The results of 21-year experience of treating anal squamous cell carcinomas.
Anal squamous cell carcinomas are one of the rare cancer types. Due to the developments in the past 35 years, surgery is no longer the first treatment of choice. The aim of this study was to retrospectively examine the outcomes of 24 patients treated in a single center in the last 21 years in terms of applied treatment, local relapse, distant metastasis, post-treatment complications, and survival. Data obtained from 24 anal squamous cell carcinoma patients, who were treated in Ankara Oncology Research and Education Hospital between 1990 and 2010, were retrospectively evaluated. Of the 24 patients, 16 had anal canal squamous cell carcinoma and eight had perianal squamous cell carcinoma. All of the patients with anal canal squamous cell carcinoma (n=16) received chemoradiotherapy. Three of these patients who did not respond to treatment, underwent abdominoperineal resection. The patients with perianal squamous cell tumors were treated by local excision. During the follow -ups, seven patients experienced local relapse, and one patient had distant organ metastasis. Only one patient died. Five-year disease free survival rate was found as 66%. Our findings suggest that the first alternative in the treatment of anal squamous cell tumors should be chemoradiotherapy; and surgery seems to be the appropriate approach for the non-responsive and relapsing cases.


Stem cell biotherapy: A new remedy for Trichinella spiralis-induced inflammatory myopathy.
Trichinella spiralis (T. spiralis)-induced myopathy is an inflammatory myopathy that is difficult to treat unless the parasite is combated in its early intestinal phase before it reaches the muscles. This study aimed to evaluate the effect of local mesenchymal stem cell (MSC) therapy on T. spiralis-induced inflammatory myopathy in rats. Rats were divided into four groups: Group 1 (non-infected non-treated group); Group 2 (infected non-treated group); Group 3 (infected albendazole (ABZ)-treated group); and Group 4 (infected MSC-treated group). Their muscle status was assessed physiologically with the righting reflex and electromyography (EMG), parasitologically with the total muscle larval count, histopathologically with hematoxylin and eosin and Mallory's trichrome stains, as well as immunohistochemically for myogenin as a marker of muscle regeneration. Additionally, serum muscle enzymes creatine kinase (CK) and lactate dehydrogenase (LDH), as well as muscle matrix metalloproteinases MMP1 and MMP9, were assayed. Finally, the immunological response was assessed by measuring the levels of the muscle inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukin-4 (IL-4). Our findings revealed that MSC therapy markedly improved muscle EMG and righting reflex, as well as the histopathological appearance of the muscles, reduced inflammatory cellular infiltrates, and increased myogenin immunostaining. It also reduced serum CK and LDH levels, as well as muscle INF-γ, TNF-α, IL-4, MMP1, and MMP9 levels. However, it had no effect on the total muscle larval count. Accordingly, due to its anti-inflammatory properties and muscle-regenerative effect, MSC therapy could be a promising new remedy for T. spiralis-induced myopathy.


"Improving with using" effect and mechanism analysis of electrodeposited poly(1,5-diaminoanthraquinone)/carbon cloth electrode for high-performance flexible supercapacitors.
As a robust and conductive substrate, carbon cloth (CC) has been modified with various pseudocapacitive materials to boost its electrochemical performance in flexible supercapacitors. Here, poly(1,5-diaminoanthraquinone) (PDAA) electrodeposited CC electrodes were developed and much higher areal specific capacitance was obtained in comparison with the functionalized CC (FCC). Most importantly, an unusual phenomenon of "improving with using" was found for the optimized one, FCC@PDAA-3, which exhibited the increased capacitance retention from 150.4% to 194.8% with increasing the number of cycles from 10,000 to 50,000. Such extraordinary cyclic life was mainly ascribed to the doping and electropolymerization of the encapsulated 1,5-diaminoanthraquinone (DAA) in the immobilized PDAA during the electrochemical cycles. These findings are expected to contribute to a deeper understanding of the pseudocapacitive materials evolution during long charging/discharging cycles, favoring the design of long-life supercapacitors for practical application.


Treatment strategies to resectable metachronous colorectal liver metastases after adjuvant oxaliplatin-based chemotherapy for primary colorectal cancer.
outcome of patients who develop resectable metachronous colorectal liver metastases (CLM) after adjuvant oxaliplatin-based chemotherapy for Stage III colorectal cancer (CRC) is not well defined and the value of preoperative chemotherapy is controversial. From 2006 to 2013, all patients undergoing liver resection for Class I metachronous CLM after adjuvant oxaliplatin-based chemotherapy for CRC, across 32 French academic centers, were included. Sixty-two patients with an average of 2 ± 1 CLM were included. Thirty-two (52%) patients received preoperative chemotherapy. There was no significant difference in the characteristics of CLM between patients with or without preoperative chemotherapy. After a median follow-up of 29 months, 3-year overall and disease-free survival rates were 79.8% and 34.6%, respectively. The median disease-free survival was not different in patients with or without preoperative chemotherapy (17 vs. 35 months respectively, p = 0.112). In multivariate analysis, only CEA level > 200 ng/ml was associated with the risk of recurrence (p = 0.027; OR = 4.7, 95% CI = 1.2-18.7). Liver resection provides a good outcome in patients with limited metachronous CLM after adjuvant oxaliplatin-based chemotherapy for CRC. The interest of preoperative chemotherapy is not obvious and should be tested in a prospective controlled study.


Diagnostic features of primary malignant lymphomas of the thyroid with monoclonal antibodies.
Primary malignant lymphomas (ML) of the thyroid are rare and their conclusive morphologic diagnosis is not always possible. The authors report diagnostic features of 11 cases of ML and one case of plasmacytoma of thyroid compared with chronic lymphocytic thyroiditis and undifferentiated carcinomas of thyroid in an immunohistochemical study using monoclonal antibodies (MoAb). The lymphoid nature of tumors could be identified in all cases with three MoAb on paraffin sections. In ML, tumor cells expressed leucocyte common antigen (Dako-LC+) with negativity for epithelial membrane antigen (Dako-EMA-) and cytokeratin (KL1-). Newer MoAb identifying B-cell (LN-1, LN-2, MB2) and T-cell-associated antigens (MT1, UCHL1) not denatured by fixation, revealed B-cell nature of tumor cells in all cases of ML. Among anti-B MoAb, LN-1 and MB2 were most consistent in their reactivity. In cryostat sections of three ML cases, the tumor cells expressed one or more B-cell-associated antigens. Plasmacytoma was negative for Dako-LC and KL1 but positive for Dako-EMA and monotypic cytoplasmic Ig.


Blood flukes (Digenea: Aporocotylidae) of epipelagic lamniforms: redescription of Hyperandrotrema cetorhini from basking shark (Cetorhinus maximus) and description of a new congener from shortfin mako shark (Isurus oxyrinchus) off Alabama.
We emend the original generic diagnosis for Hyperandrotrema Maillard and Ktari, 1978 , and redescribe its type species Hyperandrotrema cetorhini Maillard and Ktari, 1978 (Digenea: Aporocotylidae Odhner, 1912), based on the holotype and 2 paratypes collected from the heart of basking shark (Cetorhinus maximus). We also describe Hyperandrotrema walterboegeri Orélis-Ribeiro and Bullard n. sp. based on light and scanning electron microscopy of 6 adult specimens collected from the heart of a shortfin mako shark (Isurus oxyrinchus Rafinesque, 1810) captured from Viosca Knoll (29°11.70'N, 88°33.32'W; 123 km southwest of Dauphin Island, Alabama), northern Gulf of Mexico. Hyperandrotrema spp. infect lamniforms and differ from all other nominal aporocotylids at least by having a ventrolateral field of robust C-shaped spines (rather than transverse rows of minute, shaft-like spines), an inverse U-shaped intestine with extremely elongate ceca terminating near the level of the excretory bladder, and a common genital pore that comprises the dorsal opening of a common genital atrium. Adults of the new species exceeded 12 mm in total length, making them the largest of the nominal fish blood flukes. The new species further differs from H. cetorhini by the combination of having an adult body that is 7-8 times longer than wide, large midbody tegumental spines measuring 25-38 μm long × 10-12 μm wide, a long vas deferens 4-5% of the body length, a testis 9-11 times longer than wide, and a large ootype 105-150 μm long × 85-105 μm wide. This is the first report of Hyperandrotrema from the Gulf of Mexico and the second aporocotylid species reported from an epipelagic elasmobranch. Our results demonstrate that ecologically related (epipelagic, marine) and phylogenetically related (Lamniformes) definitive hosts are infected by morphologically similar (congeneric) fish blood flukes.


Antiarrhythmic and electrophysiological effects of SD-3212, a novel Na+ and Ca++ channel blocker, in anaesthetized dogs with myocardial infarction in comparison with its stereoisomer (SD-3211) and bepridil.
Antiarrhythmic and electrophysiological effects of SD-3212, a novel antiarrhythmic agent, which has both Na+ channel and Ca++ channel blocking activities, were compared with those of its (+)-stereoisomer, SD-3211, which has only a Ca++ channel blocking activity, and bepridil, a known Ca++ channel blocker with additional Na+ channel blocking activity, using the two-stage coronary ligation induced arrhythmia (24 h after the ligation of the left anterior descending coronary artery) and 7 day-old myocardial infarcted hearts in anaesthetized dogs. SD-3212 showed a dose-dependent antiarrhythmic effect on the two-stage coronary ligation induced arrhythmia. SD-3212 at a dose of 3 mg/kg reduced the arrhythmic ratio, i.e. ectopic beats per min divided by the sum of ectopic beats and sinus beats per min, significantly from 1 up to 12 min after the administration. Neither bepridil (1-6 mg/kg) nor SD-3211 (1 mg/kg) had an antiarrhythmic effect. SD-3212 (0.3-3 mg/kg) prolonged both the conduction time in the normal myocardium and the delayed potential in the infarcted myocardium in the 7 day-old myocardial infarcted hearts in anaesthetized dogs in a dose-dependent manner. This effect of SD-3212 was shown at coupling intervals of 150-1000 ms increasing with decreasing interval. In this respect, SD-3212 is similar to drugs which show fast recovery of Vmax from use-dependent block such as lidocaine. Bepidril (1-6 mg/kg) also prolonged these parameters in a dose-dependent manner, however, the prolongation induced by bedripil was limited to shorter coupling intervals as compared with that induced by SD-3212. SD-3212 (0.1-1 mg/kg) did not show this prolonging effect.(ABSTRACT TRUNCATED AT 250 WORDS)


The Application of Transposon Insertion Sequencing in Identifying Essential Genes in B. fragilis.
Essential genes are those that are indispensable for the survival of organism under specific growth conditions. Investigating essential genes in pathogenic bacteria not only helps to understand vital biological networks but also provides novel targets for drug development. Availability of genetic engineering tools and high-throughput sequencing methods has enabled essential genes identification in many pathogenic gram-positive and gram-negative bacteria. Bacteroides fragilis is one of the major bacteria specific of human gastrointestinal microbiota. When B. fragilis moves out of its niche, it turns into deadly pathogen. Here, we describe detailed method for the essential gene identification in B. fragilis. Generated transposon mutant pool can be used for other applications such as identification of genes responsible for drug resistance in B. fragilis.


Cloning and sequencing of cnf1 from Escherichia coli incriminated in mink and bovine colibacillosis.
Colibacillosis is responsible for significant losses to the mink and cattle industries. Previous work in our laboratory and by others has suggested that possession of cnf1, the gene encoding cytotoxic necrotizing factor (CNF1), may contribute to the virulence of isolates of E. coli from mink and cattle. The cnf1 gene from E. coli isolated from a mink with colisepticaemia and a bovid with scours was amplified and cloned as a 3.5 kb fragment, and the fragment was sequenced. The cnf1 sequences from the mink and bovine isolates of E. coli were compared to each other and to cnf1 sequences of E. coli from urinary tract and diarrhoea-associated infections of humans. The difference was only 7 nucleotides between the cnf1 sequences of the mink and bovine isolates of E. coli, which translated into 7 differences in amino acids. The cnf1 sequence of the mink isolate of E. coli had 15 nucleotide differences from the cnf1 sequences of the human isolate of E. coli (GenBank X70670), which translated into 11 differences in amino acids between these proteins. The cnf1 sequence of the bovine isolate of E. coli had 14 nucleotide differences from the cnf1 sequence of the human isolate of E. coli (GenBank X70670), which translated into 10 differences in amino acids between these proteins. The highly conserved sequences of the amino acids of CNF1 proteins make them a promising target for detection and control of the CNF1-producing E. coli involved in disease among various host species.


The correction of post-keratoplasty astigmatism.
The results of refractive surgery for post-keratoplasty astigmatism in 41 eyes are presented. Thirty-nine eyes regained a functional vision of 6/12 or better. Relieving incisions and compression sutures are the most useful procedures, but more than one operation may be required.


Usefulness of an electronic consultation system between primary care health centres and the rheumatology department of a tertiary hospital.
Rheumatic diseases account for almost 30% of consultations attended in Spanish primary care centres. The main objective was to analyse the demand for rheumatology consultations from Primary Care and their resolution using the electronic consultation system. Retrospective descriptive study of electronic consultations from primary care centres in the health area to the Rheumatology service of a tertiary hospital, between July 2020 and May 2021. The last 500 consecutive consultations were collected. Mean age of patients was 59.5 years; 74.2% were women. Main reasons for consultation were osteoporosis and treatment of patients with rheumatoid arthritis and spondyloarthritis under follow-up by the department. Mean response time was 2 days. Fifty-seven per cent of patients required outpatient appointments. Over 40% of queries were resolved thanks to the electronic consultation system in an average of 2 days, otherwise patients would have been referred to specialized care.


Physical state abnormality of erythrocyte membrane in myotonic dystrophy: a spin label study.
Biophysical abnormalities of the erythrocyte membrane in muscular dystrophies have been described by numerous authors. This work presents the results we have obtained on 23 subjects suffering from myotonic muscular dystrophy (MyD, Steinert disease) by the spin label method. Two types of fatty acid spin labels were used: 5-nitroxide stearic acid (5NS) and 16-nitroxide stearic acid (16NS) which probe the membranes respectively near their polar heads and in their hydrophobic core. We measured the classical order parameter, the saturation behaviour of the electron paramagnetic resonance signal, and the label apparent rotation correlation time as a function of the temperature, on fresh and in vitro stored red blood cells. With the 5NS label, no differences were found between controls and patients. With the 16NS label, a highly significant variation in the thermic behaviour of the membrane is observed in its hydrophobic and fluid core. This last result may suggest some similarities between the red blood cell membranes of adult MyD's and healthy children.


Management of the midface during rhytidectomy.
No nonsurgical technique can come close to rejuvenating the face like a cervicofacial rhytidectomy. However, one of the most difficult areas to improve during a facelift is the midface. The multi-vector high superficial musculoaponeurotic system (SMAS) facelift and extended lower-lid midface lift are important techniques that can adequately address the midface during rhytidectomy. The multi-vector high SMAS facelift is a natural extension of a traditional SMAS plication or imbrication facelift. The extended lower-lid midface lift can be an important adjunct during a facelift or as an independent procedure to address the midface.


Skin Color in Apple Fruit (Malus × domestica): Genetic and Epigenetic Insights.
Apple skin color is an important trait for organoleptic quality. In fact, it has a major influence on consumer choice. Skin color is, thus, one of the most important criteria taken into account by breeders. For apples, most novel varieties are so-called "mutants" or "sports" that have been identified in clonal populations. Indeed, many "sports" exist that show distinct phenotypic differences compared to the varieties from which they originated. These differences affect a limited number of traits of economic importance, including skin color. Until recently, the detailed genetic or epigenetic changes resulting in heritable phenotypic changes in sports was largely unknown. Recent technological advances and the availability of several high-quality apple genomes now provide the bases to understand the exact nature of the underlying molecular changes that are responsible for the observed phenotypic changes observed in sports. The present review investigates the molecular nature of sports affected in apple skin color giving arguments in favor of the genetic or epigenetic explanatory models.


Assessment of exposure to sexually explicit materials and factors associated with exposure among preparatory school youths in Hawassa City, Southern Ethiopia: a cross-sectional institution based survey.
According to the 2007 Ethiopian census, youths aged 15-24 years were more than 15.2 million which contributes to 20.6% of the whole population. These very large and productive groups of the population are exposed to various sexual and reproductive health risks. The aim of this study was to assess exposure to Sexually Explicit Materials (SEM) and factors associated with exposure among preparatory school students in Hawassa city, Southern Ethiopia. A cross-sectional institution based study involving 770 randomly selected youth students of preparatory schools at Hawassa city. Multi stage sampling technique was used to select study subjects. Data was collected using pre-tested and self-administered questionnaire. Data was entered by EPI INFO version 3.5.1 and analyzed using SPSS version 20.0 statistical software packages. The result was displayed using descriptive, bivariate and multivariate analysis. Statistical association was done for independent predictors (at p < 0.05). About 750 students were participated in this study with a response rate of 97.4%. Among this, about 77.3% of students knew about the presence of SEM and most of the respondents 566(75.5%) were watched SEM films/movies and 554(73.9%) were exposed to SE texts. The overall exposure to SEM in school youths was 579(77.2%). Among the total respondents, about 522(70.4%) claimed as having no open discussion on sexual issues with in their family. Furthermore, About 450 (60.0%) respondents complained for having no sexual and reproductive health education at their school. Male students had faced almost two times higher exposure to SEM than female students (95 % CI: AOR 1.84(C.I = 1.22, 2.78). Students who attended private school were more than two times more likely exposed to SEM than public schools (95 % CI: AOR 2.07(C.I = 1.29, 3.30). Students who drink alcohol and labelled as 'sometimes' were two times more likely exposed to SEM than those who never drink alcohol (95 % CI = AOR 2.33(C.I = 1.26, 4.30). Khat chewers who labelled "rarely", "sometimes" and "often" had shown higher exposure (95 % CI: AOR 3.02(CI = 1.65, 5.52), (95 % CI: AOR 3.40(CI = 1.93, 6.00) and (95 % CI: AOR 2.67(CI = 1.46, 4.86) than those who never chew khat, respectively. Regarding SEM access, school youths with label 'easy access were exposed in odds of six folds than youths of no access (95 % CI: AOR 5.64(C.I = 3.56, 8.9). High number of students was exposed to sexually explicit materials. Sex, school type, substance use and access to SEM were observed independent predictors of exposure to SEM. The current generation of young people is the healthiest, most educated, and most urbanized in history. However, there still remain some serious concerns. Most people become sexually active during adolescence. Premarital sexual activity is common and is on the rise worldwide. Rates are highest in sub Saharan Africa, where more than half of girls aged 15-19 are sexually experienced. Millions of adolescents are bearing children, in sub-Saharan Africa. More than half of women give birth before age 20. The need for improved health and social services aimed at adolescents, including reproductive health services, is being increasingly recognized throughout the world. Approximately 85 % of world adolescents live in developing countries. Each year, up to 100 million becomes infected with a curable sexually transmitted disease (STI). About 40 % of all new global human immunodeficiency virus (HIV) infections occur among 15-24 year olds; with recent estimates of 7000 infected each day. These health risks are influenced by many interrelated factors, such as expectations concerning early marriage and sexual relationships, access to education and employment, gender inequities, sexual violence, and the influence of mass media and popular culture. Furthermore, many adolescents lack strong stable relationships with parents or other adults whom they can talk to about their reproductive health concerns. Despite these challenges, programs that meet the information and service needs of adolescents can make a real difference. Successful programs help young people develop life-planning skill, respect the needs and concerns of young people, involve communities in their efforts, and provide respectful and confidential clinical services. Accordingly, the government of Ethiopia now works on improving adolescent's health as one part of MDG (Goal VI-halting transmission of HIV/AIDS, STI, and other communicable diseases) with a focus on adolescents, since they are most affected population. This finding, therefore, will benefit the government to partly evaluate the goal achieving through adolescents exposure status to sexually explicit materials and improvement of sexual issues free talk with in school with class mates and their family at home. For that matter, we authors decided to publish this finding in BMC Reproductive Health Journal so that on line access will be easy to all governing bodies that they use to re-plan their strategies for better product of plan. Moreover, Researchers, Practitioners, policy makers, Students, school leaders and professionals will also benefit from this finding for their future researches references, knowledge gain and practice.


Abnormal postprandial PYY response in insulin sensitive nondiabetic subjects with a strong family history of type 2 diabetes.
Gut-derived hormone peptide YY (PYY) is low in subjects with obesity and type 2 diabetes (T2D). However, it is unknown whether this is a primary defect or a consequence of metabolic disturbances. In this study, we aimed to assess whether low fasting and postprandial PYY secretion is an early defect, potentially promoting the development of obesity and T2D, and whether it is modified by macronutrient content. Prospective cross-sectional cohort study. Nine individuals with a strong family history of T2D (REL) and seven age and adiposity matched individuals with no family history of T2D (CON). Metabolic studies including hyperinsulinemic-euglycemic clamp, dual X-ray absorptiometry and two meal tests containing 1000 kcal with an either high fat (76%) or high carbohydrate (76%) content. Fasting and postprandial PYY levels were measured and analyzed for potential correlations with markers for adiposity and insulin resistance. Insulin sensitivity was not different between REL and CON. Fasting glucose, insulin, triglycerides and PYY were also not different between groups. However, the postprandial incremental area under curve (AUC) of PYY was significantly lower in REL after the high carbohydrate (HCHO) meal (+27.3 vs +60.6% increase from baseline, P=0.038). The AUC of insulin during HCHO meal correlated negatively with both AUC and fasting level of PYY (r=-0.58 and -0.60, respectively, P<0.05). A blunted postprandial PYY secretion is observed in a very early stage in the development of T2D in genetically susceptible individuals. This defect precedes the presence of insulin resistance and adiposity, and could therefore predispose to the development of T2D.


Effect of extracts of injured nerve on initiating the regenerative response in the hypoglossal nucleus in the rat.
The uptake of 2-deoxy-[14C]glucose (2-DG) by motor neurons in adult rat hypoglossal nuclei was studied 3 days after subepineural injection of 'crude' soluble protein extracts from intact and injured peripheral nerves into normal hypoglossal nerves. Injured nerve extracts were obtained from 'proximal' and 'distal' segments of sciatic nerves which were transected between two ligatures 3 days earlier. In one group of animals the hypoglossal nerve (experimental) was injected with a particular nerve extract. In another group of animals (control) the hypoglossal nerve was injected with physiological saline solution. Both proximal and distal nerve extracts caused a significant increase in 2-DG uptake. In turn, no 2-DG was detected after treatment with uncut nerve extracts or saline. These findings support the ideas that a substance(s) produced upon nerve injury is taken up by the axons and transported to the cell bodies where it triggers certain metabolic regenerative changes.


Prognostic and therapeutic relevance of phosphofructokinase platelet-type (PFKP) in breast cancer.
In the present study, we have explored the prognostic value of the Phosphofructokinase Platelet-type (PFKP) expression and its therapeutic relevance in metastatic breast cancer. PFKP immunohistochemistry was performed on Invasive ductal carcinomas (IDCs; n = 87) of breast, and its association with clinicopathological parameters were evaluated. Using online meta-analysis tools, PFKP's prognostic value was investigated in overall breast cancer as well as in triple negative subtype (TNBCs). For in vitro analysis, MDA-MB-231 cells model was used in order to elucidate mechanisms behind PFKP regulated glycolysis and its impact on cancer cell physiology. Therapeutic relevance of PFKP was further evaluated using PFKP siRNA and Quercetin. PFKP protein expression was found to be positively associated with nodal invasion (p = 0.009), receptor (ER & PR) negative status (p = 0.005 & p = 0.028) and reduced overall survival in breast cancer patients (p = 0.014). In MDA-MB-231 cells, quercetin treatment impaired PFKP-LDHA signaling axis thereby inhibiting aerobic glycolysis mediated increased migration of cancer cells. Our present study demonstrates that elevated PFKP levels are associated with basal cells/TNBC subtypes and might serve as prognostic indicator for TNBC patients. Ability of quercetin to inhibit aerobic glycolysis, cell migration and clonogenic potential of malignant breast cancer cells advocates possibility of quercetin in aggressive breast cancer treatment.


Preoperative superselective embolization of skull-base meningiomas: indications and limitations.
We evaluated the clinical significance of preoperative superselective embolization for skull-base meningiomas. The subjects consisted of 20 patients with skull-base meningiomas, and were classified into a preoperative embolized group and a non-embolized group. The volume of blood transfused during the operation, the length of the operative procedure and the neurological outcome were compared between the two groups. The results showed that, in tumors smaller than 6 cm, the blood lost during the operation was significantly less in the embolized group. In tumors larger than 6 cm, there was not difference in blood lost, perhaps because larger meningiomas tend to have tiny blood vessels that are unsuitable for preoperative embolization. There was no difference in the length of the operation between the two groups. The embolized group tended to show a better clinical outcome than the non-embolized group.


Cognitive reserve in secondary progressive multiple sclerosis.
Consistent with the cognitive reserve hypothesis, lifetime intellectual enrichment protects MS patients from cognitive impairment. As studies have focused predominately on patients with relapsing-remitting courses, it is unknown whether lifetime enrichment is protective against cognitive impairment in patients with secondary-progressive MS (SPMS), a more advanced disease course. Examine whether greater lifetime intellectual enrichment moderates/reduces the deleterious effect of SPMS on memory and cognitive efficiency. Twenty-five SPMS patients and 25 healthy controls (HC) completed neuropsychological tasks, yielding two composite scores: memory and cognitive efficiency. An estimate of lifetime enrichment was created from educational attainment and vocabulary knowledge. Regression analyses predicted memory and cognitive efficiency, with age, sex, intellectual enrichment and group (SPMS, HC) controlled in step one, and the interaction between intellectual enrichment and group evaluated within step two. Interactions emerged between intellectual enrichment and group when predicting memory (R (2)Δ=0.081, p = 0.041) and cognitive efficiency (R (2)Δ=0.064, p = 0.024), such that SPMS patients exhibited deficits relative to HCs at lower levels of enrichment, but these SPMS-related cognitive deficits were absent at higher levels of enrichment. Intellectual enrichment protects SPMS patients from cognitive impairment, thereby extending the cognitive reserve hypothesis to this more advanced MS disease course.


Fishing antitumor ingredients by G-quadruplex affinity from herbal extract on a three-phase-laminar-flow microfluidic chip.
A new method for fishing antitumor ingredients by G-quadruplex recognition from Macleaya cordata seeds extracts was established using a three-phase-laminar-flow-chip (TPL chip). The TPL chip integrated the separation of drugs from the complex ingredients and organic solvent extraction, simplifying pretreatment processes and reducing reagents and time. In addition, the chip method showed a lower false negative result, owing to the gentle membrane-free filtration process based on diffusion separation in microchannel. Four ligands with high content in alkaloids of Macleaya cordata seeds were selected, those are chelerythrine (CHE), sanguinarine (SAN), protopine (PRO), and allocryptopine (ALL), which demonstrated affinity with G-quadruplex and were potential for antitumor.


Recent advances in nucleotide analogue-based techniques for tracking dividing stem cells: An overview.
Detection of thymidine analogues after their incorporation into replicating DNA represents a powerful tool for the study of cellular DNA synthesis, progression through the cell cycle, cell proliferation kinetics, chronology of cell division, and cell fate determination. Recent advances in the concurrent detection of multiple such analogues offer new avenues for the investigation of unknown features of these vital cellular processes. Combined with quantitative analysis, temporal discrimination of multiple labels enables elucidation of various aspects of stem cell life cycle in situ, such as division modes, differentiation, maintenance, and elimination. Data obtained from such experiments are critically important for creating descriptive models of tissue histogenesis and renewal in embryonic development and adult life. Despite the wide use of thymidine analogues in stem cell research, there are a number of caveats to consider for obtaining valid and reliable labeling results when marking replicating DNA with nucleotide analogues. Therefore, in this review, we describe critical points regarding dosage, delivery, and detection of nucleotide analogues in the context of single and multiple labeling, outline labeling schemes based on pulse-chase, cumulative and multilabel marking of replicating DNA for revealing stem cell proliferative behaviors, and determining cell cycle parameters, and discuss preconditions and pitfalls in conducting such experiments. The information presented in our review is important for rational design of experiments on tracking dividing stem cells by marking replicating DNA with thymidine analogues.


Studies on the anesthetic mechanism of carbon dioxide by using Bombyx mori larvae.
The study of heartbeat variations of Bombyx mori larvae submitted to CO2 narcosis has provided new information on carbon dioxide anesthesia. Purely anoxiant action must be dismissed. Action at a nerve level is possible since CO2 produces the same effect as ether, which is a classical anesthetic.


Mapping the organization: a bibliometric analysis of nurses' contributions to the literature.
The aim of this study was to map an academic hospital's nursing contributions to the literature using bibliometric methods. Nurse executives continue to search for ways to share knowledge gained in the clinical setting. Manuscripts from clinical nurses must increase to advance the science of nursing practice and nursing administration. A search of electronic databases and curriculum vitae provided bibliographic data for University of Colorado Hospital (UCH) nurses from 1990 to 2012. Bibliometric techniques were used for publication counts and citation analysis. A review of the infrastructure supporting scholarly work was undertaken. A total of 191 journal articles, 9 books, 103 book chapters, 5 manuals, and 46 manual chapters were published by UCH nurses. Author productivity steadily increased. Citation analysis indicated that the works published were used by others. The h-index for UCH authors was 25. The hospital culture, interdisciplinary practice, and the role of the research nurse scientists had an impact on study results.


Design and synthesis of a biotinylated dopamine transporter ligand for the purification and labeling of dopaminergic neurons.
The design and synthesis of a new tool for labeling and purification of dopaminergic neurons is described.


Can screening for low vitamin D levels prevent bone health complications in paediatric oncology patients?
No international standards include vitamin D levels at diagnosis or during treatment. It is included in the Children's Oncology Group long-term follow-up guidelines. However, bone health complications (like osteopenia and atraumatic fractures) can occur at diagnosis or during treatment as well. In this small case series, we illustrate the complexity of bone health complications among our broad paediatric oncology population. If the vitamin D level is low we supplement the patient with one standard oral dose (150 000 units for 1-2 year olds, 300 000 units for 2-5 year olds and 600 000 units for >5 year olds). We do not adjust depending on diagnosis. Because of the potentially negative outcomes on short, medium and long term, we recommend checking vitamin D levels on diagnosis for all newly diagnosed patients. It is a simple, low cost test and one dose of oral supplementation can easily treat the deficiency.


Purification and properties of guanosine triphosphate cyclohydrolase II from Escherichia coli.
An enzyme that uses GTP as substrate for the formation in stoichiometric quantities of formate, inorganic pyrophosphate, and 2,5-diamino-6-hydroxy-4-(ribosylamino)pyrimidine-5'-phosphate has been purified 2200-fold from extracts of Escherichia coli B. This enzyme is named GTP cyclohydrolase II to distinguish it from a previously studied E. coli enzyme, named GTP cyclohydrolase (and called GTP cyclohydrolase I in this paper), that catalyzes the first of a series of enzymatic reactions leading to the biosynthesis of the pteridine portion of folic acid (Burg, A. W., and Brown, G. M. (1968) J. Biol. Chem. 243, 2349-2358). Some of the properties of GTP cyclohydrolase II are: (a) divalent cations are required for activity (Mg2+ is most effective); (b) its molecular weight, estimated by filtration on Sephadex G-200, is 44,000; (c) the K-m for GTP is 41 mum; (d) its pH optimum is 8.5; and (e) its activity is inhibited by inorganic pyrophosphate, one of the products of the reaction. Compounds not used as substrate are: GDP, GMP, guanosine, dGTP, ATP, ITP, and XTP. Properties a, b, c, and e (above), as well as the nature of the products, distinguish this enzyme from GTP cyclohydrolase I. Since GTP cyclohydrolase II apparently is not concerned with the biosynthesis of folic acid, the possible physiological role of this enzyme in the biosynthesis of riboflavin is considered in the light of the present investigations and the previously published work on riboflavin biosynthesis by other investigators.


A randomized controlled trial of a preventive intervention for the children of parents with depression: mid-term effects, mediators and moderators.
In a parallel randomized controlled trial the effectiveness of the family- and group-based cognitive-behavioural "Gug-Auf" intervention in preventing depression in children of depressed parents was evaluated. We hypothesized that the intervention would be associated with reduced incidence of depression at 15 months as well as with reduced symptom severity at 6, 9, and 15 months. We also explored the role of a number of mediators and moderators. Families were included if a parent (n = 100, mean age = 46.06, 61% female) had experienced depression and children (n = 135, aged 8-17 years, 53% female) had no mental illness. Families (91.5% German) were randomly allocated (50:50 block-wise; stratified by child age and parental depression) to the 12-session "GuG-Auf" intervention or no intervention. Outcomes were assessed (on an intention-to-treat basis) at 0-(T1), 6-(T2), 9-(T3) and 15-months (T4) after baseline. Primary outcome (onset of depression; T4) was assessed with standardized (blinded) clinical interviews. Secondary (unblinded) outcome was risk of depression (at T2-T4) indicated by self- and parent-reported symptoms of internalizing, externalizing and depressive disorder. Potential mediators were emotion regulation, attributional style, knowledge of depression and parenting style. Potential moderators were parental depression severity and negative life events. None of the children who received the intervention developed depression, whereas two of those in the control group did. The intervention significantly reduced depression risk (indicated by severity of self-reported internalizing symptoms) at T3 (p = .027, d = -0.45) and T4 (p = .035, d = -0.44). Both groups showed reduced depressive symptoms (p = .029, d = -0.44). Cognitive problem-solving and negative parenting emerged as mediators. There was no evidence that the intervention was associated with parent-reported internalizing symptoms or externalizing symptoms. No adverse events were observed. Children of parents with depression showed an increase in self-reported (but not parent-reported) internalizing symptoms over time. This increase was not present in children who received the GuG-Auf intervention. The intervention was not associated with changes in externalizing symptoms. Conclusions regarding prevention of the onset of depression were not possible. Despite some limitations in the generalizability, these findings contribute to reducing the burden of youth depression. The trial was registered on 16/04/2014 at ClinicalTrials.gov ( NCT02115880 ) and study protocol published in BMC Psychiatry ( https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-014-0263-2 ).


Ratio of serum vascular endothelial growth factor to platelet count correlates with disease activity in a patient with POEMS syndrome.
Vascular endothelial growth factor (VEGF) is known to be involved in the pathogenesis of POEMS (polyneuropathy, organomegaly, endocrine disorder, M-protein, and skin lesion) syndrome. Because platelets have recently been recognized as transporters of VEGF, enhanced blood coagulation activity in this syndrome may accelerate vasopermeability by releasing VEGF from platelets in vivo. Here we report a case of POEMS syndrome with anasarca showing a high ratio of serum VEGF to platelet count, indicative of massive VEGF release from aggregated platelets in vivo. Changes in the ratio clearly reflected disease activity. This observation suggests that the ratio of serum VEGF to platelet count is more precise in monitoring disease activity than serum VEGF alone, and that VEGF released in vivo is critically involved in the pathogenesis of POEMS syndrome, causing hypervasopermeability.


Urinary biomarkers profiles in patients with neurogenic detrusor overactivity according to their neurological condition.
The aim of this study was to investigate the disease-specific urinary levels variations of neurotrophins (NGF, BDNF), mediators of inflammation (TGFβ-1, PGE-2) and markers of extracellular matrix alterations (TIMP-2) in patients with multiple sclerosis (MS) spinal cord injury (SCI), or spina bifida (SB), and neurogenic detrusor overactivity (NDO). A prospective single-center study was conducted between March 2015 and March 2017. Patients aged over 18 years old, with neurological disease, with a urodynamic diagnosis of NDO were included. The urinary levels of NGF, BDNF, TIMP-2, PGE 2, and TGF-β1 were measured using dedicated ELISA kits. Forty-one patients were included: 6 with MS, 20 with SCI, and 15 with spina bifida. The average urinary level of NGF/Cr was significantly higher in MS patients compared to other neurologic populations (8 vs. 0.56 vs. 1.25 pg/mg of creatinine; p = 0.001) as well for the average urinary level of BDNF (88.3 vs. 5 vs. 4.8 pg/mg of creatinine; p < 0.0001). SCI patients had a significantly lower level of TGFβ-1 than SB patients (p = 0.04). The urinary level of PGE2 was significantly correlated with the Body Mass Index (r = 0.61; p = 0.0002). All NDO may not be created equal from the molecular standpoint. Multiple sclerosis patients had higher urinary levels of neurotrophins than in other neurologic populations with NDO. Urinary TGFβ-1, a strong determinant of extracellular matrix, was significantly higher in spina bifida patients compared to SCI patients. These findings underscore the importance of using and interpreting those possible urinary markers in a disease-specific fashion.


Sustained Reduction in Pulmonary Artery Pressures and Hospitalizations During 2 Years of Ambulatory Monitoring.
Therapy guided by pulmonary artery (PA) pressure monitoring reduces PA pressures and heart failure hospitalizations (HFH) during the first year, but the durability of efficacy and safety through 2 years is not known. The CardioMEMS Post-Approval Study investigated whether benefit and safety were generalized and sustained. Enrollment at 104 centers in the United States included 1200 patients with NYHA Class III symptoms on recommended HF therapies with prior HFH. Therapy was adjusted toward PA diastolic pressure 8-20 mmHg. Intervention frequency and PA pressure reduction were most intense during first 90 days, with sustained reduction of PA diastolic pressure from baseline 24.7 mmHg to 21.0 at 1 year and 20.8 at 2 years for all patients. Patients completing two year follow-up (n = 710) showed similar 2-year reduction (23.9 to 20.8 mmHg), with reduction in PA mean pressure (33.7 to 29.4 mmHg) in patients with reduced left ventricular ejection. The HFH rate was 1.25 events/patient/year prior to sensor implant, 0.54 at 1 year, and 0.37 at 2 years, with 59% of patients free of HFH during follow-up. Reduction in PA pressures and hospitalizations were early and sustained during 2 years of PA pressure-guided management, with no signal of safety concerns regarding the implanted sensor.


History of dietary treatment from Wilder's hypothesis to the first open studies in the 1920s.
In the ketogenic diet (KD) history, Wilder is often mentioned as the first author to report on the use of KD for patients with epilepsy. Our article aimed to understand how Wilder formulated the hypothesis of the KD effectiveness for patients with epilepsy, and how the KD was used and spread in the 1920s. In 1921, Wilder published two articles on the effects of ketonemia on epilepsy. He first reported on the interest of fasting for patients with epilepsy, suggesting that the benefits of fasting on seizures might be dependent on ketonemia. He then hypothesized that equally good results could be obtained with a KD, very rich in fat and very low in carbohydrate, which would provoke ketogenesis, and observed the effects of this diet on three patients for the first time. Following the publication of Wilder articles, 9 papers on KD were published during the 1920s, involving more than 400 patients with epilepsy. Ketogenic diet therapies (KDT) are now evidence-based treatments of epilepsy. Available experimental data do not confirm the role of ketosis as the unique mechanism of the KD. The KD is still explored to understand all the underlying mechanisms.


Norwalk virus infection associates with secretor status genotyped from sera.
ABO histo-blood group type and secretor status are two genetically determined factors that contribute to resistance and susceptibility to Norwalk virus (NV). Archived serum samples but not saliva samples are available from NV and many other norovirus challenge studies and outbreaks. A person's ABO phenotype is easily determined from their archived sera, but the individual's secretor phenotype cannot easily be ascertained without saliva. We now report that a person's secretor genotype can also be determined from the archived serum samples. Of the 51 volunteers who participated in a NV challenge study, all eight non-secretors were resistant to NV infection, all of the 42 NV-infected volunteers were secretor positive, and a single uninfected secretor was histo-blood group type B. In agreement with a previous report, secretor status was most predictive of risk of NV infection. The methods described in this report should rapidly improve our knowledge of the associations between carbohydrate antigen expression and susceptibility to different strains of the non-cultivatable noroviruses by enabling retrospective studies from previously collected volunteer challenge and outbreak sera.


Novel smart fiber/metal/chitosan composite as a filter for self-detoxifying photocatalytic wastewater remediation and biomedical applications.
Wastewater treatment remains the most significant delinquent issue world-wide. Generally, wastewater treatment involves filtration followed by acidified de-emulsification through photocatalytic reduction. The aim of the present study is to reduce the use of nanoparticles in wastewater treatment and also to find an appropriate alternative to replace cotton fiber filters used in water treatment plant. The cotton fiber filters are highly prone to bacterial film development leading to bactericidal degradation of the fibers. We developed a ZnO-chitosan nanocomposite coated fiber for wastewater treatment to enhance its photocatalytic activity under acidic condition. The fiber showed high degree of photocatalytic degradation activity, reducing rhodamine B dye, chemical oxygen demand and chromium levels in the synthetic wastewater to 37, 79 and 51% respectively under highly acidic condition. Additionally, ZnO-chitosan nanocomposite did not cause mortality on Danio rerio embryo after 72 h incubation. The ZnO-chitosan nanocomposite coated fiber showed strong antibacterial activity against Escherichia coli and Staphylococcus aureus with a reduction of 96% and 99% respectively. This study demonstrated the potential of a novel smart fiber in wastewater treatment and biomedical applications.


[Preclinical models to establish innovative therapy strategies : Ex‑vivo assessment of head and neck tumor chemo- and immune responses].
The pharmacological treatment of head and neck squamous cell carcinoma (HNSCC) is currently experiencing an expansion of the spectrum of targeting therapies. It can be expected that use of immune modulators, e.g., checkpoint-inhibitors, and their combination with chemotherapy will lead to a plethora of therapeutic options in the near future, from which the best one for the individual patient can be selected. HNSCCs are heterogeneous in their biology, and responses to chemotherapy are nonuniform and often only observable in subgroups. It would be valuable to know the chance of success of a particular treatment in advance. Evidence-based selection of the best individual treatment is difficult, since predictive biomarkers which are assessable prior to the treatment decision and reliably indicate the suitability of particular therapeutics are lacking. Pretherapeutic predictive ex-vivo chemoresponse testing of HNSCC biopsy specimens could enable identification of responders and allow a more suitable therapy regimen to be chosen for potential non-responders, without exposing them to likely ineffective therapy attempts. However, early ex-vivo assays failed regarding reliable prediction of therapeutic success, even with tolerable doses of pharmaceuticals and, in particular, their combinations. Predictive testing was hence deemed improper for the clinic. Improved methodology has now led to a reappraisal of predictive testing and its additional use in analysis of antitumor immune responses ex vivo. Here we describe recent advances and new results from ex-vivo chemoresponse testing of HNSCC and highlight their ability to facilitate establishment of innovative therapy strategies.


Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity.
Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.


Effects of temperature on tertiary nitrification in moving-bed biofilm reactors.
The effect of wastewater temperature on the rate of nitrification was studied in two pure-oxygen moving-bed biofilm reactors, fed on secondary effluent from a municipal wastewater treatment plant. The first Reactor (R1) was operated under ammonia-limiting conditions, while the second Reactor (R2) was operated under oxygen-limiting conditions. Quite surprisingly, the former showed a negligible influence of thermal changes on nitrification rates, while the latter showed a much higher dependence. In this paper, a temperature coefficient "theta" has been defined as the actual "intrinsic" biological temperature coefficient, similar to the corresponding coefficient that is usually adopted for the design of activated-sludge processes. In addition, an "apparent" coefficient theta(a) has been quantified independently, which was calculated according to the actual values of nitrification rates at different temperatures. The actual biological temperature coefficient "theta", ranged between 1.086 and 1.109 (average value 1.098) under ammonia-limiting conditions, while under oxygen-limiting conditions was in the range 1.023-1.081 (average value 1.058). The apparent value theta(a) was near to unity (i.e. no temperature effect) under ammonia-limiting conditions, while only under oxygen-limiting conditions and at constant dissolved oxygen concentration "theta(a)" coincided with "theta". An explanation was given that, under oxygen-limiting conditions, the specific biomass activity (i.e. the ratio of nitrification rate to biomass concentration) was strongly influenced by the combined effects of oxygen penetration through the biofilm and effluent temperature.


Biofilm stimulating activity of solanidine and Solasodine in Pseudomonas aeruginosa.
Biofilm formation has reported as an important virulence associated properties of Pseudomonas aeruginosa that is regulated by quorum-sensing associated genes. Biofilm and quorum-sensing interfering properties of steroidal alkaloids, Solanidine and Solasodine were investigated in the present study. Biofilm formation capacity and relative expression level of five studied genes(lasI, lasR, rhlI, rhlR and algD) were significantly increased dose-dependently after treatment with sub-inhibitory concentrations (32 and 512 µg/ml) of the both Solanidine and Solasodine. Biofilm formation capacity was more stimulated in weak biofilm formers(9 iaolates) in comparison to the strong biofilm producers(11 isolates). The lasI gene was the most induced QS-associated gene among five investigated genes. Biofilm inducing properties of the plants alkaloids and probably medicines derived from them has to be considered for revision of therapeutic guidelines. Investigating the biofilm stimulating properties of corticosteroids and other medicines that comes from plant alkaloids also strongly proposed.


Sex-specific quantitative trait loci contribute to normal variation in bone structure at the proximal femur in men.
Bone structure is an important determinant of osteoporotic fracture. In women, bone structure is highly heritable, and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed at establishing the heritability of bone structure at the proximal femur, identifying QTL contributing to normal variation in bone structure, and determining which QTL might be sex-specific. Bone structure at the proximal femur was measured in 205 pairs of brothers age 18-61. Heritability was calculated, and linkage analysis performed on phenotypes at the proximal femur. Heritability estimates ranged from 0.99 to 0.39. A genome wide scan identified suggestive QTL (LOD>2.2) for femoral shaft width on chromosome 14q (LOD=2.69 at position 99 cM), calcar femorale at chromosome 2p (LOD=3.97 at position 194 cM) and at the X chromosome (LOD=3.01 at position 77 cM), femoral neck width on chromosome 5p (LOD=2.28 at position 0 cM), femoral head width on chromosome 11q (LOD=2.30 at position 131 cM) and 15q (LOD=3.11 at position 90 cM), and pelvic axis length on chromosome 4q (LOD=4.16 at position 99 cM) and 17q (LOD=2.80 at position 112 cM). Comparison with published data in 437 pairs of premenopausal sisters from the same geographical region suggested that 3 of the 7 autosomal QTL were male-specific. This study demonstrates that bone structure at the proximal femur in healthy men is highly heritable. The occurrence of sex-specific genes in humans for bone structure has important implications for the pathogenesis and treatment of osteoporosis.


RNA processing-associated molecular mechanisms of neurodegenerative diseases.
Dysfunctions of RNA processing and mutations of RNA binding proteins (RBPs) play a fundamental role in the pathogenesis of many neurodegenerative diseases. To elucidate the function of RNA processing and RBPs mutations in neuronal cells and to increase our understanding on the pathogenic mechanisms of neurodegeneration, I have reviewed recent advances on RNA processing-associated molecular mechanisms of neurodegenerative diseases, including RBPs-mediated dysfunction of RNA processing, dysfunctional microRNA (miRNA)-based regulation of gene expression, and oxidative RNA modification. I have focused on neurodegeneration induced by RBPs mutations, by dysfunction of miRNA regulation, and by the oxidized RNAs within neurons, and discuss how these dysfunctions have pathologically contributed to neurodegenerative diseases. The advances overviewed above will be valuable to basic investigation and clinical application of target diagnostic tests and therapies.


Cells lytically infected with Epstein-Barr virus are detected and separable by immunoglobulins from EBV-seropositive individuals.
The role of Epstein-Barr virus (EBV) lytic cycle gene expression in lymphocytes in the pathogenesis of EBV-associated diseases is incompletely understood. The ability to physically separate lytically induced from latently infected cells from the same population and to examine them in parallel would significantly enhance understanding of the viral, cellular, and environmental factors that govern susceptibility of an EBV-infected cell to lytic cycle induction stimuli at the single cell level. This study demonstrates, using a flow cytometry-based system, that human serum immunoglobulins from individuals immune to EBV reproducibly discriminate between and can be used to physically separate lytically induced from latently infected B cells. Using this new quantitative and sensitive technique, two novel observations about lytic cycle activation were made. First, the kinetics of lytic cycle activation by histone deacetylase inhibitors is more rapid than induction by a DNA methyl transferase inhibitor. Second, butyrate-treated cells which are initially refractory to lytic cycle activation can be induced upon subsequent exposure to the inducing agent. Therefore, susceptibility to lytic cycle induction of a latently infected B cell is governed by environmental and physiologic factors and not by permanent cellular or viral genetic changes.


A simple method for exposing the external jugular vein for placement of a permanent transvenous pacing catheter electode.
A method is presented for cannulating the external jugular vein and implanting a pacemaker through one incision. No increase in morbidity over the conventional methods has been demonstrated. This technique is an attractive alternative to the standard emthods in use.


Innovation in cardiovascular drugs: drug development portfolios. 3-4 March 1999, London, UK.
This conference, organized by SMi, brought together representatives from some of the leading companies in cardiovascular (CV) drug development. The two-day meeting was chaired by Dr Ajay Kakkar (Thrombosis Research Institute, London, UK) and covered drug development portfolios, genetic approaches to therapy and innovative therapeutic strategies.


The influence of time of maternal exposure to 2,4,5,2',4',5'-hexachlorobiphenyl on its accumulation in their nursing offspring.
2,4,5,2',4',5'-Hexachlorobiphenyl (6-CB) is mobilized from rodent tissues during the lipid depletion associated with food restriction or lactation, the latter condition resulting in the substantial elimination of the maternal body burden of the chemical to nursing offspring. The present study was undertaken to determine whether the rate and/or magnitude of accumulation of 6-CB in nursing offspring differed with time following PCB administration to the maternal animal. Female ICR mice were administered two doses of 6-CB. Group I animals received [14C]-6-CB as weanlings (15-20 g) followed by unlabeled 6-CB 5 weeks later, after mating, on Day 1 of gestation. Group II received unlabeled 6-CB as weanlings and [14C]-6-CB on Day 1 of gestation. Thus, 14C identified the mobilization and elimination of either the first or the second dose of 6-CB in the treatment groups (I = [14C]-6-CB, 6-CB; II = 6-CB, [14C]-6-CB). Both groups of animals retained approximately 80% of the administered radiolabeled dose. The tissue distribution of [14C]-6-CB in group II as a percentage of the body burden was not different from that in group I as determined from maternal tissue concentrations on Day 14 of gestation. The percentage of the maternal body burden of [14C]-6-CB accumulated in suckling offspring of group II mothers was significantly greater than that in group I offspring on Day 1 (I, 2.2 +/- 0.5%; II, 3.5 +/- 0.4%), Day 3 (I, 14.8 +/- 1.9%; II, 24.6 +/- 2.7%), Day 5 (I, 16.8 +/- 1.4%; II, 24.8 +/- 0.8%), and Day 12 (I, 32.3 +/- 0.5%; II, 45.5 +/- 1.7%) postpartum. This differential elimination was reflected in the t1/2 of elimination of the radiolabeled dose from parametrial fat during lactation, which was significantly longer in group I (14 days) than group II maternal animals (9 days). The observations that the last dose of 6-CB administered was the first to be mobilized from the whole animal, and that this was reflected in 6-CB release from parametrial fat, suggest that this highly lipophilic chemical is not homogeneously distributed within storage depots.


Does elevated glutathione protect the cell from H2O2 insult?
Utilizing glutathione ethyl ester (GSH-EE), the glutathione (GSH) level of lens epithelial cells can be increased as much as 1.9-fold. The epithelial cells maintain the additional GSH in the reduced form. This system was utilized to examine the relative effectiveness of cells with elevated GSH to withstand H2O2 insult. Three parameters were investigated, 86Rb accumulation, a measure of membrane function, ATP levels, an indication of overall metabolism and glyceraldehyde-3-phosphate dehydrogenase (GPD) activity, indicating intracellular enzyme susceptibility to oxidative insult. Under oxidative stress, much of the GSH is in the oxidized form but upon removal of the stress, rapidly returns to the reduced state. However, a loss of approximately 20% in GSH equilibrium levels has been consistently observed. Elevated GSH does not significantly increase the cells' ability to withstand or recover from oxidative stress. Indeed, elevated GSH was found to be somewhat deleterious, causing a decreased ability to recover from oxidative insult. However, in the case of GPD, a significant protection of activity was observed. The overall conclusion is that elevating intracellular GSH concentration does not increase the cells' overall ability to withstand oxidative damage.


Transferred cross-relaxation and cross-correlation in NMR: effects of intermediate exchange on the determination of the conformation of bound ligands.
Exchange transferred effects in solution-state NMR experiments allow one to determine the conformation of ligands that are weakly bound to macromolecules. Exchange-transferred nuclear Overhauser effect spectroscopy ('TR-NOESY') provides information about internuclear distances in a ligand in the bound state. Recently the possibility of obtaining dihedral angle information from a ligand in the bound state by exchange-transferred cross-correlation spectroscopy ('TR-CCSY') has been reported. In both cases the analysis of the signal amplitudes is usually based on the assumption that rapid exchange occurs between the free and bound forms of the ligand. In this paper we show that the fast exchange condition is not easily attained for observing exchange-transferred cross-correlation effects even in systems where exchange-transferred NOE can be observed. Extensive simulations based on analytical expressions for signal intensities corresponding to fast, intermediate, and slow chemical exchange have been carried out on a test system to determine the exchange regimes in which the fast exchange condition can be fulfilled for successfully implementing TR-NOESY and TR-CCSY.


Left atrial minimum volume and reservoir function as correlates of left ventricular diastolic function: impact of left ventricular systolic function.
Left atrial (LA) maximum volume (LAV(max)) is an indicator of left ventricular (LV) diastolic function. However, LAV(max) is also influenced by systolic events, whereas the LA minimum volume (LAV(min)) is directly exposed to LV pressure. The authors hypothesised that LAV(min) may be a better correlate of LV diastolic function than LAV(max). Cross-sectional. University hospital. 357 participants from a community-based cohort study. LA volumes and reservoir function, measured as total LA emptying volume (LAEV) and LA emptying fraction (LAEF), were assessed by real-time three-dimensional echocardiography. LV diastolic function was assessed by trans-mitral early (E) and late (A) Doppler velocities and mitral early diastolic velocity by tissue-Doppler (e'). LV systolic function was assessed by LV ejection fraction (LVEF) and global longitudinal strain (GLS) by speckle-tracking. LAV(min) significantly increased with worsening diastolic dysfunction (p<0.001), whereas the increase in LAV(max) was less pronounced (p=0.07). LAEV and LAEF decreased with worsening diastolic dysfunction (both p<0.001). In linear regressions, LAV(min) and LAV(max) were significant predictors of E/e', with higher parameter estimates for LAV(min). In multivariate models, LAV(min) resulted strongly associated with E/e' (β=0.45, p<0.001), whereas LAV(max) was not (β=-0.16, p=0.08). LA reservoir function was better associated with GLS than LVEF. In multivariate analyses, GLS was significantly associated with LAV(max) (β=-0.15, p=0.002), LAEV (β=-0.37, p<0.001) and LAEF (β=-0.28, p<0.001) but not with LAV(min). LAV(min) is a better correlate of LV diastolic function than LAV(max). The impact of LV longitudinal systolic function on LA reservoir function might explain the weaker relation between LAV(max) and LV diastolic function.


Survival Outcomes in T3 Laryngeal Cancers: Primary Total Laryngectomy vs. Concurrent Chemoradiation or Radiation Therapy-A Meta-Analysis.
The management of cT3 laryngeal cancers remains controversial, with studies recommending surgical or non-surgical approaches. Despite the many papers that have been published on the subject, there is a lack of studies showing which treatment has better results in terms of survival. To determine the difference in survival outcomes following total laryngectomy (TL), concurrent chemoradiation (CRT) or radiation therapy (RT) alone in T3 laryngeal cancers. Search of PubMed, Scopus, and Google Scholar databases from 1995 to 2023 employing specific keywords and Boolean operators to retrieve relevant articles. Statistical analysis was conducted using a random-effects model, and heterogeneity was evaluated using the Q-test and I2 statistic. Funnel plot asymmetry was assessed using rank correlation and regression tests. The qualitative data synthesis comprised 10,940 patients from 16 included studies. TL was performed in 2149 (19.4%), CRT in 6723 (61.5%), RT in 295 (2.7%), while non-surgical treatment was not specified in 1773 (16.2%) patients. The pooled 2-year overall survival (OS) rates were TL = 73%, CRT = 74.7%, RT = 57.9%, 3-year OS rates were TL = 64.3%, CRT = 62.9%, RT = 52.4%, and 5-year OS rates were TL = 54.2%, CRT = 52.7%, RT = 40.8%. There was a significant heterogeneity in the included studies. There was no statistically significant difference in 2-year OS (logOR= -0.88 (95% confidence interval (CI): -1.99 to 0.23), p = 0.12), 3-year OS (logOR = -0.6 (95% CI: -1.34 to 0.15), p = 0.11), and 5-year OS (logOR = -0.54 (95% CI: -1.29 to 0.21), p = 0.16) between TL and CRT. Instead, there was significant difference in 2-year OS (logOR= -1.2383 (95% CI: -2.1679 to -0.3087), p = 0.009), 3-year OS (-1.1262 (95% CI: -1.6166 to -0.6358), p < 0.001), and 5-year OS (-0.99 (95% CI: -1.44 to -0.53)), p < 0.001) between TL and RT alone. TL followed with adjuvant (chemo)radiation on indication and CRT with salvage surgery in reserve appear to have similar OS outcomes. Both resulted in better OS outcomes compared to RT alone in the treatment of T3 laryngeal cancers. If patients are unfit for chemotherapy, making CRT impossible, surgery may become the choice of treatment.


Spinal subarachnoid metastasis from primary intracranial glioblastoma multiforme.
Twenty-five patients with glioblastoma multiforme were autopsied at our institution in 7 years. Spinal cords were examined in 20 and 5 were found to have spinal leptomeningeal metastases. Clinical and neuropathological findings of these 5 patients are presented and factors possibility influencing such spread are analyzed. Review of previous studies of intracranial glioblastomas discloses only 14 reported cases with spinal leptomeningeal metastases confirmed at autopsy since 1931. We conclude that spinal leptomeningeal metastases in glioblastoma multiforme are a common occurrence. These findings are of little significance at present with our poor success at control of the primary lesion. Frequency of involvement of the spinal subarachnoid space will be significant, when we are able to better treat the primary tumor. Knowledge of the significant possibility of this phenomenon will allow earlier and more frequent clinical diagnosis.


Clinical phenotypes of embolic strokes of undetermined source.
The embolic stroke of undetermined source (ESUS) represents a heterogeneous clinical entity. The aim of this study was to investigate whether distinct clinical phenotypes may be identified in the ESUS population. We retrospectively identified consecutive patients hospitalized for acute ischemic stroke who met the ESUS diagnostic criteria. Baseline characteristics and diagnostic workup findings were collected. Hierarchical cluster analysis was carried out to classify clinical features and identify different groups of ESUS patients. One hundred twenty-seven patients with a mean age of 68.6 (12.5) years were included. Three main clusters were identified. The first cluster associated young age, male sex, presence of patent foramen ovale, and posterior circulation infarct. The second phenotype linked hypertension, severe stroke, left atrial cardiopathy, diabetes mellitus, and involvement of multiple vascular territories. The third cluster gathered smoking, dyslipidemia, ipsilateral vulnerable sub-stenotic carotid plaque, and infarct of anterior vascular territory. Distinct clinical phenotypes have been identified within the ESUS population, which may supply clues to the underlying pathogenic mechanisms.


Mesenteric fibromatosis associated with familial polyposis.
This patient represents the 25th case report of mesenteric fibromatosis in patients with Gardner's syndrome. Her family genealogy reveals polyposis of the colon in nine members in four generations. In addition, one member has papillary carcinoma of the thyroid and one has newly discovered osteomas. To our knowledge, this family may be the first to manifest this combination of extracolonic lesions with familial polyposis, and the case supports a single-gene etiology for the complete syndrome.


Health-related quality of life after treatment for neoplasia of the major salivary glands: a pilot study.
Treatment of malignancy of the salivary glands risks damage to the cranial nerves, and clinicians' traditional view has been that this will result in adverse effects on physical function and subsequent health-related quality of life (QoL). Preservation of nerves has been advocated to lessen this impact, but we know of no evidence that sacrifice of the facial nerve has any effect on subsequent QoL. We collected data prospectively before and after operation for all malignancies of the major salivary glands treated over five years using two health-related QoL questionnaires: the University of Washington Quality of Life Questionnaire and the Patient Concerns Inventory. Fifteen of17 eligible patients fulfilled the inclusion criteria by having assessments completed both before and after operation. Scores for QoL after treatment of cancer of the submandibular gland dropped at six months, but had resolved to more than 80% of the pretreatment score by a year, with the exception of the domains taste and saliva. The four patients who had weakness of the facial nerve after treatment had appreciable reductions in the physical function components of the QoL domains, but no significant reduction in the social-emotional domains. Use of the Patient Concerns Inventory enables tailoring of services towards those clinicians who a patient feels are potentially most likely to help alleviate factors that have an adverse effect on QoL. Sacrifice of the facial nerve in malignant parotid gland disease results in a considerable reduction in functional health-related QoL scores. Methods to ensure clearance of the tumour while limiting the effects on facial nerve function should always be considered.


The Ricochet-Scepter Technique: A Balloon-Assisted Technique to Achieve Outflow Access During Pipeline-Assisted Coil Embolization of a Near-Giant Internal Carotid Artery Ophthalmic Aneurysm.
Flow diversion with or without coil embolization has become the first-line treatment for large or giant paraclinoid internal carotid artery intracranial aneurysms. Oftentimes, these sizable aneurysms impose anatomical challenges to endovascular treatment through limiting both distal outflow access and maintenance of distal vessel purchase during catheter reduction, which are required for successful stent placement. Various strategies to obtain and maintain distal access within the parent vessel have been described previously; however, new techniques may need to be employed when more standard maneuvers fail. This paper depicts a case of successful flow diversion of a near-giant internal carotid artery ophthalmic aneurysm in a middle-aged female patient using a balloon-assisted technique, designated the Ricochet-Scepter technique, to achieve distal outflow access followed by secondary system reduction via a stent retriever after standard maneuvers had failed. Giant, wide-neck aneurysms present treatment challenges that may require using adjunctive devices and advanced endovascular techniques. When routine strategies for gaining distal outflow access fail, the Ricochet-Scepter technique is a viable option for achieving distal access.


Definitive hematopoietic stem/progenitor cells from human embryonic stem cells through serum/feeder-free organoid-induced differentiation.
Ex vivo production of hematopoietic stem/precursor cells (HSPCs) represents a promising versatile approach for blood disorders. To derive definitive HSPCs from human embryonic stem cells (ESCs), we differentiated mesodermally specified embryoid bodies (EBs) on gelatin-coated plates in serum/feeder-free conditions. Seven-day EB maturation followed by an 8-day differentiation period on OP9 cells provided the highest number of definitive (CD34+ CD235a-, 69%, p < 0.01) and lowest number of primitive (CD34- CD235a+, 1.55%, p < 0.01) precursor cells along with the highest colony-forming units (149.8 ± 11.6, p < 0.01) in feeder-free conditions. Maximal HSPC fraction (CD34+ CD38- CD45RA- CD49f+ CD90+) was 7.6-8.9% after 10 days of hematopoietic differentiation with 14.5% adult β-globin expression following RBC differentiation. Myeloid and erythroid colonies were restricted strictly to the CD34+ CD43+ fraction (370.5 ± 65.7, p < 0.001), while the CD34- CD43+ fraction produced only a small number of colonies (21.6 ± 11.9). In addition, we differentiated the CD34+ CD43+ cells towards T-lymphocytes using the OP9/DLL1 co-culture system demonstrating double-positive T cells (CD4+ CD8+) with CD3+ expression displaying a broad T cell receptor (TCR) repertoire. Confocal imaging of organoid-like structures revealed a close association of CD31+ cells with CD34+ and CD43+ cells, suggesting a potential emergence of HSPCs through endothelial to hematopoietic transition. Furthermore, fluorescently labeled organoids exhibited the emergence of spherical non-attached cells from rare progenitors at the border of the organoid center. In summary, definitive HSPCs can be derived from ESCs through a dynamic cellular process from an organoid-like structure, where erythroid progeny are capable of producing adult hemoglobin and lymphoid progeny shows a diverse TCR repertoire.


Inhibitory effects of propiverine on rat and guinea-pig urinary bladder muscle.
In muscle strips isolated from guinea-pig and rat urinary bladder, propiverine (3-10 microM) inhibited carbachol-induced contractions in the presence of verapamil and Ca(2+)-induced contractions in excess K+ medium containing atropine, suggesting it has both anticholinergic and Ca2+ channel blocking actions. The Ca2+ channel blocking action was also demonstrated by recording inward Ca2+ currents in single cells dispersed from both species. The inhibition of inward currents by propiverine was three times stronger in the rat than the guinea-pig, ID50 being 7 microM for rat and 21 microM for guinea-pig. The recovery of the current after washout was faster than that of mechanical inhibition. It is concluded that propiverine blocks not only muscarinic receptors, but also Ca2+ channels at similar concentrations.


Optimizing airway wall segmentation and quantification by reducing the influence of adjacent vessels and intravascular contrast material with a modified integral-based algorithm in quantitative computed tomography.
Quantitative analysis of multi-detector computed tomography (MDCT) plays an increasingly important role in assessing airway disease. Depending on the algorithms used, airway dimensions may be over- or underestimated, primarily if contrast material was used. Therefore, we tested a modified integral-based method (IBM) to address this problem. Temporally resolved cine-MDCT was performed in seven ventilated pigs in breath-hold during iodinated contrast material (CM) infusion over 60s. Identical slices in non-enhanced (NE), pulmonary-arterial (PA), systemic-arterial (SA), and venous phase (VE) were subjected to an in-house software using a standard and a modified IBM. Total diameter (TD), lumen area (LA), wall area (WA), and wall thickness (WT) were measured for ten extra- and six intrapulmonary airways. The modified IBM significantly reduced TD by 7.6%, LA by 12.7%, WA by 9.7%, and WT by 3.9% compared to standard IBM on non-enhanced CT (p<0.05). Using standard IBM, CM led to a decrease of all airway parameters compared to NE. For example, LA decreased from 80.85±49.26mm2 at NE, to 75.14±47.96mm2 (-7.1%) at PA (p<0.001), 74.96±48.55mm2 (-7.3%) at SA (p<0.001), and to 78.95±48.94mm2 (-2.4%) at VE (p = 0.200). Using modified IBM, the differences were reduced to -3.1% at PA, -2.9% at SA and -0.7% at VE (p<0.001; p<0.001; p = 1.000). The modified IBM can optimize airway wall segmentation and reduce the influence of CM on quantitative CT. This allows a more precise measurement as well as potentially the comparison of enhanced with non-enhanced scans in inflammatory airway disease.


Further studies with a cell immortalization assay to investigate the mutation signature of aristolochic acid in human p53 sequences.
To test hypotheses on the origins of p53 mutations in human tumors, novel strategies are needed for generating mutation spectra experimentally. To this end we developed an assay employing Hupki (Human p53 knock-in) mouse embryonic fibroblasts (HUFs). Here we examine p53 mutations induced by aristolochic acid I (AAI)), the carcinogen probably responsible for Chinese herbal nephropathy. Six immortalized cultures (cell lines) from 18 HUF primary cultures exposed at passage 1 for 48 h to 50 microM AAI harbored p53 mutations in the human DNA binding domain sequence of the Hupki p53 tumor suppressor gene. The most frequently observed mutation was A to T transversion, corroborating our previous mutation study with AAI, and consistent with the presence of persistent AAI-adenine adducts found both in DNA of exposed patients and in DNA of AAI-exposed HUF cells. One of the mutations was identical in position (codon 139) and base change (A to T on the non-transcribed strand) to the single p53 mutation that has thus far been characterized in a urothelial tumor of a nephropathy patient with documented AAI exposure. Of the seven p53 mutations identified thus far in >60 HUF cell lines that immortalized spontaneously (no carcinogen treatment), none were A:T to T:A transversions. In addition, no A to T substitutions were identified among the previously reported set of 18 mutations in HUF cell lines derived from B(a)P treatment in which transversions at G:C base pairs predominated.


Dynamic stability during level walking and obstacle crossing in persons with facioscapulohumeral muscular dystrophy.
Patients with FSHD suffer from progressive skeletal muscle weakness, which is associated with an elevated fall risk. To obtain insight into fall mechanisms in this patient group, we aimed to assess dynamic stability during level walking and obstacle crossing in patients at different disease stages. Ten patients with at least some lower extremity weakness were included, of whom six were classified as moderately affected and four as mildly affected. Ten healthy controls were also included. Level walking at comfortable speed was assessed, as well as crossing a 10 cm high wooden obstacle. We assessed forward and lateral dynamic stability, as well as spatiotemporal and kinematics variables. During level walking, the moderately affected group demonstrated a lower walking speed, which was accompanied by longer step times and smaller step lengths, yet dynamic stability was unaffected. When crossing the obstacle, however, the moderately affected patients demonstrated reduced forward stability margins during the trailing step, which was accompanied by an increased toe clearance and greater trunk and hip flexion. This suggests that during level walking, the patients effectively utilized compensatory strategies for maintaining dynamic stability, but that the moderately affected group lacked the capacity to fully compensate for the greater stability demands imposed by obstacle crossing, rendering them unable to maintain optimal stability levels. The present results highlight the difficulties that FSHD patients experience in performing this common activity of daily living and may help explain their propensity to fall in the forward direction.


Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients.
FOXP3 gene is known to be important for regulatory T cell development and function, and is associated with the rejection of human kidney transplants. The present study was therefore conducted to determine the effect of FOXP3 polymorphisms on allograft rejection in renal transplant recipients. A total of 166 adult patients were categorized into either a Rejection group (65 patients) or a No rejection group (101 patients). Rs3761547, rs3761548 and rs2232365 variant alleles in the FOXP3 gene were genotyped using a TaqMan probe technique, and their relationships with rejection were investigated. There was no significant difference in the genotype frequencies of rs3761547 and rs2232365 variants between patients with and without rejection history (P > 0.05). Binary logistic regression analysis showed that the rs3761548 AA genotype carriers were associated with about a fourfold greater risk for rejection compared with CC genotype (5 years post-transplant: odds ratio 3.95, 95% confidence interval 1.27-12.29, P = 0.018). Kaplan-Meier analysis revealed a lower mean time to the first rejection in rs3761548 AA compared with CC genotype patients (Log rank = 4.303, P = 0.038). Multivariate Cox regression analysis indicated that rs3761548 AA genotype carriers have up to about a twofold (hazard ratio 2.37, 95% confidence interval 1.17-4.80, P = 0.017) higher risk for rejection than CC carriers. Our study suggests an association between FOXP3 rs3761548 polymorphisms and allograft rejection in renal transplantation. This association should be further proven in large prospective studies because of the small sample size and confounding factors in this retrospective study.


The combined use of chemical and biochemical markers to assess water quality along the Ebro River.
Carp (Cyprinus carpio) and barbel (Barbus graellsii) were collected from five sites along the Ebro River. The study was designed to assess levels of persistent organic pollutants and metals bioaccumulated by fish, and some biochemical responses (cytochrome P450 system, phase II activities, and metallothioneins) against those pollutants. The highest levels of PCBs and DDTs were detected in carp from industrialised areas, which also showed high levels of mercury and cadmium in the liver, and high levels of nonylphenol in bile. Significant alterations in some biochemical markers were observed and associated to combined exposure to pollutants. The activity 7-ethoxyresorufin O-deethylase ranged from 69 pmol/min/mg protein in carp from the reference site to 415 pmol/min/mg protein in those from polluted sites. Carp from the Ebro Delta, an agricultural area, had depressed acetylcholinesterase in muscle tissue. Metallothionein concentrations were positively correlated with copper residues, but no significant differences among sampling points were observed.


tLyp-1: A peptide suitable to target NRP-1 receptor.
Targeting vascular endothelial growth factor receptor (VEFGR) and its co-receptor neuropilin-1 (NRP-1) is an interesting vascular strategy. tLyp-1 is a tumor-homing and penetrating peptide of 7 amino acids (CGNKRTR). It is a truncated form of Lyp-1 (CGNKRTRGC), which is known to target NRP-1 receptor, with high affinity and specificity. It is mediated by endocytosis via C-end rule (CendR) internalization pathway. The aim of this study is to evaluate the importance of each amino acid in the tLyp-1 sequence through alanine-scanning (Ala-scan) technique, during which each of the amino acid in the sequence was systematically replaced by alanine to produce 7 different analogues. In silico approach through molecular docking and molecular dynamics are employed to understand the interaction between the peptide and its analogues with the NRP-1 receptor, followed by in vitro ligand binding assay study. The C-terminal Arg is crucial in the interaction of tLyp-1 with NRP-1 receptor. Substituting this residue dramatically reduces the affinity of this peptide which is clearly seen in this study. Lys-4 is also important in the interaction, which is confirmed via the in vitro study and the MM-PBSA analysis. The finding in this study supports the CendR, in which the presence of R/K-XX-R/K motif is essential in the binding of a ligand with NRP-1 receptor. This presented work will serve as a guide in the future work pertaining the development of active targeting agent towards NRP-1 receptor.


Exposure to high hydrostatic pressure rapidly selects for increased RpoS activity and general stress-resistance in Escherichia coli O157:H7.
Exposure to high hydrostatic pressure (HHP) is increasingly being used in food preservation as a non-thermal pasteurization process, and its further implementation necessitates a more thorough understanding of bacterial resistance development and intraspecies variability with regard to inactivation by HHP. In this report, we discovered that exposure to high hydrostatic pressure stress can rapidly select for strongly increased RpoS activity in a hypersensitive Escherichia coli O157:H7 strain (ATCC 43888), leading to a simultaneous increase in HHP and heat resistance. Moreover, the level of RpoS activity correlated well with the original hypersensitivity and the extent of acquired HHP resistance, and extremely HHP-resistant mutants of ATCC 43888 clearly incurred a number of additional RpoS-dependent phenotypes. These findings suggest that implementation of novel processing techniques in the food production chain can readily affect the physiology of food-borne pathogens.


Rare Cause of Late Left Aortic Sinus Obstruction Following Transcatheter Aortic Valve Replacement.
A 74-year-old woman with a history aortic stenosis with prior transcatheter aortic valve replacement presented with non-ST-segment elevation myocardial infarction secondary to a delayed left coronary sinus obstruction. With physiology and intravascular ultrasound guidance, the patient was treated with stents through the valve struts and to the left main. (Level of Difficulty: Intermediate.).


[Radiologic Diagnosis of Gastrointestinal Bleeding].
Gastrointestinal (GI) bleeding is not a single disease but a symptom and clinical manifestation of a broad spectrum of conditions in the GI tract. According to its clinical presentation, GI bleeding can be classified into overt, occult, and obscure types. Additionally, it can be divided into upper and lower GI bleeding based on the Treitz ligament. Variable disease entities, including vascular lesions, polyps, neoplasms, inflammation such as Crohn's disease, and heterotopic pancreatic or gastric tissue, can cause GI bleeding. CT and conventional angiographies and nuclear scintigraphy are all radiologic imaging modalities that can be used to evaluate overt bleeding. For the work-up of occult GI bleeding, CT enterography (CTE) can be the first imaging modality. For CTE, an adequate bowel distention is critical for obtaining acceptable diagnostic performance as well as minimizing false positives and negatives. Meckel's scintigraphy can be complementarily useful in cases where the diagnosis of CTE is suboptimal. For the evaluation of obscured GI bleeding, various imaging modalities can be used based on clinical status and providers' preferences.


Alzheimer's disease.
The current knowledge of the neuropathology, neurochemistry and genetics of Alzheimer's disease is reviewed. The hallmarks of neuropathology, namely neuritic plaques and neurofibrillary tangles, are described. The search for the aetiological agent(s) and a therapeutic strategy are briefly described and the location of a genetic locus for Alzheimer's disease on chromosome 21 is discussed. Future directions for research are suggested.


Prolongation of rat renal allograft survival time by donor pretreatment with 8-methoxypsoralen and longwave ultraviolet irradiation of the graft (PUVA therapy).
Pretreatment of the kidney donor with 8-methoxypsoralen (8-MOP) and ex vivo longwave ultraviolet irradiation (UVA) of the kidney prolonged the subsequent survival on allogeneic recipients. The efficacy of this treatment seems to be dependent on the time and dose of UVA irradiation rather than on the dose of 8-MOP. In conclusion, PUVA treatment is effective in reducing the immunogenicity of the rat kidney allograft, although the mechanism remains unclear. These experimental findings are new and preliminary results in clinical human kidney transplantation are favourable.


Ropivacaine impairs mitochondrial biogenesis by reducing PGC-1α.
Ropivacaine is one of the commonly used local anesthetics in medical and dental care. However, preclinical and observational studies indicate that ropivacaine could have substantial side effects including neurotoxicity, which has raised concern regarding the safety of this drug. In the present study, we investigated the effects of clinically relevant doses of ropivacaine on mitochondrial biogenesis and function in neuronal cells. Our data indicate that exposure to ropivacaine leads to reduced expression of the major mitochondrial regulator PGC-1α and its downstream transcription factors NRF1 and TFAM. Ropivacaine treatment induces impairment of mitochondrial biogenesis by reducing mitochondrial mass, the ratio of mtDNA to nDNA (mtDNA/nDNA), cytochrome C oxidase activity, and COX-1 expression. Additionally, treatment with ropivacaine causes "loss of mitochondrial function" by impairing the mitochondrial respiratory rate and ATP production. Mechanistically, the reduction of PGC-1α caused by ropivacaine exposure requires inactivation of CREB, while re-introduction of PGC-1α completely rescues ropivacaine-induced mitochondrial abnormalities. In summary, our results provide supporting evidence that mitochondrial impairment is a key event in ropivacaine-mediated neurotoxicity, and the reduction of PGC-1α and its downstream signals are likely the molecular mechanism behind its cellular toxicity.


IgA nephropathy in two adolescent sisters heterozygous for Fabry disease.
We report a 16-year-old girl and her one-year-younger sister, both heterozygous for the c.34del24 mutation of the GLA (alpha-galactosidase A) gene, which they inherited from their father who is affected by Fabry disease (FD). Both girls presented with macrohematuria and rapidly progressing proteinuria. Urine analysis revealed glomerular hematuria and a nephrotic range of proteinuria suggesting a concomitant glomerulonephritis. Light microscopy of kidney biopsy was characteristic of IgA nephropathy (IgA deposits in mesangial areas and glomerular capillary loops, and mesangial hypercellularity), whereas electron microscopy showed changes typical of Fabry disease (multiple osmiophilic inclusions in the subendothelial and mesangial areas). These two cases and similar reports in the literature suggest that IgA nephropathy in FD is not merely coincidental.


Effect of intracanal cryotherapy application on postoperative endodontic pain: a systematic review and metaanalysis.
To assess the influence of intracanal cryotherapy application on postoperative pain after endodontic treatment. A systematic review (SR) was conducted in seven databases. Articles that were published up to 04 February 2020 were included and randomized clinical trials that used a cold saline solution for final irrigation to manage postoperative endodontic pain were compared with those that used a saline solution at room temperature. Metaanalysis was performed to assess postoperative pain after 6, 24, 48, and 72 h using a random effects model, a confidence interval of 95%, and heterogeneity tested by the I2 index. The certainty of evidence was rated using GRADE. Qualitative and quantitative analysis included eight and six studies, respectively. Individuals treated with cryotherapy presented lower means of postendodontic pain than the controls, 6 and 24 h after endodontic treatment (MD - 1.30 [- 2.32, - 0.28] p = 0.01 and SMD - 0.68 [ - 1.21, - 0.16] p = 0.01, respectively, with very low certainty of evidence). After 48 and 72 h, both groups demonstrated similar means of postendodontic pain (MD - 0.06 [- 0.18, 0.07] p = 0.38 and SMD - 0.54 [- 1.18, - 0.11] p = 0.10, with high and low certainty of evidence, respectively). Based on the limited quality evidence, intracanal cryotherapy application reduced postoperative endodontic pain after 6 and 24 h. New clinical trials are needed to support the result of this review. This SR provides information about the use of intracanal cryotherapy in clinical practice, guides clinicians to make evidence-based decisions and suggests recommendations for further high-quality studies.


Return to Work and Sport Following Tibial Tubercle Anteromedialization.
Tibial tubercle anteromedialization (AMZ) is a commonly performed procedure for patients with patellofemoral instability or patellofemoral osteochondral disease. While prior studies have demonstrated that this form of osteotomy produces generally good outcomes, the time needed for return to work and return to sport remains unclear. This study aimed to determine the mean length of time before return to work and the rate of return to sport following AMZ. Patients who had undergone AMZ for either patellofemoral instability or isolated osteochon- dral defect with a minimum follow-up time of 1 year were identified. Patients less than 18 years of age were excluded. Patients were asked to complete a series of patient reported outcomes surveys including specific queries regarding their return to work and return to athletic activity. A total of 109 patients were included in this study. The majority were female (79 patients, 72.3%). The mean age was 30.74 ± 9.90 years at the time of surgery. The mean follow-up duration was 3.40 ± 1.97 years. Of the 109 patients, 104 (95.4%) had returned to work at the time of follow-up. Mean time to return to work was 2.96 ± 3.33 months (range: 0.25 to 24 months). Of the 90 patients who were involved in a sport or physical activity prior to injury, 64 patients (71.1%) had returned to sport at some level at the time of most recent follow-up. Of those who had returned to sport, mean time to return to sport was 9.21 ± 5.46 months (range: 1 to 24 months). At a minimum follow-up time of 1 year, patients who underwent AMZ were found to have a return to sport rate of 71% with a mean time of 9.21 months to return to athletic activity. Over 95% of AMZ patients had returned to work by 1 year after the procedure. Patients required an average of 3 months to return to work, although those with physically demanding jobs required slightly more time. Data from the current study is useful in setting expectations for patients undergoing tibial tubercle anteromedialization for patellofemoral instability or patellofemoral osteochondral disease.


Endovascular treatment of internal iliac artery aneurysms.
To describe a technique for percutaneous endovascular repair of internal iliac artery aneurysms. In a patient with an isolated internal iliac artery aneurysm and combined tight stenoses at the origins of the external and internal iliac arteries, interventional treatment consisted of coil embolization of the internal iliac artery and branches using the contralateral femoral approach. Balloon dilation of the external iliac stenosis occluded the internal iliac artery, and Palmaz stents were placed in the external iliac stenosis to overcome residual luminal narrowing. This one-step percutaneous technique allows total exclusion of the internal iliac artery aneurysm using coil embolization. This treatment may be an alternative to surgery in isolated internal iliac artery aneurysms with small orifices.