes.
A significant amount of work has been devoted to obtaining a detailed atomistic knowledge of the human hemoglobin mechanism. Despite this impressive research, to date, the ligand diffusion processes remain unclear and controversial. Using recently developed computational techniques, PELE, we are capable of addressing the ligand migration processes. First, the methodology was tested on myoglobin's CO migration, and the results were compared with the wealth of theoretical and experimental studies. Then, we explored both hemoglobin tense and relaxed states and identified the differences between the α-and β-subunits. Our results indicate that the proximal site, equivalent to the Xe1 cavity in myoglobin, is never visited. Furthermore, strategically positioned residues alter the diffusion processes within hemoglobin's subunits and suggest that multiple pathways exist, especially diversified in the α-globins. A significant dependency of the ligand dynamics on the tertiary structure is also observed.


Diltiazem-induced photodistributed hyperpigmentation.
Diltiazem is a calcium-channel antagonist commonly prescribed in the treatment of cardiovascular disease. Although an extensive spectrum of cutaneous reactions to diltiazem has been described, only two published reports of hyperpigmentation induced by diltiazem are known. We report the cases of a 71-year-old black male and a 49-year-old Hispanic male, who both presented with characteristic hyperpigmentation on sun-exposed areas after taking an extended-release form of diltiazem hydrochloride (Tiazac).


Galactinol synthase enzyme activity influences raffinose family oligosaccharides (RFO) accumulation in developing chickpea (Cicer arietinum L.) seeds.
To understand raffinose family oligosaccharides (RFO) metabolism in chickpea (Cicer arietinum L.) seeds, RFO accumulation and corresponding biosynthetic enzymes activities were determined during seed development of chickpea genotypes with contrasting RFO concentrations. RFO concentration in mature seeds was found as a facilitator rather than a regulating step of seed germination. In mature seeds, raffinose concentrations ranged from 0.38 to 0.68 and 0.75 to 0.99 g/100 g, whereas stachyose concentrations varied from 0.79 to 1.26 and 1.70 to 1.87 g/100 g indicating significant differences between low and high RFO genotypes, respectively. Chickpea genotypes with high RFO concentration accumulated higher concentrations of myo-inositol and sucrose during early seed developmental stages suggesting that initial substrate concentrations may influence RFO concentration in mature seeds. High RFO genotypes showed about two to three-fold higher activity for all RFO biosynthetic enzymes compared to those with low RFO concentrations. RFO biosynthetic enzymes activities correspond with accumulation of individual RFO during seed development.


Oil-contaminated sites act as high-risk pathogen reservoirs previously overlooked in coastal zones.
In addition to the organic pollutants and disturbance to the microbial, plant and animal systems, oil contamination can also enrich opportunistic pathogens. But little is known about whether and how the most common coastal oil-contaminated water bodies act as reservoirs for pathogens. Here, we delved into the characteristics of pathogenic bacteria in coastal zones by constructing seawater-based microcosms with diesel oil as a pollutant. 16S rRNA gene full-length sequencing and genomic exploration revealed that pathogenic bacteria with genes involved in alkane or aromatic degradation were significantly enriched under oil contamination, providing a genetic basis for them to thrive in oil-contaminated seawater. Moreover, high-throughput qPCR assays showed an increased abundance of the virulence gene and enrichment in antibiotics resistance genes (ARGs), especially those related to multidrug resistance efflux pumps, and their high relevance to Pseudomonas, enabling this genus to achieve high levels of pathogenicity and environmental adaptation. More importantly, infection experiments with a culturable P. aeruginosa strain isolated from an oil-contaminated microcosm provided clear evidence that the environmental strain was pathogenic to grass carp (Ctenopharyngodon idellus), and the highest lethality rate was found in the oil pollutant treatment, demonstrating the synergistic effect of toxic oil pollutants and pathogens on infected fish. A global genomic investigation then revealed that diverse environmental pathogenic bacteria with oil degradation potential are widely distributed in marine environments, especially in coastal zones, suggesting extensive pathogenic reservoir risks in oil-contaminated sites. Overall, the study uncovered a hidden microbial risk, showing that oil-contaminated seawater could be a high-risk pathogen reservoir, and provides new insights and potential targets for environmental risk assessment and control.


The relationship between word length and threshold character size in patients with central scotoma and eccentric fixation.
Understanding limitations on text reading with eccentric fixation is of major concern in low vision research. Our objective was to determine, in patients with a central scotoma, whether threshold character size is similar for different word lengths and paragraphed texts. In 19 patients, we retrospectively analyzed the relationship between minimum readable character size for isolated words and text. Isolated letters, two, five, and ten-letter words and a paragraphed text were presented randomly through a scanning laser ophthalmoscope in eight different character sizes. Threshold character size varied according to the text stimulus (p<0.05). Threshold character sizes for single letters and two-letter words were matched (p>0.99), as were those for five-letter words, ten-letter words, and paragraphed text (p>0.99). Threshold character size for single letters and two-letter words was significantly lower than that measured with other text stimuli. Reading performance is influenced by a variety of factors such as crowding, contextual effects, visual span, degree of oculomotor adaptation needed, and frequency of a defined word. Globally, when reading with a central scotoma, it appears that within word characteristics have more impact than inter-word parameters on threshold character size.


Accelerated functional maturation of isolated neonatal porcine cell clusters: in vitro and in vivo results in NOD mice.
Neonatal porcine cell clusters (NPCCs) might replace human for transplant in patients with type 1 diabetes mellitus (T1DM). However, these islets are not immediately functional, due to their incomplete maturation/ differentiation. We then have addressed: 1) to assess whether in vitro coculture of islets with homologous Sertoli cells (SC) would shorten NPCCs' functional time lag, by accelerating the beta-cell biological maturation/differentiation; 2) to evaluate metabolic outcome of the SC preincubated, and microencapsulated NPCCs, upon graft into spontaneously diabetic NOD mice. The islets, isolated from < 3 day piglets, were examined in terms of morphology/viability/function and final yield. SC effects on the islet maturation pathways, both in vitro and in vivo, upon microencapsulation in alginate/poly-L-ornithine, and intraperitoneal graft into spontaneously diabetic NOD mice were determined. Double fluorescence immunolabeling showed increase in beta-cell mass for SC+ neonatal porcine islets versus islets alone. In vitro insulin release in response to glucose, as well as mRNA insulin expression, were significantly higher for SC+ neonatal porcine islets compared with control, thereby confirming SC-induced increase in viable and functional beta-cell mass. Graft of microencapsulated SC+ neonatal porcine islets versus encapsulated islets alone resulted in significantly longer remission of hyperglycemia in NOD mice. We have preliminarily shown that the in vitro NPCCs' maturation time lag can dramatically be curtailed by coincubating these islets with SC. Graft of microencapsulated neonatal porcine islets, precultured in Sertoli cells, has been proven successful in correcting hyperglycemia in stringent animal model of spontaneous diabetes.


Reactivity of 3-HBA-6-hydroxylase with diethylpyrocarbonate and N-bromosuccinimide: effect of chemical modifications on kinetic and spectral properties of the enzyme.
The rapid inactivation of 3-HBA-6-hydroxylase by 100 microM diethylpyrocarbonate or 40 microM N-bromosuccinimide and protection offered by the substrate, 3-hydroxybenzoate, against these chemical modifications implicate the involvement of histidine and tryptophan in the catalytic activity of the enzyme. Inactivation of the enzyme by diethylpyrocarbonate followed pseudo-first-order kinetics, and an "n" value of 1.3 was obtained. Inactivation of the enzyme by N-bromosuccinimide was instantaneous and failed to follow pseudo-first-order kinetics. Distinct and incremental changes in the UV absorption, emission fluorescence, and near UV-CD spectra of the enzyme upon its titration with increasing concentrations of diethylpyrocarbonate or N-bromosuccinimide may be ascribed to modification and/or changes in the microenvironment of aromatic amino acid residue(s) such as tryptophan in the enzyme.


Keynote review: intestinal Peyer's patch M cells and oral vaccine targeting.
Specialized M cells in the follicle-associated epithelium of intestinal Peyer's patches serve as portals for diverse particulates. Following antigen handover to dome lymphocytes, a protective mucosal antibody secretion ensues. One approach to oral vaccine delivery is to mimic the entry pathways of pathogens via M cells. The paucity of human tissue for in vitro investigation has hampered the discovery of M-cell pathogen receptors; however an in vitro human M like-cell culture model displays many expected phenotypic features. Comparative studies using microarrays reveal several novel M-cell surface receptors that could be used to potentially target orally delivered antigens.