Effects of human chorionic gonadotropin, estradiol, and progesterone on interleukin-18 expression in human decidual tissues.
Interleukin (IL)-18 is a proinflammatory cytokine which mediates a myriad of inflammatory responses during pregnancy. Changes in IL-18 levels have been linked to complications during pregnancy. This study was designed to assess the effects of estradiol, human chorionic gonadotropin (hCG), and progesterone on IL-18 expression in human decidual tissues. Uterine deciduas from women with normal pregnancy, spontaneous abortion, and progesterone treated spontaneous abortion were collected, and the effects of hormones on the viability of decidual cells and IL-18 secretion were detected by MTT and ELISA assays. We found that Estradiol, hCG, and progesterone inhibited decidual cell growth independent of dosage and time.IL-18 secretion in the spontaneous abortion group was increased in the decidual cells over time, but all hormones significantly reduced its secretion (p < 0.05). Our results indicate that estradiol, hCG, and progesterone can reduce IL-18 secretion in the cultured endometrial stromal cells from patients who experienced spontaneous abortion to the levels observed following normal pregnancy. Progesterone can significantly reduce IL-18 expression and increase growth of CD56+ CD16- uNK cells, suggesting that these activities may underlie the mechanism by which progesterone improves pregnancy outcomes.


[Signet ring cell carcinoid of the appendix. Morphological, histochemical and immunohistochemical study of a case].
A case of carcinoid tumor of the appendix with "signet ring" cells pattern and asymptomatic clinical course is presented. The tumor was detected during a Bilroth I gastrectomy procedure. Mucin-secreting cells with cytoplasms often containing argentaffin and argyrophil granules was the predominant histologic pattern. Lack of neuron-specific enolase activity and their positivity for lysozyme and EMA marker indicate an origin from crypt cell and not a neural crest source. After simple appendectomy, the patient was healthy 3 years following surgery.


Identification of new p63 targets in human keratinocytes.
p63 is a transcription factor involved in the development of ectodermal tissues, including limb, skin and, in general, multilayered epithelia. We identified both activated and repressed genes in human keratinocytes via gene expression profiling of p63-depleted cells and validated 21 new primary targets by RT-PCR and ChIP location analysis. The p63 isoforms differentially activate or repress selected promoters. ChIPs in primary keratinocytes indicate that p63 targets are generally shared with p53, but some are p63-specific. Several growth suppressors are among repressed genes. The newly identified genes belong to pathways of growth and differentiation and are regulated in HaCaT differentiation and in stratification of human skin.


Quantum random number generator based on twin beams.
We produce two strings of quantum random numbers simultaneously from the intensity fluctuations of the twin beams generated by a nondegenerate optical parametric oscillator. Two strings of quantum random numbers with bit rates up to 60 Mb/s are extracted simultaneously with a suitable post-processing algorithm. By post-selecting the identical data from two raw sequences and using a suitable hash function, we also extract two strings of identical quantum random numbers. The obtained random numbers pass all NIST randomness tests. The presented scheme shows the feasibility of generating quantum random numbers from the intensity of a macroscopic optical field.


Arterial stiffness and cognitive function.
Arterial stiffness is an independent predictor of morbidity (infarction, fatal stroke) and cardiovascular mortality, especially in elderly, hypertensive patients with pre-terminal renal insufficiency and in coronary disease patients. The gold standard of its measurement is the pulse wave velocity assessment. The important increase in arterial stiffness that occurs during midlife is associated with the occurrence of severe cardiovascular and cerebrovascular events and also cognitive decline. The causal relationship between stiffening of the arterial tree and cognitive disorders has not yet been clearly established, however, many studies show a relationship between higher levels of aortic stiffness and poorer performance on cognitive memory tests. Arterial stiffness is associated with microvascular alterations, with an increase in microvascular resistance, an increase in leukoaraisosis and also medial temporal lobe atrophy. These damages contribute to dementia pathogenesis (including Alzheimer's disease) and confirm the importance of early detection and management of arterial stiffness increase.


Patient Accessibility and Budget Impact of Orphan Drugs in South Korea: Long-Term and Real-World Data Analysis (2007-2019).
This study aimed to identify orphan drug accessibility and impact on pharmaceutical budgets in South Korea by analyzing the status of orphan drug designation, approval, reimbursement, and pharmaceutical expenditure. We analyzed the dataset on orphan drugs designated, approved, and reimbursed from 2007 to 2019 based on long-term real-world data. The designated and approved orphan drugs were 165 and 156, respectively, and 88 out of 156 approved products were reimbursed. Total expenditure on orphan drugs increased annually to account for about 1.44% of total pharmaceutical expenditure in 2018. Orphan drug expenditure per patient increased on average by 8.7% per year. The average annual cost of orphan drugs was USD 27,000-USD 47,000, with the maximum value of USD 260,000-USD 560,000. As there are a number of orphan drugs that have not yet been reimbursable after approval, a reimbursement policy should be established that considers the characteristics of orphan drugs. Since the rapid increase in orphan drug expenditure can be a potential threat to the insurance budget, budget management should also be considered. In conclusion, it is necessary to take preemptive measures to manage the health insurance budget efficiently while improving patient accessibility to orphan drugs.


Overcoming bias and systematic errors in next generation sequencing data.
Considerable time and effort has been spent in developing analysis and quality assessment methods to allow the use of microarrays in a clinical setting. As is the case for microarrays and other high-throughput technologies, data from new high-throughput sequencing technologies are subject to technological and biological biases and systematic errors that can impact downstream analyses. Only when these issues can be readily identified and reliably adjusted for will clinical applications of these new technologies be feasible. Although much work remains to be done in this area, we describe consistently observed biases that should be taken into account when analyzing high-throughput sequencing data. In this article, we review current knowledge about these biases, discuss their impact on analysis results, and propose solutions.


Primary somatosensory cortex discriminates affective significance in social touch.
Another person's caress is one of the most powerful of all emotional social signals. How much the primary somatosensory cortices (SIs) participate in processing the pleasantness of such social touch remains unclear. Although ample empirical evidence supports the role of the insula in affective processing of touch, here we argue that SI might be more involved in affective processing than previously thought by showing that the response in SI to a sensual caress is modified by the perceived sex of the caresser. In a functional MRI study, we manipulated the perceived affective quality of a caress independently of the sensory properties at the skin: heterosexual males believed they were sensually caressed by either a man or woman, although the caress was in fact invariantly delivered by a female blind to condition type. Independent analyses showed that SI encoded, and was modulated by, the visual sex of the caress, and that this effect is unlikely to originate from the insula. This suggests that current models may underestimate the role played by SI in the affective processing of social touch.


Antibiotics induce mitonuclear protein imbalance but fail to inhibit respiration and nutrient activation in pancreatic β-cells.
Chloramphenicol and several other antibiotics targeting bacterial ribosomes inhibit mitochondrial protein translation. Inhibition of mitochondrial protein synthesis leads to mitonuclear protein imbalance and reduced respiratory rates as confirmed here in HeLa and PC12 cells. Unexpectedly, respiration in INS-1E insulinoma cells and primary human islets was unaltered in the presence of chloramphenicol. Resting respiratory rates and glucose stimulated acceleration of respiration were also not lowered when a range of antibiotics including, thiamphenicol, streptomycin, gentamycin and doxycycline known to interfere with bacterial protein synthesis were tested. However, chloramphenicol efficiently reduced mitochondrial protein synthesis in INS-1E cells, lowering expression of the mtDNA encoded COX1 subunit of the respiratory chain but not the nuclear encoded ATP-synthase subunit ATP5A. Despite a marked reduction of the essential respiratory chain subunit COX1, normal respiratory rates were maintained in INS-1E cells. ATP-synthase dependent respiration was even elevated in chloramphenicol treated INS-1E cells. Consistent with these findings, glucose-dependent calcium signaling reflecting metabolism-secretion coupling in beta-cells, was augmented. We conclude that antibiotics targeting mitochondria are able to cause mitonuclear protein imbalance in insulin secreting cells. We hypothesize that in contrast to other cell types, compensatory mechanisms are sufficiently strong to maintain normal respiratory rates and surprisingly even result in augmented ATP-synthase dependent respiration and calcium signaling following glucose stimulation. The result suggests that in insulin secreting cells only lowering COX1 below a threshold level may result in a measurable impairment of respiration. When focusing on mitochondrial function, care should be taken when including antibiotics targeting translation for long-term cell culture as depending on the sensitivity of the cell type analyzed, respiration, mitonuclear protein imbalance or down-stream signaling may be altered.


The arrhythmogenic right ventricular cardiomyopathy in comparison to the athletic heart.
Intense exercise-induced right ventricular remodeling is a potential adaptation of cardiac function and structure. The features of the remodeling may overlap with those of a very early form of arrhythmogenic right ventricular cardiomyopathy (ARVC): at this early stage, it could be difficult to discriminate ARVC, from exercise-induced cardiac adaptation that may develop in normal individuals. The purpose of this paper is to discuss which exercise-induced remodeling may be a pathological or a physiological finding. A complete evaluation may be required to identify the pathological features of ARVC that would include potential risk of sudden cardiac death during sport or, to avoid the false diagnosis of ARVC. The most recent expert assessment of arrhythmogenic cardiomyopathy focuses on endurance athletes presenting with clinical features indistinguishable from ARVC.


Prevalence of cystic echinococcosis among Muslim and Jewish populations in southern Israel.
Following a review of records at the Soroka University Medical Center (SUMC) showing a recent increase in the annual incidence of hydatidosis among the Bedouin population of southern Israel, a seroepidemiological survey was conducted. A total of 1439 blood samples were collected from Bedouins and Jews living in the Negev area in southern Israel. An enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G, indirect haemagglutination (IHA) and immunoelectrophoresis (IEP) were used to detect anti-Echinococcus granulosus antibodies. The seroprevalence in the Bedouin group was 0.68% (7/1026), including two children under the age of 10. Among Jews, a seroprevalence of 0.5% was recorded in patients over 60 years of age only. A high rate of infection was shown in goats and sheep slaughtered in abattoirs in Bedouin localities. The results indicate that echinococcosis is a common disease in the Muslim communities of southern Israel.


Natural resistance to cancer: A window of hope.
As healthcare systems are improving and thereby the life expectancy of human populations is increasing, cancer is representing itself as the second leading cause of death. Although cancer biologists have put enormous effort on cancer research so far, we still have a long way to go before being able to treat cancers efficiently. One interesting approach in cancer biology is to learn from natural resistance and/or predisposition to cancer. Cancer-resistant species and tissues are thought-provoking models whose study shed light on the inherent cancer resistance mechanisms that arose during the course of evolution. On the other hand, there are some syndromes and factors that increase the risk of cancer development, and revealing their underlying mechanisms will increase our knowledge about the process of cancer formation. Here, we review natural resistance and predisposition to cancer and the known mechanisms at play. Further insights from these natural phenomena will help design future cancer research and could ultimately lead to the development of novel cancer therapeutic strategies.


Use of a Machine Learning-Based High Content Analysis Approach to Identify Photoreceptor Neurite Promoting Molecules.
High content analysis (HCA) has become a leading methodology in phenotypic drug discovery efforts. Typical HCA workflows include imaging cells using an automated microscope and analyzing the data using algorithms designed to quantify one or more specific phenotypes of interest. Due to the richness of high content data, unappreciated phenotypic changes may be discovered in existing image sets using interactive machine-learning based software systems. Primary postnatal day four retinal cells from the photoreceptor (PR) labeled QRX-EGFP reporter mice were isolated, seeded, treated with a set of 234 profiled kinase inhibitors and then cultured for 1 week. The cells were imaged with an Acumen plate-based laser cytometer to determine the number and intensity of GFP-expressing, i.e. PR, cells. Wells displaying intensities and counts above threshold values of interest were re-imaged at a higher resolution with an INCell2000 automated microscope. The images were analyzed with an open source HCA analysis tool, PhenoRipper (Rajaram et al., Nat Methods 9:635-637, 2012), to identify the high GFP-inducing treatments that additionally resulted in diverse phenotypes compared to the vehicle control samples. The pyrimidinopyrimidone kinase inhibitor CHEMBL-1766490, a pan kinase inhibitor whose major known targets are p38α and the Src family member lck, was identified as an inducer of photoreceptor neuritogenesis by using the open-source HCA program PhenoRipper. This finding was corroborated using a cell-based method of image analysis that measures quantitative differences in the mean neurite length in GFP expressing cells. Interacting with data using machine learning algorithms may complement traditional HCA approaches by leading to the discovery of small molecule-induced cellular phenotypes in addition to those upon which the investigator is initially focusing.


Intrauterine devices and acute pelvic inflammatory disease.
One of the most serious problems among women using the intrauterine device (IUD) has been pelvic inflammatory disease (PID). Subjects for the present investigation were chosen from 15- to 44-year-old women seeking emergency medical attention at a large city hospital. Febrile and afebrile patients with PID and appropriate controls were asked to complete a self-administered questionnaire concerning their demographic, reproductive, and contraceptive histories. Results showed a significantly higher proportion of IUD users among febrile cases of PID (38%) than among controls (11%). This implies that febrile PID is five times as likely to develop in an IUD user as in a nonuser.


Comparison of two DNA extraction protocols from leave samples of Cotinus coggygria, Citrus sinensis and Genus juglans.
High quality DNA is essential for molecular research. Secondary metabolites can affect the quantity and quality DNA. In current research two DNA isolation methods including CTAB and Delaporta (protocols 1 & 2 respectively) were applied in three leave samples from Cotinus coggygria, Citrus sinensis and Genus juglans that their leaves are rich of secondary metabolites. We successfully isolated DNA from C. coggygria, C. sinensis and Genus Juglans using the two protocols described above. Good quality DNA was isolated from C. coggygria, C. sinensis and Genus Juglans using protocol 1, while protocol 2 failed to produce usable DNA from these sources. The highest amount of DNA (1.3-1.6) was obtained from them using protocol 1. As we discovered, procedure 1 may work better for plants with secondary metabolites.


Research Review: The role of obstetric and neonatal complications in childhood attention deficit and hyperactivity disorder - a systematic review.
Attention deficit and hyperactivity disorder (ADHD) is a developmental disorder characterized by an inability to sustain attention, activity levels and impulse control, and, according to the latest studies, the prevalence is about 8% and in some countries less than 1%. Currently, it is well-known that complications during the perinatal period have significant implications on child's physical and mental health. Purpose of the present paper is to review the literature about the association between perinatal complications and future risk of an ADHD diagnosis. A research in the main database sources has been conducted to obtain a systematic review on the perinatal risk factors of ADHD. Among perinatal complications, available data indicate low birth weight (LBW) (Cohen's d effect size range: 0.31-1.64-small effect size) and preterm birth (PB) (range d: 0.41-0.68) as the most important factors associated with a future diagnosis of ADHD. PB and LBW children should be carefully monitored for an early diagnosis of ADHD limiting the impact of the disease in life span. A systematic review focusing on these risk factors have not been published until now, in the next future preventive strategies should be developed in order to minimize ADHD onset.


Thrombin receptor-dependent prostaglandin E2 synthesis in hamster fibroblasts: synergistic interactions with interleukin-1beta.
Cellular responses to alpha-thrombin are mediated through a G-protein-coupled receptor that undergoes proteolytic cleavage, unveiling a tethered peptide ligand with the amino-terminal sequence SFLLRN. The synthetic peptide SFLLRN can mimic many of thrombin's actions via directly stimulating the thrombin receptor. Thrombin has been implicated in several cellular events associated with tissue injury, including fibroblast growth, matrix deposition, and inflammatory responses. The role of the thrombin receptor in fibroblast-dependent release of the inflammatory mediator prostaglandin E2 was evaluated and compared to its well-characterized effect on cell proliferation. Both thrombin and SFLLRN stimulated [3H]thymidine incorporation into DNA but failed to induce prostaglandin E2 release from CCL39 cells. The inflammatory cytokine interleukin-1beta synergized with thrombin and SFLLRN to induce the release of prostaglandin E2, whereas it had no effect on thrombin receptor-mediated DNA synthesis. Interleukin-1beta had no direct effects on thrombin receptor-mediated phosphoinositide hydrolysis, suggesting that its effects were downstream from early signal transduction events. Thrombin and interleukin-1beta together significantly increased the expression of prostaglandin H synthase-2 in accordance with the prostaglandin E2 results. These studies indicate that the fibroblast thrombin receptor differentially couples to intracellular signaling pathways leading to distinct functional responses and that thrombin receptor-effector interactions could be modulated by interleukin-1beta.


[Surgery of the laryngeal framework: type I thyroplasty].
Eight type I thyroplasties were performed. All the patients had a breathy voice related with unilateral vocal cord paralysis. Several causes were involved. All 8 patients achieved good glottic closure and the free edges of the vocal cords mi closed uniformly. Acoustic parameters were studied using Dr. Speech version 2.0 for Windows. The SPSS program was used for statistical analysis. The study showed significant improvement in maximum phonation time, shimmer, and normalized noise energy. Modifications in the surgical technique are discussed.


Maternal opioid use disorder and neonatal abstinence syndrome in northwest Ontario: a 7-year retrospective analysis.
Opioid use in pregnancy is increasing globally. In northwest Ontario, rates of neonatal abstinence syndrome (NAS) are alarmingly high. We sought to document the increasing rates of opioid exposure during pregnancy and associated cases of NAS over a 7-year period in northwest Ontario. We conducted a retrospective chart review at the Sioux Lookout Meno Ya Win Health Centre catchment area (population 29 000) maternity program in northwest Ontario of mother-infant dyads of live births from Jan. 1, 2009, to Dec. 31, 2015. The Integrated Pregnancy Program provides maternal, neonatal and addiction care for obstetrical patients at the health centre. We collected data on prenatal opioid exposure due to illicit and opioid agonist therapy (OAT) from patient/prescription histories and urine toxicology reports. Rates of NAS (diagnosed as a Finnegan score > 7) were recorded retrospectively from neonatal hospital charts. There were 2743 live births during the study period. Opioid exposure occurred in 672 pregnancies (335 OAT, 337 illicit). The incidence of prenatal opioid exposure increased significantly between 2009 and 2012 (11.1% to 28.5%, p < 0.001) but remained relatively constant at around 30% thereafter. Despite this, absolute rates of NAS remained relatively stable, with an average of 22.2 cases per 1000 live births over the study period. In comparison, the North West Local Health Integration Network (LHIN) experienced an average of 52.8 cases of NAS per 1000 live births in 2009-2012. The incidence of NAS in our centre decreased significantly over the study period (17.6% of opioid-exposed pregnancies in 2009 v. 4.0% in 2015, p = 0.001). There was a gradual transition toward a preponderance of OAT- versus illicit-exposed pregnancies, increasing from 0% in 2009 to 76.9% in 2015 (p < 0.001). Despite our continually increasing rates of opioid exposure in pregnancy, rates of NAS decreased annually and were substantially lower than those of our regional LHIN. In contrast to 2009, most opioid exposure in our region is now iatrogenic as a result of OAT. These improvements may be attributable in part to the rural community-based prenatal and addictions services developed in our catchment area.


Poor Families Striving to Save in Matched Children's Savings Accounts: Findings from a Randomized Experimental Design in Uganda.
This study examines participants' savings in children's savings accounts (CSAs) set up for AIDS-orphaned children ages 10-15 in Uganda. Using a cluster randomized experimental design, we examine the extent to which families participating in a CSA program report more savings than their counterparts not participating in the program, explore the extent to which families who participate in the CSA program report using formal financial institutions compared with families who do not have a CSA, and consider whether families participating in the CSA program bring new money into the CSA or whether they reshuffle existing household assets. We find that participating in a CSA increased families' likelihood to report having saved money. However, our results show no intervention effect either on the amount of self-reported savings or on the likelihood of using formal financial institutions. Further research is needed to understand whether use of a CSA helps families generate new wealth.


Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway.
The discovery of epidermal growth factor receptor (EGFR) mutations in never-smokers has been the most relevant finding ever in non-small cell lung cancer. When patients whose tumors bear the sensitizing mutations are treated with the tyrosine kinase inhibitors gefitinib or erlotinib, we witness response rates and durations never before reported, including complete responses. At the same time, the presence of EGFR mutations has raised numerous new questions, tantalizing data, and new challenges for treatment. This is particularly true as we try to generalize the findings in lung cancer to other malignancies. The indiscriminate use of gefitinib or erlotinib in the general lung cancer population results in meager survival benefit for patients. Similarly, the tyrosine kinase inhibitors have limited activity in a variety of tumor types with EGFR overexpression. This has led to the question of whether EGFR remains a viable target in patients other than those whose tumors contain mutations, and whether the modest activity of cetuximab in colorectal cancer and head and neck cancer represents all that we can expect from inhibition of this pathway in the absence of mutation. Mechanisms of pathway activation other than mutation have been discovered in recent years, and include overexpression mediated by gene amplification or by amplification of a dinucleotide repeat in the EGFR promoter, mutation of an extracellular region on EGFR generating a mutant protein termed EGFRvIII, and enhanced signaling due to heterodimerization with other members of the EGFR family, particularly overexpression of HER2/HER3. The extent to which these paths to EGFR activation will confer sensitivity to the tyrosine kinase inhibitors or to EGFR monoclonal antibodies is being explored. Thus far, published clinical data suggest that there is little room for the administration of gefitinib or erlotinib in the absence of EGFR mutations. The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance.


Failure to upregulate cell surface PD-1 is associated with dysregulated stimulation of T cells by TGN1412-like CD28 superagonist.
The CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics.


Substitution processes in molecular evolution. I. Uniform and clustered substitutions in a haploid model.
A computer simulation of the process of nucleotide substitutions in a finite haploid population subject to selection in a randomly fluctuating environment provides a number of unexpected results. For rapidly fluctuating environments, substitutions are more regular than random. A small mutation-rate approximation is used to explain the regularity. The explanation does not depend heavily on the particulars of the haploid model, leading to the conjecture that many symmetrical models of molecular evolution with rapidly changing parameters may exhibit substitutions that are more regular than random. When fitnesses change very slowly, the simulation shows that substitutions are more clumped than random. Here a small-mutation approximation shows that the clustering is due to the increase in fitness that accompanies each successive substitution with a consequent lowering of the effective mutation rate. The two observations taken together suggest that the common observation that amino acid substitutions are clustered in time is due to the presence of parameters that change very slowly.


Pathological evaluation and quality of surgery in radical cystectomy in New South Wales, Australia.
Australian bladder cancer patients especially women are thought to have worse outcomes when compared to the other international series. The objective of this study was to assess the pathological pattern of primary bladder cancer at the time of radical cystectomy as well as assessing the quality of resection in New South Wales. Pathology reports of radical cystectomy performed for primary bladder cancer were reviewed for a period of 10 years in a single major pathology centre servicing the state of New South Wales. Two hundred one specimens reviewed over 10 years. The tumour stage at the time of cystectomy was: CIS 29 (14%), Tx,a 5 (2%), T1 24 (12%), T2 49 (24%), T3 57 (28%) and T4 37 (18%). Lymphovascular invasion was seen in 94 (47%). Soft tissue margins were positive in 31 (15%), pelvic lymph node dissection was not performed in 64 (32%) of patients and only 32 (16%) of the patients had 10 or more lymph nodes harvested. No significant differences between men and women were noted in tumour stages, soft tissue positive margin rates and performance of pelvic lymph node dissection. Improving trends were noted in rates of negative soft tissue margins and the lymph node count during this period. Pattern of disease at the time of cystectomy was similar to the North American and European cohorts. Higher main specimen margin rates as well as lower lymph nodes retrieval rates were observed. No sex discrimination was observed. Further study is recommended to investigate the survival impact of this finding.


An expedient biocatalytic procedure for abasic site precursors useful in oligonucleotide synthesis.
Preparation of abasic site precursors through a divergent chemoenzymatic synthesis has been accomplished. Several biocatalysts and acylating agents were studied furnishing a practical and scalable green method useful for industrial applications. Highly regioselective acylation and deacylation reactions with 1,2-dideoxy-D-ribose are described resulting in excellent yield. A fast, atom-efficient and convenient synthesis of 3-, and 5-O-DMTr-1,2-dideoxyribose 17 and 19 has been achieved. These compounds are useful precursors for the preparation of phosphoramidites required for the assembly of oligonucleotides containing the tetrahydrofuran abasic lesions.


Abundance of plasma cells in a case of lipodermatosclerosis.
Plasma cells have been considered as an important morphological clue in the diagnosis of some sclerosing cutaneous diseases such as morphea, so much so that humoral immunology has been suggested to have a role in the pathogenesis of such diseases. Nevertheless, they are hardly ever described as a prominent feature in lipodermatosclerosis in which granulocytes have been claimed as the main pathogenic cell. We report a case of lipodermatosclerosis in a 77-year-old woman, in which plasma cells were abundant in the thickened fibrous septa of the hypodermis. They were highlighted on immunohistochemical study with CD79a, CD138 and EMA, and showed polyclonal immunoexpression of kappa and lambda immunoglobulin light chains.


Application of Solution-Focused Brief Therapy (SFBT) in individuals after stroke.
To examine the effects of Solution Focused Brief Therapy (SFBT) in individuals after stroke on self-efficacy, symptoms of depression and anxiety. Randomized controlled trial. Clinic of Adult Neurology of Medical University of Gdańsk and M. Copernicus Pomeranian Traumatology Centre in Gdańsk. A total of 62 patients, aged 54.0 ± 9.6 years. They were randomly assigned to one of the two groups: SFBT participating in 10 therapy sessions and control - not participating in any psychotherapy. Symptoms of depression and anxiety according to Hospital Anxiety and Depression Scale, Mini-Mental Adjustment to Cancer (scale originally designed for cancer patients) and Self-efficacy Scale were examined at baseline of the study and later in the same time intervals in both groups. The intensity of depression and anxiety complaints drops in the SFBT group (from 5.0 to 2.0 and 8.0 to 4.0 respectively; both p < .001 Friedman's ANOVA (analysis of variance)) whilst in the control group remains unchanged. In addition to the gradual reduction of destructive attitudes (from 34.5 to 17.0), the increase in the number of constructive attitudes (from 42.0 to 50.5) and increased self-efficacy (from 79.0 to 96.0) was observed after therapy but not in the control group. The authors suggest SFBT as a simple, beneficial and inexpensive method to manage patients after stroke.


Meeting the needs of an ever-demanding market.
Balancing cost and performance in packaging is critical. This article outlines techniques to assist in this whilst delivering added value and product differentiation. The techniques include a rigorous statistical process capable of delivering cost reduction and improved quality and a computer modelling process that can save time when validating new packaging options.


Pedicle Descemet membrane endothelial keratoplasty performed using a new corneal punch.
To create a Descemet membrane endothelial keratoplasty (DMEK) graft with a pedicle that allows better control of orientation, centration, and unrolling of the DMEK scroll. Macquarie University Hospital, Sydney, NSW, Australia. Prospective nonrandomized interventional case series. Eleven eyes of 10 patients with corneal endothelial failure underwent the modified DMEK surgery. A new corneal punch with a 7.5 mm central zone and a 3.0 mm long pedicle was used to produce a graft with a tail. The pedicle was used to orient and drag the graft into the anterior chamber, and the tail was extravasated. The graft was unrolled and centered using the pedicle, and 24% SF6 gas was injected to applanate the graft. The pedicle was truncated. The graft manipulation time, defined as the time from graft insertion to gas injection, was measured. The patient and donor characteristics, postoperative corrected distance visual acuity (CDVA), and endothelial cell count (ECC) at 3 months were reported. Ten grafts attached with 1 requiring reinjection of gas. The CDVA improved to ≥6/9 in 9 eyes, and the remaining were limited by preexisting disease. The ECC loss for the first 5 grafts was 28% ± 5% with manipulation time of 12 ± 6 minutes. This improved to 18% ± 7% (P = .03) and 3 ± 2 minutes (P = .007) for the last 6 grafts. The new corneal punch generated a keyhole-shaped DMEK graft. After a period of learning, the manipulation time was decreased, improving ECC. The pedicle seemed to improve control over orientation, unrolling, centration, and rebubbling, potentially increasing the ease of DMEK surgery. The pedicle was safely truncated without sequelae.


A rare case of gliomatosis cerebri presenting as dementia.
Dementia with the onset before the age of 65 years is classified as early-onset dementia. Although uncommon, it has considerable impact on the lives of patients and care givers, alike. A substantial subset of patients may have underlying reversible causes. Yet, many, especially those of the very young may be initially misdiagnosed. A case of young woman with rapid mental decay is described here. She was finally diagnosed with gliomatosis cerebri (GC) involving only right frontal lobe. This atypical radiological feature of GC with primary presentation as memory loss needs special attention and clinicians should be aware of such conditions.


Constructing Unique Cross-Sectional Structured Mixed Matrix Membranes by Incorporating Ultrathin Microporous Nanosheets for Efficient CO2 Separation.
Ultrathin microporous nanosheets denoted as Zn-tetra-(4-carboxyphenyl)porphyrin (Zn-TCPP) were synthesized and incorporated into a Pebax MH 1657 (Pebax) polymer to fabricate mixed matrix membranes (MMMs) for efficient CO2 separation. The Zn-TCPP nanosheets with a microporous structure provide high-speed channels for fast CO2 transport and shorten the diffusion pathways, both contributing toward high CO2 permeability. Furthermore, scanning electron microscopy results indicate that the ultrathin Zn-TCPP nanosheets with an ultrahigh aspect ratio (>200) tend to arrange horizontally in the Pebax matrix. The obtained unique cross-sectional structure of the MMMs functions as a selective barrier, allowing repeated discrimination of gases due to the tortuous interlayer of horizontal nanosheets, thus improving the selectivity of the MMMs. In addition, the horizontally arranged microporous nanosheets were found to strongly interact with the membrane matrix and endowed the MMMs with excellent interfacial compatibility, which improved the CO2 permeability and eliminated unselective permeation pathways. Significantly, the optimized CO2 separation performance of the MMMs surpassed the 2008 Robeson's limit.


Origin and diversification of fibroblasts from the sclerotome in zebrafish.
Fibroblasts play an important role in maintaining tissue integrity by secreting components of the extracellular matrix and initiating response to injury. Although the function of fibroblasts has been extensively studied in adults, the embryonic origin and diversification of different fibroblast subtypes during development remain largely unexplored. Using zebrafish as a model, we show that the sclerotome, a sub-compartment of the somite, is the embryonic source of multiple fibroblast subtypes including tenocytes (tendon fibroblasts), blood vessel associated fibroblasts, fin mesenchymal cells, and interstitial fibroblasts. High-resolution imaging shows that different fibroblast subtypes occupy unique anatomical locations with distinct morphologies. Long-term Cre-mediated lineage tracing reveals that the sclerotome also contributes to cells closely associated with the axial skeleton. Ablation of sclerotome progenitors results in extensive skeletal defects. Using photoconversion-based cell lineage analysis, we find that sclerotome progenitors at different dorsal-ventral and anterior-posterior positions display distinct differentiation potentials. Single-cell clonal analysis combined with in vivo imaging suggests that the sclerotome mostly contains unipotent and bipotent progenitors prior to cell migration, and the fate of their daughter cells is biased by their migration paths and relative positions. Together, our work demonstrates that the sclerotome is the embryonic source of trunk fibroblasts as well as the axial skeleton, and local signals likely contribute to the diversification of distinct fibroblast subtypes.


The effect of neoprene shorts on leg proprioception in Australian football players.
Our purpose was to assess the effect of wearing close-fitting neoprene shorts on swinging leg movement discrimination (MD) scores in elite level Australian Football players. Twenty players had their swinging leg MD assessed using the active movement extent discrimination apparatus (AMEDA), once wearing close-fitting neoprene and once wearing loose-fitting running shorts. Subjects were randomly allocated to one of the shorts conditions prior to repeating the test in the other condition. The AMEDA was used to assess the accuracy at which subjects judge the extent of a standing backward swinging leg movement corresponding to the late swing early stance phase of running. Each subject performed 40 movements made to one of five randomly set physical limits, and without the aid of vision made a judgment as to the perceived limit position. From the accuracy of these judgments, a movement discrimination (MD) score was calculated for each subject under each condition. Subjects were grouped as having low or high neuromuscular control, or ability to use proprioception when controlling active movements without vision, based on their loose-shorts MD score. Analysis was performed on the MD scores obtained for each limb from subjects in the two groups, under the two shorts-wearing conditions. There was no main effect of wearing close-fitting shorts when the cohort was treated as a whole. A significant interaction effect was obtained (F=17.027, p=0.0006) whereby the mean MD score of the low neuromuscular control ability group was improved when wearing neoprene shorts but was reduced for the high ability group. Wearing close-fitting neoprene shorts has a beneficial effect on leg swing judgment accuracy in subjects with low neuromuscular control ability. Conversely, leg swing judgment accuracy for subjects with high ability was reduced by wearing neoprene shorts.


Cryptic speciation in the Triatoma sordida subcomplex (Hemiptera, Reduviidae) revealed by chromosomal markers.
Chagas disease vectors (Hemiptera-Reduviidae) comprise more than 140 blood-sucking insect species of the Triatominae subfamily. The largest genus is Triatoma, subdivided in several complexes and subcomplexes according to morphology, ecology and genetic features. One of them is the sordida subcomplex, involving four species: Triatoma sordida, T. guasayana, T. garciabesi and T. patagonica. Given the great morphological similarity of these species, their taxonomic identification, evolutionary relationships and population differentiation have been controversial for many years and even today remain under discussion. We simultaneously analyzed two chromosomal markers, C-heterochromatin distribution and 45S ribosomal genes chromosomal position, of 139 specimens from several sordida subcomplex populations from Argentina, Bolivia, Brazil and Paraguay, collected both in nature and from several established insectaries. Our results were compared with COI sequences deposited in GenBank. We recognized five chromosomal taxa with putative hybrids, which each differ in at least one chromosome marker. Most of them present significant differences in their mtDNA sequences. The chromosomal taxa here show a significant chromosome differentiation involving changes in the C-heterochromatin content and in the ribosomal clusters position. This paper identifies several erroneously classified populations by morphological methods, delimits the geographical distribution of each taxon and proposes the existence of a new cryptic species, widely distributed in Argentina. We also suggest that sordida sibling species involve closely related as well as evolutionary distant species. Taxonomic status of each chromosomal taxon is discussed considering phenotypic and genetic results previously published.


Overrecruitment in the aging brain as a function of task demands: evidence for a compensatory view.
This study used fMRI to investigate the neural effects of increasing cognitive demands in normal aging and their role for performance. Simple and complex go/no-go tasks were used with two versus eight colored letters as go stimuli, respectively. In both tasks, no-go stimuli could produce high conflict (same letter, different color) or low conflict (colored numbers) with go stimuli. Multivariate partial least square analysis of fMRI data showed that older adults overengaged a cohesive pattern of fronto-parietal regions with no-go stimuli under the specific combination of factors which progressively amplified task demands: high conflict no-go trials in the first phase of the complex task. This early neural overrecruitment was positively correlated with a lower error rate in the older group. Thus, the present data suggest that age-related extra-recruitment of neural resources can be beneficial for performance under taxing task conditions, such as when novel, weak, and complex rules have to be acquired.


Comparison of Shetty ankle test and Ottawa ankle rules in ankle injuries.
Foot and ankle injuries are the most common extremity trauma and have an important place among the admissions to the emergency service. Ankle injuries are the most frequent form of orthopedic emergencies. Currently, Ottawa ankle rules (ORL) is the most popular test used worldwide for the ankle injuries. Shetty test is an important test used to evaluate the clinical status of patients admitted for the ankle trauma. This study was initiated in the emergency service between May 1, 2018, and May 1, 2019, after the approval of the Ethics Committee. The patients were classified according to gender, age, and admission, Ottawa test results, Shetty test results, and radiography status. Shetty test can be used to differentiate between the foot sprains and fractures as a simple and inexpensive method. Despite its effectiveness, Ottawa ankle rules is not widely used due to the detailed implementation of the Ottawa ankle rules and the components of the test. The ease of applicability of the Shetty test in primary care makes the test stand out. In our study, although the sensitivity of Shetty and Ottawa tests resulted in close percentages (82.86% - 85.71%), the specificity of Ottawa test was found to be higher. Detecting a fracture in emergency services is more valuable than excluding a fracture. Even though Shetty test is simple to use, we recommend Ottawa test for the foot and ankle sprains due to the legal problem that could be caused by Shetty test.


Medial Collateral Ligament Injury of the Knee: A Review on Current Concept and Management.
The medial collateral ligament (MCL) is a major stabilizer of the knee joint, providing support against rotatory and valgus forces; moreover, it is the most common ligament injured during knee trauma. The MCL injury results in valgus instability of the knee and makes the patient susceptible to degenerative knee osteoarthritis. Although it has been nearly a dogma to manage MCL injury nonoperatively, recent literature has suggested operative MCL management as a suitable option for specific patient populations. The present review aimed to assess the current literature on the management of MCL injuries of the knee. In this regard, we go over the anatomy, physical examination, and MCL imaging.


Evidence for a selective role of the delta-opioid agonist [8R-(4bS*,8aalpha,8abeta, 12bbeta)]7,10-Dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) in blocking hyperalgesia associated with inflammatory and neuropathic pain responses.
The specific involvement of the delta-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant delta-opioid agonist. [8R-(4bS*,8aalpha,8abeta,12bbeta)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (Ki = 4.81 +/- 0.39 nM) for the delta-opioid receptor, full agonist activity, and binding selectivity versus the mu- and kappa-opioid receptors of 189-fold and 52-fold, respectively. Perorally administered SB-236863 was inactive in the rat tail-flick and hot-plate tests of acute pain response, but potently reversed thermal hyperalgesia in rats resulting from a carrageenan-induced inflammatory response. This activity could be blocked by the delta-opioid antagonist naltrindole (3 mg/kg s.c.), but selective mu- and kappa-opioid antagonists were ineffective. Naltrindole (1 microg i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates delta-opioid receptor sites in the central nervous system. SB-235863 was additionally effective at reversing chronic hyperalgesia in the Seltzer rat model of partial sciatic nerve ligation after peroral administration. These data show that the delta-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of mu- and kappa-opioid receptor activation (slowing of gastrointestinal transit and motor incoordination, respectively) were not observed after administration of 70 mg/kg (p.o.) SB-235863, nor was evoked seizure activity affected. These results suggest a selective and limited role of delta-opioid receptors in the modulation of nociception.


Pod shatter-resistant Brassica fruit produced by ectopic expression of the FRUITFULL gene.
Arabidopsis has proven to be extremely useful as a reference organism for studies in plant biology, and huge efforts have been employed to unravel various mechanisms of Arabidopsis growth. A major challenge now is to demonstrate that this wealth of knowledge can be used for global agricultural and environmental improvement. Brassica species are closely related to Arabidopsis and represent ideal candidates for model-to-crop approaches as they include important crop plants, such as canola. Brassica plants normally disperse their seeds by a pod-shattering mechanism. Although this mechanism is an advantage in nature, unsynchronized pod shatter constitutes one of the biggest problems for canola farmers. Here, we show that ectopic expression of the Arabidopsis FRUITFULL gene in Brassica juncea is sufficient to produce pod shatter-resistant Brassica fruit and that the genetic pathway leading to valve margin specification is conserved between Arabidopsis and Brassica. These studies demonstrate a genetic strategy for the control of seed dispersal that should be generally applicable to diverse Brassica crop species to reduce seed loss.


Incorporating Trialkylsilylethynyl-Substituted Head-to-Head Bithiophene Unit into Copolymers for Efficient Non-Fullerene Organic Solar Cells.
Mediating the backbone coplanarity and solubility of oligothiophenes, especially the head-to-head (HH) disubstituted bithiophene, to achieve an optically and electronically advantageous building block for organic semiconductor materials is a vital yet challenging task. On the other hand, exploring polymer solar cells (PSCs) processed from nonhalogenated solvents is necessary toward their large-scale applications. In this contribution, we develop a HH-type bithiophene analogue (TIPS-T2) by strategically applying the triisopropylsilylethynyl (TIPS) scaffold as the side chain. TIPS can serve to narrow optical band gaps, lower the highest occupied molecular orbital level, reduce intrachain steric hindrance, and guarantee sufficient solubility of the involving polymers. Upon alternating with difluorobenzotriazole (FTAZ) or benzodithiophene-4,8-dione (BDD) acceptor units, two polymers named PT4Si-FTAZ and PT4Si-BDD are synthesized. Encouragingly, non-fullerene PSCs incorporating PT4Si-FTAZ yield a power conversion efficiency of 6.79% when processed from an environment-friendly solvent of trimethylbenzene because of its promoted backbone planarity, as demonstrated by density functional theory, higher hole mobility, and superior film morphology. The results indicate that TIPS-T2 is a promising building block for constructing photovoltaic polymers, and our findings offer an avenue for the ingenious use of TIPS as functional side chains.


Glycemic variability: adverse clinical outcomes and how to improve it?
Glycemic variability (GV), defined as an integral component of glucose homoeostasis, is emerging as an important metric to consider when assessing glycemic control in clinical practice. Although it remains yet no consensus, accumulating evidence has suggested that GV, representing either short-term (with-day and between-day variability) or long-term GV, was associated with an increased risk of diabetic macrovascular and microvascular complications, hypoglycemia, mortality rates and other adverse clinical outcomes. In this review, we summarize the adverse clinical outcomes of GV and discuss the beneficial measures, including continuous glucose monitoring, drugs, dietary interventions and exercise training, to improve it, aiming at better addressing the challenging aspect of blood glucose management.


Impact of antenatal corticosteroids on frequency and mortality due to respiratory distress syndrome in preterm neonates.
Prematurity is still a major problem for health care services throughout the world. Before the late 1980s, respiratory distress syndrome (RDS) was the primary cause of morbidity and mortality in preterm new-borns. Frequency of RDS and ensuing mortality in infants treated with antenatal steroid is less than those delivered without this therapy. Many pregnant females deliver before term or 37 weeks, hence may be advised this prophylactic therapy without creating significant maternal or foetal side effects. It was a descriptive case-series conducted in the department of obstetrics and gynaecology, unit II of Jinnah Hospital Lahore for a period of 6 months. The study sample of 230 was divided into two groups on the basis of exposure to dexamethasone. RDS was reported 76 (33.0%) cases (preterm neonates) in the study, out of these 26 (22.4%) cases belonged to exposed group and 50 (43.9%) cases belonged to non-exposed group. Mortality due to RDS among all preterm neonates with RDS occurred in total 29 (12.6%) preterm neonates in the study, out of these 5 (4.3%) cases belonged to exposed group and 24 (21.1%) belonged to non-exposed group. Frequency of RDS and mortality due to this disease in group of infants treated with antenatal steroid is far less than the group of preterm new-borns delivered without this therapy.


Remote orbital recurrence of olfactory neuroblastoma (esthesioneuroblastoma).
Olfactory neuroblastoma is a rare and often locally aggressive malignancy that invades the orbit via local destruction. It is known to recur in a delayed fashion, particularly to the neck lymph nodes. This is a case of a 65-year-old gentleman who presents with recurrence in the orbit and a neck lymph node 19 years after treatment for his initial disease. This report describes the longest known interval in orbital recurrence and should alert the monitoring physician that extreme delays in recurrence can occur.


Citron C-05 inhibits both the penetration and colonization of Xanthomonas citri subsp. citri to achieve resistance to citrus canker disease.
Citrus canker, caused by Xanthomonas citri subsp. citri (Xcc), is a serious bacterial disease that affects citrus production worldwide. Citron C-05 (Citrus medica) is the only germplasm in the Citrus genus that has been identified to exhibit strong resistance to Xcc. However, it has not been determined when, where, and how Xcc is restricted in the tissues of Citron C-05 during the infection process. In the present study, we investigated the spatiotemporal growth dynamics of an eGFP-labeled virulent Xcc (eGFP-Xcc) strain in Citron C-05 along with five susceptible biotypes (i.e., lemon, pummelo, sour orange, sweet orange, and ponkan mandarin) upon inoculation via the spraying or leaf infiltration of a bacterial suspension. The results from extensive confocal laser scanning microscopy analyses showed that while Xcc grew rapidly in plants of all five susceptible genotypes, Xcc was severely restricted in the epidermal and mesophyll cell layers of the leaves of Citron C-05 in the early stage of infection. Not surprisingly, resistance against Xcc in Citron C-05 was found to be associated with the production of reactive oxygen species and hypersensitive response-like cell death, as well as greater upregulation of several defense-related genes, including a pathogenesis-related gene (PR1) and a glutathione S-transferase gene (GST1), compared with sweet orange as a susceptible control. Taken together, our results not only provide further valuable details of the spatiotemporal dynamics of the host entry, propagation, and spread of Xcc in both resistant and susceptible citrus plants but also suggest that resistance to Xcc in Citron C-05 may be attributed to the activation of multiple defense mechanisms.


Assessment of the Relationship between Selected Factors and Stress-Coping Strategies in Handcyclists-A Preliminary Study.
Background and Objectives: Playing competitive sports is associated with stress, especially during the starting season. Disabled athletes are additionally burdened with physical and/or emotional factors, resulting from the trauma they have experienced. The aim of the work was to assess the relationship between strategies of coping with stress and the level of education, category of disability and its duration of handcyclists before the competition. Materials and Methods: 44 handcyclists with a mean age of 41.8 ± 11.6, from European countries, were divided according to the severity of mobility impairments, education and duration of the disability. The participants were asked to fill in the Mini-COPE Inventory for Measuring Coping with Stress, which provided answers in writing to some sociodemographic questions regarding age, sex, education, type of mobility impairment and duration of the disability. Results: The subjects who had suffered spinal injury at the cervical section obtained the lowest scores regarding their subjective assessment of their active stress management in difficult situations (p = 0.007). They scored the lowest, 1.5 points, when asked about acceptance in difficult circumstances compared to those with university education (p = 0.02). A statistically significant correlation was found to exist between education levels and positive revaluation, acceptance and seeking instrumental support. A negative correlation was observed between education and sustained use of psychoactive substances and denial. Conclusions: Highly educated cyclists with short-lasting disability, damage to the lower spine section or amputations tend to cope better with stress than other study participants.


Induction of chromosomal aberrations by DNase I.
Chinese hamster ovary (CHO) cells were treated with bovine pancreatic DNase I using the method of electroporation. The enzyme induced chromosomal aberrations in a S-phase independent manner. The frequencies of polycentric chromosomes induced in the G1 phase of the cell cycle are positively correlated with the dose of DNase I. The distributions of DNase I-induced polycentric chromosomes were overdispersed.


Best Practices for COVID-19 Mass Vaccination Clinics.
The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented global public health crisis. Mass vaccination is the safest and fastest pandemic exit strategy. Mass vaccination clinics are a particularly important tool in quickly achieving herd immunity. Primary care physicians have played a crucial role in organizing and running vaccination clinics. In this special report, we synthesize existing guidelines and peer-reviewed studies to provide physicians with practical guidance on planning and implementing COVID-19 mass vaccination clinics. PubMed, Ovid MEDLINE and Embase were used to search for relevant literature using search terms that included COVID-19, mass vaccination, and best practice. We also identified and analyzed national and international guidelines. Forty-six relevant articles, reports, and guidelines were identified and synthesized. Articles included mass vaccination clinic guidelines and studies before and during the COVID-19 pandemic. Key considerations for COVID-19 mass vaccination clinics include leadership and role designation, site selection, clinic layout and workflow, day-to-day operations, infection prevention, and communication strategies. Planning and implementing a successful COVID-19 mass vaccination clinic requires several key considerations. Primary care plays an important role in organizing clinics and ensuring populations made vulnerable by social and economic policies are being reached. Ongoing data collection is required to evaluate and continuously improve COVID-19 mass vaccination efforts. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine rollout occurs in various countries, research will be required to identify the main factors for success to inform future pandemic responses.VISUAL ABSTRACT.


Circulating primitive erythroblasts establish a functional, protein 4.1R-dependent cytoskeletal network prior to enucleating.
Hematopoietic ontogeny is characterized by distinct primitive and definitive erythroid lineages. Definitive erythroblasts mature and enucleate extravascularly and form a unique membrane skeleton, composed of spectrin, 4.1R-complex, and ankyrinR-complex components, to survive the vicissitudes of the adult circulation. However, little is known about the formation and composition of the membrane skeleton in primitive erythroblasts, which progressively mature while circulating in the embryonic bloodstream. We found that primary primitive erythroblasts express the major membrane skeleton genes present in similarly staged definitive erythroblasts, suggesting that the composition and formation of this membrane network is conserved in maturing primitive and definitive erythroblasts despite their respective intravascular and extravascular locations. Membrane deformability and stability of primitive erythroblasts, assayed by microfluidic studies and fluorescence imaged microdeformation, respectively, significantly increase prior to enucleation. These functional changes coincide with protein 4.1 R isoform switching and protein 4.1R-null primitive erythroblasts fail to establish normal membrane stability and deformability. We conclude that maturing primitive erythroblasts initially navigate the embryonic vasculature prior to establishing a deformable cytoskeleton, which is ultimately formed prior to enucleation. Formation of an erythroid-specific, protein 4.1R-dependent membrane skeleton is an important feature not only of definitive, but also of primitive, erythropoiesis in mammals.


Patterns of anaphylaxis after diagnostic workup: A follow-up study of 226 patients with suspected anaphylaxis.
Most published studies on anaphylaxis are retrospective or register based. Data on subsequent diagnostic workup are sparse. We aimed to characterize patients seen with suspected anaphylaxis at the emergency care setting (ECS), after subsequent diagnostic workup at our Allergy Center (AC). Prospective study including patients from the ECS, Odense University Hospital, during May 2013-April 2014. Possible anaphylaxis cases were daily identified based on a broad search profile including history and symptoms in patient records, diagnostic codes and pharmacological treatments. At the AC, all patients were evaluated according to international guidelines. Among 226 patients with suspected anaphylaxis, the diagnosis was confirmed in 124 (54.9%) after diagnostic workup; 118 of the 124 fulfilled WAO/EAACI criteria of anaphylaxis at the ECS, while six were found among 46 patients with clinical suspicion but not fulfilling the WAO/EAACI criteria at the ECS. The estimated incidence rate of anaphylaxis was 26 cases per 100 000 person-years and the one-year period prevalence was 0.04%. The most common elicitor was drugs (41.1%) followed by venom (27.4%) and food (20.6%). In 13 patients (10.5%), no elicitor could be identified. Mastocytosis was diagnosed in 7.7% of adult patients and was significantly associated with severe anaphylaxis. Atopic diseases were significantly associated only with food-induced anaphylaxis. Cofactors were present in 58.1% and were significantly associated with severe anaphylaxis. A broad search profile in the ECS and subsequent diagnostic workup is important for identification and classification of patients with anaphylaxis. Evaluation of comorbidities and cofactors is important.


Desmoplastic Ameloblastoma-A Case Report.
Desmoplastic ameloblastoma (DA) is a rare variant of conventional ameloblastoma. It accounts for only 4%-13% of all ameloblastomas. DA was included in the World Health Organization Classification of Head and Neck Tumors (WHO-2005) as a variant of ameloblastoma with specific clinical, imaging, and histological features. The desmoplastic variant of ameloblastoma usually appears in the anterior and premolar regions as a mixed radiolucent and radiopaque lesion, sometimes resembling a benign fibro-osseous lesion.Ameloblastoma is a locally aggressive tumor that may cause recurrence and in rare cases, malignant transformation with repeated postsurgical recurrences. In this paper, we present a case of a 28-year-old female with swelling in the left upper jaw, a biopsy of which turned out to be DA.


The Phytochemical Scoulerine Inhibits Aurora Kinase Activity to Induce Mitotic and Cytokinetic Defects.
To identify novel bioactive compounds, an image-based, cell culture screening of natural product extracts was conducted. Specifically, our screen was designed to identify phytochemicals that might phenocopy inhibition of the chromosomal passenger protein complex in eliciting mitotic and cytokinetic defects. A known alkaloid, scoulerine, was identified from the rhizomes of the plant Corydalis decumbens as being able to elicit a transient mitotic arrest followed by either apoptosis induction or polyploidy. In examining the mitotic abnormality further, we observed that scoulerine could elicit supernumerary centrosomes during mitosis, but not earlier in the cell cycle. The localization of NUMA1 at spindle poles was also inhibited, suggesting diminished potential for microtubule recruitment and spindle-pole focusing. Polyploid cells emerged subsequent to cytokinetic failure. The concentration required for scoulerine to elicit all its cell division phenotypes was similar, and an examination of related compounds highlighted the requirement for proper positioning of a hydroxyl and a methoxy group about an aromatic ring for activity. Mechanistically, scoulerine inhibited AURKB activity at concentrations that elicited supernumerary centrosomes and polyploidy. AURKA was only inhibited at higher concentrations, so AURKB inhibition is the likely mechanism by which scoulerine elicited division defects. AURKB inhibition was never complete, so scoulerine may be a suboptimal AURK inhibitor or work upstream of the chromosomal passenger protein complex to reduce AURKB activity. Scoulerine inhibited the viability of a variety of human cancer cell lines. Collectively, these findings uncover a previously unknown activity of scoulerine that could facilitate targeting human cancers. Scoulerine, or a next-generation analogue, may be useful as a nontoxic component of combination therapies where inhibiting the chromosomal passenger protein complex is desired.


Seven transmembrane receptors as nature's prototype allosteric protein: de-emphasizing the geography of binding.
The article in this issue by Redka et al. (p. 834) illustrates some interesting interactions between classified orthosteric (bind to the same recognition site as endogenous agonist) and allosteric (bind to a different site) ligands. Of particular interest are the methods used to deal with an obfuscating factor in these kinds of studies, namely the propensity of seven transmembrane receptors to form dimers and thus demonstrate allosteric effects through binding at the orthosteric site. The judicious use of kinetics to detect and quantify allosteric action also is demonstrated. The various unique properties of allosteric modulators are discussed in the context of the increasing prevalence of allosteric ligands as investigational drugs.


Comparison of internet attitudes between industrial employees and college students.
Most studies of attitudes toward the Internet have been focused on a single entity. There is a gap when it comes to comparative study of Internet attitudes between college students and employees in the workforce. This study explored Internet attitudes between two different samples-employees in the work force and college students on campus. Four Internet attitude subscales-namely, enjoyment, usefulness, anxiety, and self-efficacy-from 296 college students were compared with a sample from 680 industrial employees. Age differences were found in the enjoyment and self-efficacy subscales, where younger people expressed more enjoyment than older people with the exception of female college students. Younger people expressed more self-efficacy than the older people. Factorial ANOVA analyses detected statistically significant differences between two samples among all subscales. In general, industrial employees reported more positive attitudes than college students. The employees reported more enjoyable Internet experience, felt the Internet was more useful, had less anxiety, and had more self-efficacy on the Internet than college students. Female college students showed more positive attitudes than male students, and male employees showed more positive attitudes than female employees. Interaction effects of different sample groups, gender, and age were found to have significant differences in the Internet anxiety and self-efficacy subscales. Recommendations for future research on these types of comparisons were included.


Cystic lesions of the pancreatico-biliary tree: A schematic MRI approach.
Although a common occurrence, cystic lesions of the pancreatico-biliary tree (PBT) may pose a diagnostic dilemma because they encompass a large number of neoplastic and benign processes with varied clinical symptoms. Knowledge of lesion classification and characterization are essential in making an accurate prospective diagnosis. This is necessary for identifying clinically significant cystic masses, which at times may require invasive intervention from indolent, nonneoplastic lesions, for which surveillance may suffice. Today, there is an arsenal of modalities for assessing the PBT, however, magnetic resonance imaging (MRI) remains at the forefront for characterizing cystic morphology and fluid content, internal septations, solid component, enhancement patterns, as well as assessing the surrounding normal structures. This pictorial review aims to review the spectrum of MRI features, which will aid in the differential diagnoses of cystic lesions of the PBT and mimickers, enabling the radiologist to reach a more confident diagnosis.


Reducing Ex-offender Health Disparities through the Affordable Care Act: Fostering Improved Health Care Access and Linkages to Integrated Care.
Despite steadily declining incarceration rates overall, racial and ethnic minorities, namely African Americans, Latinos, and American Indians and Alaska Natives, continue to be disproportionately represented in the justice system. Ex-offenders commonly reenter communities with pressing health conditions but encounter obstacles to accessing care and remaining in care. The lack of health insurance coverage and medical treatment emerge as the some of the most reported reentry health needs and may contribute to observed health disparities. Linking ex-offenders to care and services upon release increases the likelihood that they will remain in care and practice successful disease management. The Affordable Care Act (ACA) offers opportunities to address health disparities experienced by the reentry population that places them at risk for negative health outcomes and recidivism. Coordinated efforts to link ex-offenders with these newly available opportunities may result in a trajectory for positive health and overall well-being as they reintegrate into society.


Massive heterotopic ossification around the ankle in a patient with macrodactyly of the foot: a case report.
A 40-year-old man with macrodactyly of the left great toe presented with progressive enlargement of the ipsilateral ankle and increasing pain after minor trauma. Radiographs and computed tomographic scans of the foot and ankle revealed macrodactyly of the great toe and a large heterotopic ossified mass in the anteromedial aspect of the ankle. The large osseous lesion in the ankle was operatively excised. The lesion was easily excised en bloc after releasing the adhesion and histologically diagnosed as normal mature bone with osteoarthritic changes. Massive heterotopic ossification developing around the ankle in a patient with macrodactyly has not been previously reported. The current case was classified as hyperostotic macrodactyly. Operative treatment relieved the pain and improved the range of the motion of the ankle.


Neck management in patients undergoing postradiotherapy salvage laryngeal surgery for recurrent/persistent laryngeal cancer.
To determine a plan for the management of cervical lymph nodes in patients undergoing salvage laryngeal surgery (SLS) for recurrent/persistent laryngeal cancer after primary radiotherapy (RT). : Retrospective chart review. Charts of 51 consecutive patients who had salvage total or supracricoid laryngectomy with or without neck dissection for recurrent/persistent laryngeal squamous cell carcinoma after primary RT from 1988 to 2005 in our institution were reviewed. No patients received concomitant or neo-adjuvant chemotherapy. Thirty-four patients underwent SLS along with unilateral or bilateral neck dissection, whereas 17 patients underwent the SLS without neck dissection. Reports of preRT and preSLS staging of the primary tumor and the neck, recorded using the TNM system, were reviewed. Reports of the final histopathologic examination for the excised laryngeal cancer and cervical lymph nodes were reviewed. Thirty-four patients underwent SLS with unilateral or bilateral neck dissection. The preRT staging of the primary tumor for those 34 patients showed that 32 (94%) were staged T-1 (14) and T-2 (18), whereas the preSLS staging of the primary tumor for those 34 patients showed that 29 (85%) were staged T-3 and T-4. The postSLS final histopathologic examination of the excised lymph nodes in those 34 patients demonstrated that 30 (88%) did not have any evidence of nodal metastasis. On comparing patients with and without nodal metastasis (on their postSLS final histopathology), we found that the preSLS neck staging, based on computed tomographic (CT) scanning of the neck, was significantly associated with the negative/positive postSLS status of nodal metastasis (P = .006). Of 29 patients staged preSLS as N-0, 28 (97%) patients did not have nodal metastasis on their postSLS final pathology (negative predictive value = 97%, confidence interval, 82.2-99.9). PreRT neck staging, preRT and preSLS staging of the primary tumor, along with laryngeal subsite involvement (supraglottis, glottis, subglottis) did not significantly correlate with the status of neck metastasis on final postSLS histopathology (P = .68, 0.78, 0.49, and 0.42, respectively). None of the 34 patients had any neck tumor recurrence in the postSLS follow-up period (median, 3 yr). In addition, all 17 patients who underwent SLS without neck dissection were staged N-0 both before RT as well as preSLS, and none developed neck disease in the postSLS follow-up period (median, 2.5 yr). Management of the neck in patients undergoing salvage total or supracricoid laryngectomy for laryngeal cancer recurrence/persistence after primary RT should be based on the preSLS CT staging of the neck. Patients staged N-0 preSLS are not likely to harbor occult nodal metastasis and therefore may not require elective neck dissection.


Framing a Knowledge Base for a Legal Expert System Dealing with Indeterminate Concepts.
Despite decades of development of formal tools for modelling legal knowledge and reasoning, the creation of a fully fledged legal decision support system remains challenging. Among those challenges, such system requires an enormous amount of commonsense knowledge to derive legal expertise. This paper describes the development of a negotiation decision support system (the Parenting Plan Support System or PPSS) to support parents in drafting an agreement (the parenting plan) for the exercise of parental custody of minor children after a divorce is granted. The main objective here is to discuss problems of framing an intuitively appealing and computationally efficient knowledge base that can adequately represent the indeterminate legal concept of the well-being of the child in the context of continental legal culture and of Polish law in particular. In addition to commonsense reasoning, interpretation of such a concept demands both legal expertise and significant professional knowledge from other domains.


Microbial detoxification of metalaxyl in aquatic system.
Four microorganisms, Pseudomonas sp. (ER2), Aspergillus niger (ER6), Cladosporium herbarum (ER4) and Penicilluim sp. (ER3), were isolated from cucumber leaves previously treated with metalaxyl using enrichment technique. These isolates were evaluated for detoxification of metalaxyl at the recommended dose level in aquatic system. The effect of pH and temperature on the growth ability of the tested isolates was also investigated by measuring the intracellular protein and mycelia dry weight for bacterial and fungal isolates, respectively. Moreover, the toxicity of metalaxyl after 28 d of treatment with the tested isolates was evaluated to confirm the complete removal of any toxic materials (metalaxyl and its metabolites). The results showed that the optimum degree pH for the growth of metalaxyl degrading isolates (bacterial and fungal isolates) was 7. The temperature 30 degrees C appeared to be the optimum degree for the growth of either fungal or bacterial isolates. The results showed that Pseudomonas sp. (ER2) was the most effective isolate in metalaxyl degradation followed by Aspergillus niger (ER6), Cladosporium herbarum (ER4) and Penicilluim sp. (ER3), respectively. There is no toxicity of metalaxyl detected in the supernatant after 28 d of treatment with Pseudomonas sp. (ER2). The results suggest that bioremediation by Pseudomonas sp. (ER2) isolate was considered to be effective method for detoxification of metalaxyl in aqueous media.


Characterization of Factors Affecting the Detection Limit of EGFR p.T790M in Circulating Tumor DNA.
Circulating tumor DNA is a promising noninvasive tool for cancer monitoring. One of the challenges in applying this tool is the detection of low-frequency mutations. The detection limit of these mutations varies between different molecular methods. The aim of this study is to characterize the factors affecting the limit of detection for epidermal growth factor receptor p.T790M mutation in circulating tumor DNA of patients with lung adenocarcinoma. DNA was extracted from plasma samples of 102 patients. For sequencing the DNA, we used 2 different next-generation sequencing-based platforms: Ion Torrent Personal Genome Machine (56 cases) and Roche/454 (46 cases). Serially diluted synthetic DNA samples carrying the p.T790M mutation were sequenced using the Ion Torrent Personal Genome Machine for validation. Limit of detection was determined through the analysis of non-hot-spot nonreference reads, which were regarded as sequencing artifacts. The frequency of the non-hot-spot nonreference reads was higher in Ion Torrent Personal Genome Machine compared to Roche/454 (0.07% ± 0.08% and 0.03% ± 0.06%, respectively, P < .001). We found that different base type substitutions occur with different frequency. Since the base substitution leading to p.T790M mutation is C>T transition, its frequency was used to determine the limit of detection for the assay. Based on the C>T non-hot-spot nonreference allele frequency, we found that the limit of detection is 0.18% in Ion Torrent Personal Genome Machine and 0.1% in Roche/454. Based on these values, 48% and 56% of the cases were positive for T790M mutation in Ion Torrent Personal Genome Machine and Roche/454 groups, respectively. Agreement between duplicates was 76% in Ion Torrent Personal Genome Machine and 72% in Roche/454. Using serially diluted synthetic DNA samples carrying the p.T790M mutation, we could identify mutations with allele frequency of 0.18% or more using the Ion Torrent Personal Genome Machine, supporting our approach to determine the detection limit. Both the sequencing platform and the specific nucleotide change affect the limit of detection and should therefore be determined in the validation process of new assays.


Modeling mercury porosimetry using statistical mechanics.
We consider mercury porosimetry from the perspective of the statistical thermodynamics of penetration of a nonwetting liquid into a porous material under an external pressure. We apply density functional theory to a lattice gas model of the system and use this to compute intrusion/extrusion curves. We focus on the specific example of a Vycor glass and show that essential features of mercury porosimetry experiments can be modeled in this way. The lattice model exhibits a symmetry that provides a direct relationship between intrusion/extrusion curves for a nonwetting fluid and adsorption/desorption isotherms for a wetting fluid. This relationship clarifies the status of methods that are used for transforming mercury intrusion/extrusion curves into gas adsorption/desorption isotherms. We also use Monte Carlo simulations to investigate the nature of the intrusion and extrusion processes.


Changes in alcoholic beverage preference and consumption in Taiwan following accession to the World Trade Organization.
Given the growing concerns that international trade agreements may increase the supply of health-harming commodities, including alcohol, this study aimed to investigate the changes in alcoholic beverage preference and consumption after Taiwan's accession to the World Trade Organization (WTO). A before-and-after comparison analysis using data from two waves (1993-1996 and 2005-2008) of the Nutrition and Health Survey in Taiwan (NAHSIT), before and after Taiwan's accession to the WTO in 2002. Taiwan. A total of 5031 and 2910 participants aged 19 years or older in NAHSIT 1993-1996 and 2005-2008, respectively. Alcohol measures included beverage-specific preference, mean daily ethanol consumption, and heavy drinking. Logistic regression was used to estimate the prevalence rate ratios and rate differences of beverage preferences between the two waves and the risk ratios of heavy drinking associated with different beverage preferences. A reduced prevalence rate of drinkers who preferred rice spirits (prevalence rate ratio [PRR] = 0.47; 95% confidence interval [CI] = 0.24, 0.91) and Asian wine (PRR = 0.11; 95% CI = 0.04, 0.29) was found in contrast to an increase in the preference for fruit wine (PRR = 2.90; 95% CI = 1.75, 4.79); the preference for Asian spirits showed a non-significant increase (PRR = 1.63; 95% CI = 0.88, 3.02). Similarly, the mean daily ethanol consumption decreased for Asian wine and increased for Asian spirits. Compared with beer, an increased risk of heavy drinking was associated with rice spirits (adjusted risk ratio [aRR] = 3.30; 95% CI = 1.68, 6.47) and Asian spirits (aRR = 2.64; 95% CI = 1.38, 5.01). After Taiwan became a member of the World Trade Organization and abolished its alcohol monopoly in 2002, the pattern of alcoholic beverage preference changed markedly, including a decrease in drinkers who preferred rice spirits and Asian wine (53% and 89% decrease, respectively) and an increase in drinkers who preferred fruit wine and Asian spirits (2.9-fold and 1.6-fold increase, respectively).


Lighted ureteral stents in laparoscopic colorectal surgery; a five-year experience.
Ureteral injuries during colorectal surgery are a rare event, ranging in the literature from 0.28-7.6%. Debate surrounds the use of prophylactic lighted ureteral stents to help protect the ureter during laparoscopic surgery. It has been suggested that they help to identify injuries but do not prevent them. The authors look to challenge this. Over 66 months, every laparoscopic or colectomy involving ureteral stents was recorded. Researchers documented any injury to the ureter intraoperatively. The chart was also reviewed for the complications of urinary tract infection (UTI) and urinary retention post-operatively. During the 66 months, 402 laparoscopic colon resections were done. There were no ureteral injuries. The lighted ureteral stent was identified during every case in the effort to prevent injury during dissection and resection. No catheter associated UTIs were identified, while 14 (3.5%) suffered from post-operative urinary retention. The authors of this study present a large series of colon resections with no intraoperative ureteral injuries. In addition, these catheters were not associated with any UTIs and a rate of urinary retention similar to that of the at large data. This series provides compelling data to use lighted ureteral stents during laparoscopic colon surgery.


Pulmonary artery obstruction due to malignant fibrous histiocytoma.
Obstruction of the pulmonary artery can be due to a variety of conditions, including chronic thromboembolic disease, neoplasia, and fibrosing mediastinitis. Differentiation can be difficult. We report a case of malignant fibrous histiocytoma causing intravascular obstruction and include a review of the literature.


[Knockdown of Grb7 inhibits growth of oral squamous cell carcinoma, cell proliferation and promoted apoptosis through ERK/FOXM1 pathway].
To investigate the effect of growth factor receptor-bound 7 (Grb7) on oral squamous cell carcinoma growth and tumor xenografts. Cal27 and hNOK cells were cultivated, real-time PCR and Western blotting were used to detect the expression of Grb7 in hNOK and Cal27. Cal27 was transfected with Grb7 siRNA for 48 h, cell proliferation was assayed using MTT. Flow cytometry was used to determine the cell cycle and apoptosis. Western blot was used to evaluate the expression of caspase3, Bax, bcl-2, Cyclin D1, Rb, E2F1, ERK and FOXM1. Grb7 siRNA and negative control were designed and injected subcutaneously into the mice, tumor volume and weight were measured. Statistical analysis was performed using SPSS 11.0 software package. Grb7 was highly expressed in Cal27 compared with hNOK. Depletion of Grb7 significantly inhibited cell proliferation, blocked G1/S phase transition, promoted cell apoptosis. Knockdown of Grb7 suppressed the expression of Cyclin D1 and Rb, upregulated E2F1 expression. Moreover, c-caspase 3 and Bax was also reduced after inhibition of Grb7. ERK/FOXM1 signaling pathway was also inhibited by Grb7. In addition, the volume and weight of tumor xenografts were reduced by siGrb7. Depletion of Grb7 inhibits cell proliferation, promotes apoptosis and reduces tumor xenografts through ERK/FOXM1 pathway.


Parameterization of the shape of intracranial saccular aneurysms using Legendre polynomials.
Our recent studies of the nonlinear mechanics of saccular aneurysms suggest that it is unlikely that these lesions enlarge or rupture via material (limit point) or dynamic (resonance) instabilities. Rather, there is a growing body of evidence from both vascular biology and biomechanical analyses that implicate mechanosensitive growth and remodeling processes. There is, therefore, a pressing need to quantify regional multiaxial wall stresses which, because of the membrane-like behavior of many aneurysms, necessitates better information on the applied loads and regional surface curvatures. Herein, we present and illustrate a method whereby regional curvatures can be estimated easily for sub-classes of human aneurysms based on clinically available data from magnetic resonance angiography (MRA). Whereas Legendre polynomials are used to illustrate this approach, different functions may prove useful for different sub-classes of lesions.


Bubble Point Measurements of Mixtures of HFO and HFC Refrigerants.
Bubble point pressures of six binary mixtures at two compositions each have been measured utilizing a static method. The performance of the apparatus was characterized from bubble point measurements of R32 + R125 for which 19 literature studies are available for comparison. The mixtures studied were as follow: R1234yf + R134a, R134a + R1234ze (E), R1234yf + R1234ze (E), R125 + R1234yf, R1234ze (E) + R227ea and R1234yf + R152a. For each mixture measurements were conducted from 270 K to 360 K or to within approximately 10 K of the critical temperature of the pure component with the lower critical temperature. A total of 196 bubble point pressures are reported with combined expanded uncertainties (k = 2) ranging from 0.1% - 0.6%. The measured data are graphically compared to available literature data.


Chondrosarcoma of the trachea. A case report and literature review.
The cytologic presentation of a case of chondrosarcoma of the trachea in a 72-year-old man is described. A mass detected on routine chest roentgenogram and defined by CT scan was used to make a touch imprint smear during partial tumor resection. The cytologic findings included round or polygonal cells with occasional binucleation, round hyperchromatic nuclei and prominent nucleoli, present in an amorphous pink-violet or light-blue background containing fragments of chondroid tissue. The histopathology was interpreted as a low-grade chondrosarcoma. Cartilaginous tumors of the trachea should be considered in the differential diagnosis of upper airway obstruction.


Reduction of Serum Uric Acid Associated with Attenuation of Renal Injury, Inflammation and Macrophages M1/M2 Ratio in Hyperuricemic Mice Model.
Hyperuricemia contributed to endothelial dysfunction, activation of the RAS system, increased oxidative stress and maladaptive immune system response. M1 and M2 macrophages were known to contribute to the onset of renal fibrosis. This study aimed to look at the effect of lowering serum uric acid levels on renal injury in mice. This study used 25 male mice, 3 months old, that divided into 5 groups. We injected uric acid intraperitoneally, 125mg/kg/day for 7 days (UA7) and 14 days (UA14), to induce hyperuricemia and then gave allopurinol 50mg/kg/day for 7 days to lower serum uric acid levels (UA7AL7 and UA14AL7). At the end of the treatment, we measured serum uric acid levels, Glomerular Injury Score (GIS) and Arteriolar Injury Score (AIS) with PAS staining, eNOS and MCP-1 expression with Reverse Transcriptase-PCR (RT-PCR), macrophages M1/M2 ratio with anti-CD68 and anti-arginase I immunohistochemical staining. Data were analyzed by one-way ANOVA and Kruskal-Wallis test. Uric acid injection increased serum uric acid levels in UA7 and UA14 group (p<0.05), followed by the increase in GIS and AIS. RT-PCR showed increased expression of MCP-1 and decreased expression of eNOS. M1 macrophages count was higher than control in UA7 and UA14 whereas M2 macrophages did not show any increased count, so the ratio of macrophages M1 / M2 is higher. Decrease in serum uric acid levels reduced GIS, AIS, MCP-1 expression and macrophages M1/M2 ratio (p<0.05). Reduction of serum uric acid levels significantly reduced renal injury that occurred in mice model of hyperuricemia.


Intrathoracic desmoid tumor: CT and MRI appearance.
Intrathoracic desmoid tumors are extremely rare, only 12 cases having been reported in the literature. In the 14-year-old girl we describe, a desmoid tumor manifested as an intrathoracic mass. Computed tomography of the chest after administration of intravenous contrast medium showed a large intrathoracic heterogeneous mass and lysis of multiple adjacent vertebral bodies. After incomplete resection of the tumor, T1-weighted magnetic resonance imaging showed residual tumor that produced signal intensity equal to that of skeletal muscle. Intense enhancement after intravenous administration of gadolinium allowed improved delineation of adjacent tissue involvement.


DNA vaccine using hemagglutinating virus of Japan-liposome encapsulating combination encoding mycobacterial heat shock protein 65 and interleukin-12 confers protection against Mycobacterium tuberculosis by T cell activation.
We investigated the immunogenicity and protective efficacy of DNA vaccine combinations expressing mycobacterial heat shock protein 65 (Hsp65) and interleukin-12 (IL-12) using gene gun bombardment and the hemagglutinating virus of Japan (HVJ)-liposome method. A mouse IL-12 expression vector (mIL-12 DNA) encoding single-chain IL-12 proteins comprised of p40 and p35 subunits were constructed. In a mouse model, a single gene gun vaccination with the combination of Hsp65 DNA and mIL-12 DNA provided a remarkably high degree of protection against challenge with virulent Mycobacterium tuberculosis; bacterial numbers were 100-fold lower in the lungs compared to BCG-vaccinated mice. To explore the clinical use of the DNA vaccines, we evaluated HVJ-liposome encapsulated Hsp65 DNA and mIL-12DNA (Hsp65 + mIL-12/HVJ). The HVJ-liposome method improved the protective efficacy of the Hsp65 DNA vaccine compared to gene gun vaccination. Hsp65 + mIL-12/HVJ induced CD8+ cytotoxic T lymphocyte activity against Hsp65 antigen. Most importantly, Hsp65+mIL-12/HVJ vaccination resulted in a greater degree of protection than that evoked by BCG. This protective efficacy was associated with the emergence of IFN-gamma-secreting T cells and activation of proliferative T cells and cytokines (IFN-gamma and IL-2) production upon stimulation with Hsp65 and antigens from M. tuberculosis. These results suggest that Hsp65 + IL-12/HVJ could be a promising candidate for a new tuberculosis DNA vaccine, which is superior to BCG vaccine.


Experimental and theoretical investigations of ionization/dissociation of cyclopentanone molecule in a femtosecond laser field.
The ionization/dissociation mechanism of cyclopentanone has been experimentally investigated in molecular beam by irradiating with intense 394 and 788 nm laser fields with pulse duration of 90 fs. The range of laser intensities varied from 3 x 10(13) to 4 x 10(14) W/cm(2). For both wavelengths, the singly charged parent ion is observable while the doubly charged one cannot be found easily, although the fragmentation pattern supports its presence. Meanwhile, the extent of fragmentation at 788 nm is less than that in the 394 nm case. We quantitatively analyze the ionization processes of cyclopentanone in intense femtosecond laser by comparing the calculation results of ionization rate constants obtained from Ammosov-Delone-Krainov, Keldysh, and Keldysh-Faisal-Reiss (KFR) theories based on hydrogenlike atom model. We also compare the experimental and theoretical results; the generalized KFR theory is found to be useful in predicting the ionization yields of singly and doubly charged cyclopentanone ion. To interpret the dissociation patterns of the cyclopentanone ions, we have used the Rice-Ramsperger-Kassel-Marcus theory with the potential surfaces obtained from the ab initio quantum chemical calculations.


[Oily chemoembolization of hepatoma].
Since 1983 we have performed transcatheter oily chemoembolization (TOCE) using adriamycin (40-100 mg), Lipiodol (5-20 ml) and Gelfoam in the treatment of 100 cases with unresectable hepatocellular carcinoma. Adriamycin was dissolved in a fluid equal in specific gravity to Lipiodol and the adriamycin solution was mixed with 3 volumes of Lipiodol, making an adriamycin-in-oil emulsion (AOE). After TOCE, the blood concentration of adriamycin was obviously lower than that after one-shot injection because of the slow release of adriamycin from the AOE. Also, in cases of hepatic resection after TOCE, there was a clear difference in the adriamycin concentration between the tumor and the normal hepatic tissue. The cumulative survival rates for the 100 patients treated by TOCE were: 6 months 81.9%, 1 year 53.8% and 2 years 36.5%. Thus, improvement was found in comparison with the cumulative survival rates for 104 patients who underwent hepatic embolization without Lipiodol, which were 6 months 67.4%, 1 year 45.2% and 2 years 16.3%. AOE retained in the tumor as microemboli brings about the slow-releasing effect of adriamycin. Furthermore, by adding the effect of Gelfoam embolization, TOCE has a strong antitumor effect.


Necrosis and apoptosis in hepatocellular carcinoma following low-dose versus high-dose preoperative chemoembolization.
Our purpose was to study necrosis and apoptosis of hepatocellular carcinoma (HCC) cells after preoperative transcatheter arterial chemoembolization (TACE) with use of low-dose and high-dose anticancer drugs in HCCs. Fifty-four patients with advanced but surgically resectable HCC were studied. Thirty-four patients who elected to undergo preoperative superselective TACE were randomized to low- and high-dose TACE. Patients in group A (n = 16) received low-dose anticancer drugs: 2 mg mitomycin C (MMC), 10 mg epirubicin (EPI), and 100 mg carboplatin (CBP). Patients in group B (n = 18) were given high doses of anticancer drugs (10 mg MMC, 40 mg EPI, and 300 mg CBP). Hepatic resection was subsequently performed. Group C comprised 20 patients who underwent resection without TACE. In all patients the necrosis rates and apoptosis index of tumor cells were evaluated by pathologic examinations and terminal deoxynucleotidyl transferase-mediated nick-end labeling assay. There was no significant difference between group A and group B in tumor response (p [ 0.05) after TACE. Necrosis rates in groups A, B, and C were 88.4 +/- 11.1%, 87.1 +/- 12.5%, and 7.3 +/- 3.5%, respectively. There was no significant difference between group A and group B (p [ 0.05), while statistical difference was found between group A and group C (p \ 0.001) and between group B and group C (p \ 0.001). Apoptosis indexes in the three groups were 11.0 +/- 4.0%, 10.7 +/- 3.9%, and 5.6 +/- 2.6%, respectively. Statistical difference exhibited between group A and group C (p \ 0.001) and group B versus group C (p \ 0.001). No significant difference was observed between group A and group B (p [ 0.05). In conclusion, superselective TACE with low- and high-dose chemotherapeutic agents induced similar degrees of cellular apoptosis and necrosis.