Distribution and regulation of expression of the putative human chemokine receptor HCR in leukocyte populations.
Human chemokine receptor (HCR) is a putative chemokine receptor sharing high similarity with CCR1, CCR2, CCR3 and CCR5. Its gene is located within the main cluster of CC-chemokine receptor genes, in the 3p21 region of the human genome. We generated monoclonal antibodies directed at human HCR, and studied its distribution in human leukocyte populations and cell lines, and its regulation following maturation or activation of these populations. In peripheral blood leukocytes, HCR is expressed on CD4+ and CD8+ T lymphocytes, including most memory and part of naive cells, but is absent from B cells. Expression of HCR was enhanced following stimulation of T cells by OKT3 and IL-2. HCR is present on monocytes and macrophages. Monocyte-derived dendritic cells harbored HCR, and expression was enhanced following stimulation by lipopolysaccharides, poly (I:C), IFN-gamma or CD40L. Neutrophils strongly expressed HCR. A similar distribution was found in bone marrow,and HCR was also expressed in CD34+ precursors. Expression of HCR and its regulation were confirmed by real-time PCR. In a panel of human tissues, we found abundant HCR transcripts in thymus, spleen, lymph nodes and lung. This large distribution across leukocyte populations, and the up-regulation during DC maturation, represent a new profile among chemokine receptors. We speculate that HCR responds to inflammatory chemokines, and might be involved in the interaction between antigen presenting and T cells, and in hematopoiesis.


Enzyme-linked immunosorbent assay for distinguishing serological responses of lepromatous and tuberculoid leprosies to the 29/33-kilodalton doublet and 64-kilodalton antigens of Mycobacterium tuberculosis.
Immunoblot assays for the antibodies to Mycobacterium tuberculosis sonic extracts showed that all serum specimens of 40 lepromatous and of 28 tuberculoid leprosy patients reacted in a significant manner to 29/33-kilodalton (kDa) doublet and 64-kDa antigens, respectively. By using an enzyme-linked immunosorbent assay, we observed a significantly high immunoglobulin G antibody titer to the purified M. tuberculosis 29/33-kDa doublet and 64-kDa antigens in lepromatous and tuberculoid leprosy patients, respectively, as compared with normal subjects and tuberculosis patients. This enzyme-linked immunosorbent assay serology may be useful for distinguishing two polar types of leprosy and for diagnosing leprosy in general.


Examining the heterogeneity inexcess risks of coronary heart disease, stroke, dialysis, and lower extremity amputation associated with type 2 diabetes mellitus across demographic subgroups in an Asian population: A population-based matched cohort study.
To examine whether the excess risks of coronary heart disease (CHD), stroke, dialysis, and lower extremity amputation (LEA) associated with type 2 diabetes mellitus (T2DM) differ across age, sex, and ethnicity in Singapore. Using a 10-year administrative data, we matched individuals with T2DM using nearest neighbour matching, to those without, in 1:2 ratio. To examine whether the excess risks were heterogeneous across age, sex, and ethnicity, we generated interaction terms of age, sex, and ethnicity with T2DM status in Cox proportional hazard (PH) models. The main analyses included ~1 million person years, comprising 66,099 and 120,485 individuals with and without T2DM, respectively. The associations of T2DM with CHD and dialysis, split into two time periods to address violation of PH assumption, were higher with older age in short-term but lower with older age in long-term. The association of T2DM with stroke and LEA were lower with older age. The associations of T2DM with CHD and stroke were also consistently higher in women than men. The associations of T2DM with LEA were higher in ethnic Malays than ethnic Chinese. The excess risks of CHD, stroke, dialysis, and LEA associated with T2DM were heterogeneous across some demographic subgroups.


Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.
Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.


Viruses - a major cause of amyloid deposition in the brain.
Clinically, Alzheimer's disease (AD) is a syndrome with a spectrum of various cognitive disorders. There is a complete dissociation between the pathology and the clinical presentation. Therefore, we need a disruptive new approach to be able to prevent and treat AD. In this review, the authors extensively discuss the evidence why the amyloid beta is not the pathological cause of AD which makes therefore the amyloid hypothesis not sustainable anymore. They review the experimental evidence underlying the role of microbes, especially that of viruses, as a trigger/cause for the production of amyloid beta leading to the establishment of a chronic neuroinflammation as the mediator manifesting decades later by AD as a clinical spectrum. In this context, the emergence and consequences of the infection/antimicrobial protection hypothesis are described. The epidemiological and clinical data supporting this hypothesis are also analyzed. For decades, we have known that viruses are involved in the pathogenesis of AD. This discovery was ignored and discarded for a long time. Now we should accept this fact, which is not a hypothesis anymore, and stimulate the research community to come up with new ideas, new treatments, and new concepts.


Ultrasonographic parameters of fetal well-being and development in alpacas.
In this study, a database of fetal and maternal parameters was developed in pregnant alpacas from 120 days of gestation to term for evaluation of fetal well-being and development. Ten pregnancies were examined every 2 weeks from 120 to 300 days of gestation, then weekly until parturition. Five more pregnancies were evaluated weekly during the last 4 weeks prepartum. Maternal weight and heart rate were recorded. Indicators of fetal well-being (mean, minimum, and maximum fetal heart rate, fetal movement, and tone), development (size of the aorta, thorax, abdomen, stomach, kidney, head, eye orbit, radius, and umbilical vessels), and uterine environment (combined thickness of the uterus and placenta, depth and character of allantoic and amnionic fluids) were assessed using transabdominal ultrasound. Reference values and fetal growth curves were created. Weights of the cria, fetal membranes, and dam at parturition were associated with parameters of fetal growth. Mean (R(2) = 0.65), minimum (R(2) = 0.57), and maximum (R(2) = 0.64) fetal heart rate decreased from midgestation to term (P < 0.0001). Fetal activity also decreased as pregnancy advanced (P < 0.0001). Fetal presentation was anterior in all fetuses by 10 months. Increases in depth of allantoic (R(2) = 0.11) and amniotic (R(2) = 0.02) fluid, combined thickness of the uterus and placenta (R(2) = 0.31), and maternal weight (R(2) = 0.09) were significantly but poorly associated with gestation length. All parameters of fetal development were positively associated with gestational age (P < 0.0001). Size of the aorta (R(2) = 0.88), abdomen (R(2) = 0.87), kidney (R(2) = 0.83), and thorax (R(2) = 0.82) provided the best estimates of gestational age. Birth weight was associated with the size of the aorta (R(2) = 0.71), kidney (R(2) = 0.61), and radius (R(2) = 0.73) (P < 0.05). This information might be of value in the assessment of fetal well-being and development in alpacas.


AIDS in Namibia.
The purpose of this article is to examine the AIDS epidemic in Namibia, a country for which little data currently exists. An examination of published and unpublished literature about the historical, socioeconomic and health factors as well as an analysis of updated data from other sub Saharan countries presented at the IXth International Conference on AIDS in Berlin may shed light on the pandemic as it relates to Namibia. Despite inadequate data, it is clear that the AIDS epidemic has already reached Namibia, though the country has not been afflicted as severely as some of its neighbors. Because of 75 years of apartheid, the new government is faced with a formidable array of problems, both in health care and in the economic domain. The strategies being adopted to confront the AIDS epidemic will take years to evolve, a period of time the nation can ill-afford if it is to wrest control over a virus that is relentlessly spreading into susceptible populations.


Endovascular aortic arch repair: A comparison of outcomes and current trends.
Application of thoracic endovascular aortic repair (TEVAR) to the aortic arch has been met with the development of purpose-made endoprostheses for on-label use in the aortic arch. An appraisal of the clinical efficacy of each major device is therefore useful towards informing clinical decision making for patients eligible for endovascular arch repair (EAR) rather than open surgical reconstruction. A literature review of publications outlining clinical experience with the RELAY™ Branched and Zenith™ devices was undertaken, and the results therefrom analysed to evaluate the clinical efficacies of each device. Early- and long-term mortality rates associated with EAR appear favourable, especially compared against open surgical repair. EAR is also associated with good neurological outcomes and target vessel patency rates. However, EAR continues to be associated with substantial reintervention rates. At the present stage, EAR represents a promising alternative option to open surgical reconstruction in patients that meet its eligibility criteria. Though there remains a substantial learning curve associated with EAR, its favourable outcome profile is likely to increase its applicability in the future.


Thyroid function and the development of endothermy in a marsupial, the Tasmanian bettong, Bettongia gaimardi (Demarest 1822).
The Tasmanian bettong (Bettongia gaimardi) is a small rat-kangaroo (marsupial) found only in Tasmania, Australia. The duration of pouch life is 15 weeks. Adults and older young display non-shivering thermogenesis and this paper examines the role of thyroxine in the development of endothermy in pouch young. Free thyroxine (T4) concentrations varied throughout pouch life. The mean (+/-SE) concentration was 6.2+/-1.9 pmol L(-1) in week 7, increased and peaked at 19.2+/-4.3 pmol L(-1) in week 12, and declined to 5.6+/-0.4 pmol L(-1) by week 20. This was similar to adult levels (3.2+/-3.8 pmol L(-1)). These concentrations showed significant differences. From pouch week 12 onwards, T4 injection raised oxygen consumption. Maximum levels of VO2 after T4 injection occurred at weeks 14-15. Although adult levels were lower, the increase in adult oxygen consumption after T4 injection was about 50%. Peak free T4 levels and metabolic responses to nor-adrenalin occur at week 12 and we hypothesize that thyroid hormone may facilitate the development of adrenergic-receptors in this species. The data presented in the paper further attest to the likely important role of the thyroid gland in the development of endothermy in marsupial pouch young.


Treatment of coronary malperfusion in type A acute aortic dissection.
Coronary malperfusion is one of the most dreadful complications of acute aortic dissection because it causes catastrophic acute myocardial infarction in patients who are already severely ill. Our strategy was as follows. After the administration of heparin, emergency percutaneous coronary intervention (PCI) was urgently performed at the same time as starting to prepare the operating room. A stent was then placed to cover the full length of dissected coronary artery. Patients whose cardiac function improved after successful coronary artery reperfusion were transferred to the operating room to undergo central repair surgery. If the cardiac function did not recover even after coronary reperfusion, and the patient required extracorporeal membrane oxygenation, we considered the best supportive care without performing central repair surgery. In patients with left coronary malperfusion, we believe that preoperative PCI must be performed immediately. Preoperative PCI might delay central repair surgery and potentially increase the risk of catastrophic cardiac tamponade. However, the benefit of PCI in preserving cardiac function exceeds the risk of cardiac tamponade. The indications of PCI before central repair in patients with right coronary malperfusion should be considered after assessing each patient's condition, including the presence or absence of cardiac tamponade and right ventricular infarction, left ventricular function, the immediate availability of cardiologists or cardiac surgeons, and the speed of preparing the operating room.


Neurogenesis in the basal forebrain of the Chinese hamster (Cricetulus griseus). I. Time of neuron origin.
The time of neuron origin has been determined in the basal ganglia and related basal forebrain structures of the Chinese hamster with the aid of 3H-thymidine autoradiography. Large-celled structures like the globus pallidus, nucleus of the horizontal limb of the diagonal band of Broca as well as large cells in the rostral part of the substantia innominata, in the caudate-putamen-complex and in the olfactory tubercle arise early (E12--E16), whereas medium-sized and small cells in the basal forebrain have a persistent origin over a much longer period. Neuron formation in the basal forebrain persists decrementally until P4. A clear caudorostral spatiotemporal gradient as well as a distinct 'outside-in' gradient have been observed in the caudate-putamen-complex. Medium-sized neurons in the neostriatum and in the nucleus accumbens, generated simultaneously, are usually arranged in scattered clusters. The present data on time of neuron origin strongly support other evidence which points to the conclusion that the nucleus accumbens can be considered as a ventromedial extension of the caudate-putamen-complex.


Over-all accuracy of 99mTc-pertechnetate brain scanning for brain tumours--study of 471 patients.
A 3-year follow-up and re-evaluation of all scans on all patients referred for brain scanning in Iceland during 1 year was performed in order to assess the diagnostic reliability of radioisotope scanning for brain tumours. The study included 471 patients. Of these 25 had primary brain tumours and 7 brain metastases. Scans were positive and correctly interpreted in 68% of the patients with primary brain tumours and in 3 of the 7 patients with metastases. The over-all accuracy of brain scanning for brain tumours defined as the total number of correct positive scans and correct negative scans versus total number of scans examined was 96%, this figure being mainly influenced by the high number of true negative scans.


Cost-Effectiveness of Low-Dose Antithymocyte Globulin Versus Other Immunotherapies for Treatment of New-Onset Type 1 Diabetes.
Objective: Several immunotherapies have shown efficacy in slowing C-peptide decline in new-onset type 1 diabetes. Although most of these biologic drugs are expensive, they offer the opportunity to reduce downstream disease management costs and risk of complications. The objective of this study is to examine the cost-effectiveness of immunotherapies versus no treatment for patients with new-onset type 1 diabetes. Methods: Using Markov microsimulation modeling and efficacy data from immunotherapy trials, we examined the cost-effectiveness of six immunotherapies for new-onset type 1 diabetes, namely, low-dose (2.5 mg/kg) antithymocyte globulin (ATG), high-dose (6.5 mg/kg) ATG, abatacept, alefacept, rituximab, and teplizumab, versus no treatment. Effectiveness was measured by quality-adjusted life-years (QALYs). Costs were estimated from a health system perspective. Results: Low-dose ATG treatment saves US$10,270, on average, over a patient's lifetime and generates 0.09 additional QALYs compared with no treatment. These cost savings arise as low-dose ATG generates downstream savings in disease management costs that more than offset its cost. In contrast, treatment with other immunotherapies yields smaller QALY gains (0.02-0.05 additional QALYs) and increases lifetime costs by US$9500-US$168,380 relative to no treatment, with incremental cost-effectiveness ratios that exceed the willingness-to-pay threshold of US$100,000 per QALY. Conclusions: Low-dose ATG treatment is both less costly and more effective relative to other immunotherapies and no treatment for new-onset type 1 diabetes.


Balancing Success and Risk in Orthopedic Trauma Surgery: The Ridge-Walking between Sound Accepting "Good" and Risky Striving for "Better".
Immediate post-operative rating of surgical performance can be a valuable source of learning when trying to analyze the reasons for the difference between "work as planned" and "work as done". There are many reasons for the difference, but they can only be found if complete documentation of the surgical steps allows retrospective scrutiny. Documentation like ICUC1 provides this opportunity for scrutiny and may allow better understanding of some unexpected post-operative evolutions.


The flushing patient: differential diagnosis, workup, and treatment.
Cutaneous flushing-a common presenting complaint to dermatologists, allergists, internists, and family practitioners-results from changes in cutaneous blood flow triggered by multiple conditions. Most cases are caused by very common, benign diseases, such as rosacea or climacterum, that are readily apparent after a thorough taking of history and physical examination. However, in some cases, accurate diagnosis requires further laboratory, radiologic, or histopathologic studies to differentiate several important clinicopathologic entities. In particular, the serious diagnoses of carcinoid syndrome, pheochromocytoma, mastocytosis, and anaphylaxis need to be excluded by laboratory studies. If this work-up is unrevealing, rare causes, such as medullary carcinoma of the thyroid, pancreatic cell tumor, renal carcinoma, and others, should be considered. At the completion of this learning activity, participants should be familiar with the mechanisms of flushing, its clinical differential diagnosis, the approach to establish a definitive diagnosis, and management of various conditions that produce flushing.


Robotic versus laparoscopic versus open surgery in morbidly obese endometrial cancer patients - a comparative analysis of total charges and complication rates.
To compare the complications and charges of robotic vs. laparoscopic vs. open surgeries in morbidly obese patients treated for endometrial cancer. Data were obtained from the Nationwide Inpatient Sample from 2011. Chi-squared, Wilcoxon rank sum two-sample tests, and multivariate analyses were used for statistical analyses. Of 1087 morbidly obese (BMI ≥40kg/m(2)) endometrial cancer patients (median age: 59years, range: 22 to 89), 567 (52%) had open surgery (OS), 98 (9%) laparoscopic (LS), and 422 (39%) robotic surgery (RS). 23% of OS, 13% of LS, and 8% of RS patients experienced an intraoperative or postoperative complication including: blood transfusions, mechanical ventilation, urinary tract injury, gastrointestinal injury, wound debridement, infection, venous thromboembolism, and lymphedema (p<0.0001). RS and LS patients were less likely to receive blood transfusions compared to OS (5% and 6% vs. 14%, respectively; p<0.0001). The median lengths of hospitalization for OS, LS, and RS patients were 4, 1, and 1days, respectively (p<0.0001). Median total charges associated with OS, LS, and RS were $39,281, $40,997, and $45,030 (p=0.037), respectively. In morbidly obese endometrial cancer patients, minimally invasive robotic or laparoscopic surgeries were associated with fewer complications and less days of hospitalization relative to open surgery. Compared to laparoscopic approach, robotic surgeries had comparable rates of complications but higher charges.


The non-Mendelian inheritance of Lewis-c blood group substance, as demonstrated in the case of a Bombay, Le(a-b-c-) saliva.
A Bombay, Le(a-b-) saliva was shown to lack Pneumococcus type XIV activity, an unusual situation, since this sample should be rich in this precursor to the ABO blood group substances. However, the sample was found to contain a new serological specificity, Le-c. It is argued that simple Mendelian inheritance does not occur with Le-c and single gene control cannot be demonstrated. Failure to repress a fetal gene at birth, as implicated by the similarity in structure between Le-c and carcinoembryonic antigen [SIMMONS and PERLMANN], has been excluded as the mechanism of inheritance of this blood group substance, due to the inability to detect carcinoembryonic antigen in the test saliva.


Adenophostins A and B: potent agonists of inositol-1,4,5-trisphosphate receptor produced by Penicillium brevicompactum. Taxonomy, fermentation, isolation, physico-chemical and biological properties.
New inositol-1,4,5-trisphosphate (InsP3) agonists, adenophostins A(1) and B(2), were isolated from the culture broth of Penicillium brevicompactum SANK 11991 and SANK 12177. Its structures were related to adenine nucleotides. The agonistic activity of adenophostins A or B for binding to the InsP3 receptor was higher than InsP3 itself.


Vertical variation of bulk and metabolically active prokaryotic community in sediment of a hypereutrophic freshwater lake.
This study was conducted to acquire novel insight into differences between bulk (16S rDNA) and metabolically active (16S rRNA) prokaryotic communities in the sediment of a hypereutrophic lake (Japan). In the bulk communities, the class Deltaproteobacteria and the order Methanomicrobiales were dominant among bacteria and methanogens. In the metabolically active communities, the class Alphaproteobacteria and the order Methanomicrobiales and the family Methanosaetaceae were frequently found among bacteria and methanogens. Unlike the bulk communities of prokaryotes, the composition of the metabolically active communities varied remarkably vertically, and their diversities greatly decreased in the lower 20 cm of sediment. The metabolically active prokaryotic community in the sediment core was divided into three sections based on their similarity: 0-6 cm (section 1), 9-18 cm (section 2), and 21-42 cm (section 3). This sectional distribution was consistent with the vertical pattern of the sedimentary stable carbon and nitrogen isotope ratios and oxidation-reduction potential in the porewater. These results suggest that vertical disturbance of the sediment may influence the communities and functions of metabolically active prokaryotes in freshwater lake sediments. Overall, our results indicate that rRNA analysis may be more effective than rDNA analysis for evaluation of relationships between actual microbial processes and material cycling in lake sediments.


Gastroesophageal reflux disease complicating laparoscopic sleeve gastrectomy: current knowledge and surgical therapies.
Laparoscopic sleeve gastrectomy (LSG) is currently the most commonly performed bariatric procedure worldwide. However, the incidence of gastroesophageal reflux disease (GERD) after LSG is high. The aim of this systematic review was to identify the optimal surgical strategy for treating GERD after LSG. West China Hospital, Sichuan University, Chengdu, China. A systematic literature search was performed to identify studies on surgical treatments for GERD after LSG. The effectiveness and safety profile of surgical management on GERD after LSG were analyzed. A total of 40 articles enrolling 2049 patients were included in this review. Surgical strategies to prevent GERD after LSG were mainly of 2 types: concomitant LSG + antireflux procedures (hiatal hernia repair or fundoplication) and secondary procedures (conversion to Roux-en-Y gastric bypass [RYGB] or repeat sleeve gastrectomy). The short-term remission or improvement rate of GERD was 34.6%-100% after concomitant LSG + antireflux procedures. The postoperative complication rate was the same (3.0%) for both LSG + antireflux procedures and LSG alone. The remission or improvement rate of GERD was 57.1%-100% after conversion to RYGB and 100% after repeat sleeve gastrectomy. The effectiveness and safety profile of concomitant LSG + antireflux procedures is uncertain. However, secondary operations after LSG, such as conversion to RYGB, appear to provide good results. The data overall are heterogeneous, with imprecise methods of documenting and defining GERD complicating LSG. More cohort studies or RCT studies of high quality with long-term follow-up are needed in the future.


Cellular roles of ADAM12 in health and disease.
ADAM12 belongs to the large family of ADAMs (a disintegrin and metalloproteases) and possesses extracellular metalloprotease and cell-binding functions, as well as intracellular signaling capacities. Interest in ADAM12 has increased recently because its expression is related to tumor progression and it is a potential biomarker for breast cancer. It is therefore important to understand ADAM12's functions. Many cellular roles for ADAM12 have been suggested. It is an active metalloprotease, and has been implicated in insulin-like growth factor (IGF) receptor signaling, through cleavage of IGF-binding proteins, and in epidermal growth factor receptor (EGFR) pathways, via ectodomain shedding of membrane-tethered EGFR ligands. These proteolytic events may regulate diverse cellular responses, such as altered cell differentiation, proliferation, migration, and invasion. ADAM12 may also regulate cell-cell and cell-extracellular matrix contacts through interactions with cell surface receptors - integrins and syndecans - potentially influencing the actin cytoskeleton. Moreover, ADAM12 interacts with several cytoplasmic signaling and adaptor molecules through its intracellular domain, thereby directly transmitting signals to or from the cell interior. These ADAM12-mediated cellular effects appear to be critical events in both biological and pathological processes. This review presents current knowledge on ADAM12 functions gained from in vitro and in vivo observations, describes ADAM12's role in both normal physiology and pathology, particularly in cancer, and discusses important areas for future investigation.


Asthma in older adults.
Asthma is underdiagnosed and undertreated in older adults. The classic symptoms, including episodic wheezing, shortness of breath, and chest tightness, are nonspecific in this age group. Older patients may underrate symptoms, and other diseases, such as chronic obstructive pulmonary disease, congestive heart failure, and angina, may have similar presentations. Objective measurements of lung function always should complement the history taking and physical examination. Management of asthma in older adults should include careful monitoring, controlling triggers, optimizing and monitoring pharmacotherapy, and providing appropriate asthma education. Adverse effects to commonly used asthma medications are more common in older adults, and careful monitoring of their use and adverse effects is important.


A study of the PEMT gene in schizophrenia.
The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X2=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X2=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X2=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X2=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.


[Endocytoscopy in the colorectum].
Endocytoscopy (EC; Olympus), which involves a contact light microscopy system (380- or 450-fold) on the distal tip of a colonoscope, is a novel emerging endoscopic system. EC enables prediction of the lesion histology or the depth of a cancer by on-site observation of both structural and cytological atypia. According to the retrospective analysis of 514 colorectal lesions observed with use of EC, the diagnostic accuracy of differentiating neoplastic change was 96.5%, while that of differentiating massively invasive submucosal cancers was 96.3%. In this article, we report the usefulness of EC focusing on the EC classification which classifies colorectal lesions on the basis of EC findings.


Emerging child competencies and personality pathology: toward a Developmental Cascade model of BPD.
The guiding principle of this synthesis is to organize research on predictors of BPD features within a developmentally specific framework (e.g. infancy, preschool, middle childhood, adolescence). In addition, studies are prioritized that have longitudinal and observational components. On the basis of current literature, a Developmental Cascade Model of BPD is offered in which specific difficulties during one developmental period contribute to specific difficulties in a succeeding period, resulting in increasingly broad areas of dysregulation over time. Furthermore, to address specificity, we contrast trajectories toward BPD with trajectories toward antisocial behavior, noting shared and divergent predictors. The review highlights the importance of locating research findings in relation to the competencies and challenges of particular developmental periods when modelling developmental trajectories toward BPD.


HIV Testing and HIV Serostatus-Specific Sexual Risk Behaviour Among Men Who Have Sex with Men Living in England and Recruited Through the Internet in 2001 and 2008.
Using data from two large internet-recruited surveys in England in 2001 and 2008, we examine HIV status-specific patterns of unprotected anal intercourse (UAI). In adjusted comparisons between our 2008 and 2001 samples, there was evidence of a greater proportion of men living with diagnosed HIV, a reduction in sexual partners and in UAI with partners of unknown HIV status among men not tested HIV positive, increases in anal intercourse and UAI among men with diagnosed HIV and an increase in insertive UAI with HIV-positive men among men never tested for HIV. However, we found no evidence for increases in negotiated safety or sero-sorting. The data are compatible with a concentration of sexual risk among men with diagnosed HIV, countering an overall trend towards less risk taking among men not tested HIV positive.


Swimming exercise improves SIRT1, NF-κB, and IL-1β protein levels and pancreatic tissue injury in ovariectomized diabetic rats.
In this study, we investigated the beneficial effects of swimming exercise on the SIRT1, NF-κB, IL-1β protein levels, and pancreatic tissue damage in an ovariectomized diabetic rat model based on the anti-inflammatory effect of exercise. Forty mature female Wistar rats were purchased and divided into sham (n=10) and OVX (bilateral ovariectomy) (n=30) groups. The ovariectomized rats were divided into 1-OVX, 2-ovariectomized diabetic (OVX.D), 3-OVX.D + exercise (OVX.D. E). After surgical recovery, animals in the diabetic group received a high-fat diet for one month. Swimming exercise (1 h/day) was performed concurrently with the start of the HFD diet for eight weeks. At the end of the high-fat diet, streptozotocin (30 mg/kg) was injected intraperitoneally. At the end of the second month, pancreatic tissue was collected from the animals after deep anesthesia for molecular evaluation and histology by Western blotting and hematoxylin-eosin, respectively. Swimming exercise significantly decreased inflammatory cytokines and tissue damage, and this decrease in cytokine expression appears to be associated with SIRT1 expression. The increase in SIRT1 by training was associated with decreased NF-κB-p65 and IL-1β expression and preventing tissue damage. Induction of diabetes in the ovariectomized group (OVX.D) resulted in a significant increase in NF-κB-p65 and IL-1β proteins and a decrease in the expression of SIRT1 compared with the sham group. However, swimming training significantly reversed these effects compared with the OVX.D group. Increased inflammation of β-cells impairs insulin secretion in estrogen insufficiency. Swimming exercise eliminates inflammation in post-menopausal diabetes and supports the potential to prevent pancreatic activity after menopause.


Recurrent miscarriage is associated with the dopamine receptor (DRD2) genotype.
The purpose of this research is to compare the prevalence of dopamine receptor D2 polymorphisms in women with recurrent miscarriage (RM) and healthy patients. Fifty-four women were enrolled in this case-control study. We performed DNA extraction of peripheral blood, followed by polymerase chain reaction to confirm single-strand polymorphisms and to sequence two polymorphisms: polymorphism 1 (rs6275) and polymorphism 2 (rs6277) in exon 7 of the dopamine receptor D2 (DRD2). The frequency of DRD2 polymorphism 2 (rs6277) was increased in the subjects with RM. An analysis of the DRD2 genotypes demonstrated an odds ratio of 2.37 (1.05-5.36, 95% confidence interval) for the polymorphism 2 (rs6277) in RM. The mean of the serum prolactin level was higher in the patients with RM (12.5 ng/ml) than in healthy women (8.1 ng/ml) p = 0.03. An excess homozygosity of the DRD2 polymorphism suggests a genetic predisposition to RMs, which could result in a mild serum prolactin increase. Thus, because of the potential role of prolactin in reproductive regulation, this polymorphism could play an important role in early pregnancy implantation and pregnancy maintenance.


Referral pattern and surgical outcome of sagittal synostosis.
Sagittal synostosis (SS) is the commonest form of craniosynostosis, and in the Birmingham Craniofacial Unit has been preferably managed by strip craniectomy when the baby is under 6 months of age or calvarial remodelling when over 6 months old. The unit uses cephalic index (CI) as an objective measure of head shape. This retrospective study analysed referral patterns and the correlation between age at operation and CI. Patients' unit notes and images of 47 patients referred for SS between July 1999 and December 2003 were reviewed. Thirty-three non-syndromic SS patients were studied and demographics, referral information and preoperative and postoperative CI measurements were recorded. Paediatricians referred 91% (mean age 15 months) of cases and general practitioners 9% (all beyond 6 months). There was a significant difference between pre- and postoperative CI for patients operated at less than 12 months (P=0.02). No difference was demonstrated for patients operated at greater than 12 months. Early surgery for SS was associated with a better aesthetic result in this series, although CI may be a crude form of head shape analysis. Later referral was associated with a more complex referral pathway. A fast track system for general practitioners and paediatricians to aid early referrals may improve surgical outcome.


DNA polymorphisms of lipase related genes.
We previously determined sequenced the PNLIP gene encoding pancreatic lipase in cell lines of subjects with clinical deficiency of pancreatic lipase (MIM 246600) and found no putative disease-causing mutations. As part of the ongoing analysis of the genomic DNA of these subjects, we now report the development of genomic amplification primers to sequence the coding regions of CLPS, CEL, PLRP1, and PLRP2, encoding pancreatic co-lipase, carboxyl-ester lipase, and pancreatic-lipase-related proteins-1 and -2, respectively. Whereas we found no putative disease-causing missense or nonsense mutations in these samples, we discovered a total of 13 common polymorphisms (12 single nucleotide polymorphisms) in these four genes. Genotypes of these polymorphisms may be useful in future association analyses.


Factors affecting the pressure resistance of some Campylobacter species.
To compare pressure resistance between strains of Campylobacter jejuni, Campylobacter coli, Campylobacter lari and Campylobacter fetus, and to investigate the effect of suspending medium on pressure resistance of sensitive and more resistant strains. Six strains of C. jejuni and four each of C. coli, C. lari and C. fetus were pressure treated for 10 min at 200 and 300 MPa. Individual strains varied widely in pressure resistance but there were no significant differences between the species C. jejuni, C. coli and C. lari. Campylobacter fetus was significantly more pressure sensitive than the other three species. The pressure resistance of C. jejuni cultures reached a maximum at 16-18 h on entry into stationary phase then declined to a minimum at 75 h before increasing once more. Milk was more baroprotective than water, broth or chicken slurry but did not prevent inactivation even of a resistant strain at 400 MPa. Pressure resistance varies considerably between species of Campylobacter and among strains within a species, and survival after a pressure challenge will be markedly influenced by culture age and food matrix. Despite the strain variation in pressure resistance and protective effects of food, Campylobacter sp. do not present a particular problem for pressure processing.


Maxillary expansion: a surgical technique based on surgical-orthodontic treatment objectives and anatomical considerations.
Maxillary transverse expansion is usually done as an ancillary, not primary surgical movement in the surgical-orthodontic correction of dentofacial deformities. A maxillary osteotomy technique is described which permits combinations of movements, including expansion. Releasing the palatal soft tissue to disperse the resulting soft tissue tension, bone grafting and adequate stabilization and retention of the segments are stressed to achieve success. Also described is the use of local bone grafts and the rotation of soft tissues to cover surgical defects. Results are encouraging and the complication rate has been low in this series of 104 patients.


Elastic Properties and Electronic Properties of MxNy (M = Ti, Zr) from First Principles Calculations.
The elastic properties and electronic properties of MxNy (M = Ti, Zr) TiN, Ti₂N, Zr₃N₄, ZrN with different structures have been investigated using density functional theory. Through the calculation of the elastic constants, it was found that all of these structures meet the mechanical stability except for ZrN with space group P6₃mc. Their mechanical properties are studied by a comparison of various parameters. The stiffness of TiN is larger than that of ZrN with space group Fm 3 ¯ m. Ti₂N's stiffness with space group I4₁/amdz is larger than Ti₂N with space group P4₂/mnm. Zr₃N₄'s stiffness with space group Pnam is largest in three structures of Zr₃N₄. TiN, Ti₂N and ZrN are non-central force, Zr₃N₄ is central force. TiN and ZrN with space group Fm 3 ¯ m are brittle, and TiN is brittler than ZrN with space group Fm 3 ¯ m. The two kinds of Ti₂N are brittle and Ti₂N with space group I4₁/amdz is larger. Three structures of Zr₃N₄ are tough and Zr₃N4 with space group I 4 ¯ 3d is the toughest. Meanwhile, the electronic properties of TiN, Ti₂N, Zr₃N₄ and ZrN were calculated, possible superconducting properties of the studied materials were predicted.


New technology for endoscopic retrograde cholangiopancreatography: improving safety, success, and efficiency.
Known and documented factors attributable to ERCP-related complications include the experience and technique of the endoscopist as well as anatomic and pathologic factors pertaining to the papilla. In an effort to minimize trauma, facilitate deep entry to the biliary system, and improve the efficiency of therapeutic ERCP, new cannulation, sphincterotomy, and guide wire devices have been developed, based on principles of safe and successful therapeutic ERCP learned over the years. By totally re-engineering familiar accessories into smaller, more flexible, and more versatile devices, the 0.025-inch guide wire-based DASH system attempts to minimize the trauma at deep CBD cannulation and thereby increase the safety and success of achieving deep cannulation and sphincterotomy. Limited clinical experience to date suggests that the DASH system can provide full-function ERCP while reducing risks and costs. Attention to cannulation has led to the development of the RX Biliary System which provides the endoscopist and the assistant with increased control of the guide wire and exchange compared with traditional devices, resulting in less stress, less hand and wrist force used for contrast injection, and easier guide wire management, all of which have been shown in clinical trials to improve the speed and efficiency of ERCP while reducing complications.


Is it Safe to Save Levels and Choose the Lowest Instrumented Vertebra as Touched Vertebra While Selectively Fusing Lenke 1/2 Curves? A Proportional Meta-Analysis of Existing Evidence.
Meta-analysis. To compare the clinical and radiological outcomes in patients with Adolescent Idiopathic scoliosis (AIS) treated by selective thoracic fusion (STF) with lowest instrumented vertebra (LIV) at touched vertebra (TV) vs stable vertebra (SV). The databases PubMed, Embase and Google Scholar were searched until November 2020.Studies which had Lenke type 1 curves and Lenke type 2 curves in adolescent population treated by STF and which reported pre- and post-operative curve characteristics including correction percentage and complications were included. Studies which did not report the LIV selection, curve correction percentages and whose full text could not be acquired were excluded. Eight studies were included for analysis of which seven were found to be retrospective studies (level III evidence) and one was prospective study (level II evidence) each. Overall proportional meta-analysis found no significant difference in correction rate, total srs-22 scores, and complication rates. The evaluation of SV group and TV group as LIV for selective thoracic fusions in AIS reveals a comparable outcome in terms of curve correction, patient satisfaction scores and complication rates. The TV can be chosen safely as the LIV especially in type A and B Lenke 1&2 curves, as it saves more motion segments when compared to SV.


Long-Term Outcomes of Birdshot Chorioretinopathy Treated with Corticosteroids: A Case Reports.
To report the progression of patients diagnosed with birdshot chorioretinopathy (BSCR) initially treated with corticosteroids. We included 39 BSCR patients that were followed for ≥1 year. We analyzed their progression under treatment after 1, 3, 6 months, 1 year, and at the end of follow-up. In order to determine the efficiency of initial loading doses, patients were classified into two groups according to their initial treatment: methylprednisolone followed by prednisone (n = 28) and prednisone alone (n = 11). At the end of follow-up, 31/39 (79.5%) patients had reached inflammation control. Thirteen out of 28 (46.4%) and 6/11 (54.5%) patients were treated exclusively with corticosteroids, and 18/19 (94.7%) of them had reached inflammation control at the end of follow-up; their mean (range) corticosteroid dose was 3.5 (0-10) mg/day. We found that the prolonged corticosteroid therapy treatment strategy resulted in inflammation control in half of BSCR patients. This control was maintained with low doses of cortisone, usually <5 mg/day.


Effects of biglycan on physico-chemical properties of ligament-mineralized tissue attachment sites.
Matrix proteoglycans define matrix structure, mineralization, and resulting biomechanics of tissues and their attachment sites. We therefore investigated physical and (bio)chemical differences in enamel and periodontal tissues/attachment sites from mice that lack a specific nanoscale small leucine-rich proteoglycan (SLRPs) named biglycan (BGN). Experimental groups consisted of N=4, biglycan knockout (BGNKO) and N=5 wildtype (WT) 8-week-old, male C3H mice. Morphology, histochemical and mechanical analyses were performed through micro X-ray computed tomography (Micro XCT™), immunohistochemistry, and microindentation. Unless mentioned otherwise, all differences between BGNKO and WT were demonstrated to be statistically significant through Student's t-tests with a 95% confidence interval (P≤0.05). Histomorphometry performed by using Micro XCT™ images indicated significantly higher BGNKO-enamel (0.46 ± 0.03mm(3)) and BGNKO-root (1.81 ± 0.10mm(3)) volumes compared to WT-enamel (0.37 ± 0.02mm(3)) and WT-root (1.65 ± 0.07mm(3)). BGNKO tooth size was relatively larger than WT mice, with no significant difference between skull sizes. Immunohistochemistry indicated BGN expression in the periodontal ligament (PDL), alveolar bone (AB), at the bone-PDL and cementum-PDL attachment sites in WT mice. Deeper AB resorption pits within interdental region of BGNKO specimens compared to WT resulting in significant differences in PDL-space of BGNKO (93 ± 13μm) and WT (74 ± 11μm) were observed. Microhardness of BGNKO-enamel (2.46 ± 0.60GPa) and BGNKO-AB (0.52 ± 0.10GPa) was significantly lower than WT-enamel (2.67 ± 0.60GPa) and WT-AB (0.54 ± 0.10GPa). Results indicate that BGNKO-mice exhibit significant differences in tissue properties compared to WT-mice.


Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality.
To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate-specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993. Comparison of prostate cancer mortality rates in Tyrol and the rest of Austria was accomplished through a generalized additive model. A piecewise linear change-point Poisson regression model was used to compare mortality rates in Tyrol and the rest of Austria. Standardized mortality ratios were calculated with reference to the mortality rates in 1986-1990. In all, 86.6% of eligible men have been tested at least once since 1993. Cancer deaths in Tyrol in 2005 were 54% (95% confidence interval [CI] 34-69%) lower than expected compared with 29% (95% CI 22-35%) in the rest of Austria. The decreasing trend in prostate cancer mortality was significantly greater in Tyrol compared with the rest of Austria (P = 0.001). A significant migration to lower stage disease occurred and radical prostatectomy was associated with low morbidity. In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer.


Laparoscopic partial gastrectomy for a giant bleeding GIST of the stomach: A case report.
Gastrointestinal stromal tumors (GIST) are rare neoplasms often located in the stomach. Elective laparoscopic surgery is the well-established treatment. Often these tumors have a presentation with acute gastrointestinal bleeding and/or as large masses that challenge mini invasive laparoscopic approach. This article describes the case of a patient with large gastric GIST with bleeding onset and discusses the feasibility and safety of emergency laparoscopy. A 36-year-old man presented with melena and severe anaemia. An upper endoscopy and abdominal CT scan showed a large gastric fundal submucosal mass of more than 10 cm of diameter close to the superior splenic pole. Because of relapsing bleeding he was submitted to emergency laparoscopy with complete resection of the gastric mass by partial gastrectomy. Laparoscopic approach to GIST larger than 10 cm is still a challenging surgical task and the feasibility depends on multiple factors including the location and size of the lesions. Few series of patients have been described in the literature. This case described a giant GIST with major and relapsing gastrointestinal bleeding that induced an emergency surgically approach with a minimally invasive laparoscopic partial gastric resection. This report described a case of giant gastric GIST that presented with repeated and severe gastrointestinal bleeding and was treated by emergency laparoscopic gastric resection. The feasibility and advantages of the surgical technique are discussed. The best surgical approach in these rare cases has still to be evaluated on individual basis.


Five-year clinical follow-up of prostatic cancer patients treated with fosfestrol and bromocriptine.
A five-year follow-up is presented of 123 patients with recently diagnosed prostatic cancer, confirmed histopathologically and treated with fosfestrol and bromocriptine. The combined treatment has been shown to prevent most of the complications and side effects of therapy, thus it is considered to be worthy of recommendation.


Staphylococcus and the healing power of pus.
Staphylococcus aureus infections induce formation of neutrophil-rich abscesses filled with debris from dead phagocytes. Corbin and colleagues report that this pus has antimicrobial powers through the activity of calprotectin. Calprotectin, a member of the S100 family of proinflammatory proteins, acts through chelation of manganese. As manganese is an essential cofactor for several enzymes in S. aureus, this impacts bacterial growth and the bacterium's ability to withstand oxidative stress.


Electron microscopic study of alcoholic liver disease with special attention to the changes of mesenchymal cells of the liver.
The authors investigated electron microscopically the biopsy material of 48 chronic alcoholic liver patients. On the basis of clinical and histological criteria 5 stages were differentiated: fatty liver, fatty liver with increased mesenchymal activity, acute alcoholic hepatitis, chronic alcoholic hepatitis, alcoholic cirrhosis. In each group changes of liver cell organelles and mesenchymal cells were compared. In this investigation it was demonstrated that liver cell damage--except for acute alcoholic hepatitis was not parallel with the severity of the clinical picture. On the contrary, the proliveration of mesenchymal cells, signs of its secretory activity and fibre forming, were in correlation with the progression of liver disease. The authors suggest that an intermediate stage must be taken into account between acute alcoholic hepatitis and alcoholic cirrhosis: the chronic progressive alcoholic hepatitis. It reminds morphologically to a great extent of the active chronic hepatitis and it is characterized not by severity of the injury of liver cell organelles, but by great proliferation of mesenchymal cells and lymphoid infiltration.


Analysis of Acropora muricata calmodulin (CaM) indicates that scleractinian corals possess the ancestral exon/intron organization of the eumetazoan CaM gene.
Calmodulin (CaM), belonging to the tropinin C (TnC) superfamily, is one of the calcium-binding proteins that are highly conserved in their protein and gene structure. Based on the structure comparison among published vertebrate and invertebrate CaM, it is proposed that the ancestral form of eumetazoan CaM genes should have five exons and four introns (four-intron hypothesis). In this study, we determined the gene structure of CaM in the coral Acropora muricata, an anthozoan cnidarian representing the basal position in animal evolution. A CaM clone was isolated from a cDNA library constructed from the spawned eggs of A. muricata. This clone was composed of 908 nucleotides, including 162 base pairs (bp) of 5'-untranslated region (UTR), 296 bp of 3'-UTR, and an open reading frame 450 bp in length. The deduced amino acid indicated that the Acropora CaM protein is identical to that of the actiniarian, Metridinium senile, and has four putative calcium-binding domains highly similar to those of other vertebrate or invertebrate CaMs. Southern blot analysis revealed that Acropora CaM is a putative single-copy gene in the nuclear genome. Genomic sequencing showed that Acropora CaM was composed of five exons and four introns, with intron II not corresponding to any region in the actiniarian CaM gene, which possesses only four exons and three introns. Our results highlight that the coral CaM gene isolated from A. muricata has four introns at the predicted positions of the early metazoan CaM gene organization, providing the first evidence from the basal eumetazoan phylum to support the four-intron hypothesis.


Is radial Extracorporeal Shock Wave Therapy (rEWST) combined with supervised exercises (SE) more effective than sham rESWT and SE in patients with subacromial shoulder pain? Study protocol for a double-blind randomised, sham-controlled trial.
Subacromial shoulder pain is a common complaint. Radial Extracorporeal Shock Wave Therapy (rESWT) has being increasingly used to treat calcific and non-calcific tendinosis, although there is no evidence of the effectiveness of rESWT in non-calcific tendinosis of the rotator cuff. A randomised single blind study showed that the short-term effect of supervised exercises (SE) was significantly better than rESWT on subacromial shoulder pain, but both groups improved. In a clinical trial on achilles tendinopathy rESWT improved the effectiveness of treatment with eccentric loading. The objective of this present study is to evaluate if rESWT in addition to SE is more effective in improving shoulder pain and function compared with sham rESWT and SE in patients with subacromial shoulder pain. This is a double blind, randomised sham-controlled trial which is performed at the shoulder clinic at the Department of Physical Medicine and Rehabilitation in Oslo University Hospital, Norway. One-hundred-forty-four patients with subacromial shoulder pain lasting at least 3 months, age from 25 to 70 years old are included in the trial. Patients are randomly allocated in 1:1 ratio to receive either rESWT or sham rESWT once a week in addition to SE once a week for the initial 4 weeks. Subsequently SE are provided twice a week for 8 weeks. The primary outcome measure is a change in the Shoulder Pain and Disability Index (SPADI) at 24 weeks follow-up. Secondary outcomes include return to work, pain at rest and on activity, function, and health related quality of life. The patients, the physiotherapist providing the exercise regimen and the outcome assessor are blinded to group assignment. The physiotherapist providing the rESWT is not blinded. Because of the extensive use of rESWT in the treatment of subacromial shoulder pain the results of this trial will be of importance and have impact on clinical practice. ClinicalTrials.gov NCT01441830.


Older patients with EGFR mutation-positive non-small cell lung cancer treated with afatinib in clinical practice: A subset analysis of the non-interventional GIDEON study.
Lung cancer is most common in older patients; despite this, older patients are historically under-represented in clinical studies. Here we present data from GIDEON, a study undertaken in Germany in patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) receiving first-line afatinib. GIDEON enrolled a high proportion of patients aged ≥70 years, providing an opportunity to study afatinib use in older patients. In GIDEON (NCT02047903), a prospective non-interventional study, patients with EGFRm+ NSCLC received first-line afatinib in routine clinical practice until disease progression, death or intolerable adverse events. Key objectives were twelve-month progression-free survival (PFS) rate and objective response rate (ORR). Overall survival (OS) and safety were also assessed. This post hoc analysis explores outcomes of patients grouped by age (≥70 and <70 years). In the 152 patients enrolled in GIDEON (69.7% female, 64.5%/22.4%/13.2% with Del19/L858R/other exon 18-21 mutations, 33.6% with brain metastases), the median age was 67 years (range 38-89) and 43.4% were aged ≥70 years. In the ≥70 years age group and the <70 years age group, twelve-month PFS rate was 58.9% and 43.9%, median PFS was 17.2 months and 10.6 months, ORR was 72.0% and 76.5%, twelve-month OS rate was 79.1% and 79.2%, 24-month OS rate was 52.0% and 61.7%, and median OS was 30.4 months and 27.4 months, respectively. In the ≥70 years age group and the <70 years age group, grade ≥3 adverse drug reactions (ADRs) were observed in 34.8% and 40.7% of patients, respectively; the most common were diarrhea (13.6% and 14.0%), acneiform dermatitis (7.6% and 7.0%), stomatitis (1.5% and 4.7%) and maculopapular rash (1.5% and 4.7%). Patients with EGFRm+ NSCLC aged ≥70 years showed clinical benefit from first-line afatinib with no unexpected safety signals, supporting the use of afatinib in this setting.


The effect on the cornea of alpha cyclodextrin vehicle for cyclosporin eye drops.
We tested four different combinations of alpha-CD and CYA: 0.075% and 80 mg/mL alpha-CD, 0.025% CYA and 40 mg/mL alpha-CD, 0.009% CYA and 20 mg/mL alpha-CD, and 0.003% CYA and 10 mg/mL alpha-CD. We found that 0.025% CYA (alpha-CD[40 mg/mL]) resulted in the least corneal toxicity and penetrated in the cornea 5 to 10 times more than did lipophilic vehicle with CYA.


Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation.
The absence of dystrophin in Duchenne muscular dystrophy disrupts the dystrophin-associated glycoprotein complex resulting in skeletal muscle fiber fragility and atrophy, associated with fibrosis as well as microtubule and neuromuscular junction disorganization. The specific, non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was recently shown to regulate acetylcholine receptor distribution and muscle atrophy. Here, we report that administration of the HDAC6 selective inhibitor tubastatin A to the Duchenne muscular dystrophy, mdx mouse model increases muscle strength, improves microtubule, neuromuscular junction, and dystrophin-associated glycoprotein complex organization, and reduces muscle atrophy and fibrosis. Interestingly, we found that the beneficial effects of HDAC6 inhibition involve the downregulation of transforming growth factor beta signaling. By increasing Smad3 acetylation in the cytoplasm, HDAC6 inhibition reduces Smad2/3 phosphorylation, nuclear translocation, and transcriptional activity. These findings provide in vivo evidence that Smad3 is a new target of HDAC6 and implicate HDAC6 as a potential therapeutic target in Duchenne muscular dystrophy.


Clear regression of harvested intertidal mollusks. A 20-year (1994-2014) comparative study.
Intertidal mollusks are subjected to an intense environmental pressure, from human-induced stressors, mainly harvesting, to competition for food and space with other species. Here we used mollusk shell size as a measure of size distribution and reproductive potential of intertidal limpets. Two species of exploited limpets (Patella candei crenata and Patella aspera) were monitored throughout the littoral of Tenerife (Canary Islands, NE Atlantic Ocean), an overpopulated island with a high coastal pressure. The exploitation of these two limpet species is controlled by regional legislation, with seasonal closures and limits of harvest for professional (10 kg) and recreational harvesters (3-5 kg). A long-term comparison (1994-2014) of limpet size has been conducted as a surrogate of the state of conservation of these two limpets. Both species showed populations dominated largely by small-sized individuals (<30 mm) and a lack of large adults (>60 mm). The proximity to coastal settlements was not a factor to explain limpet assemblage structure. The temporal (1994-2014) comparative study showed a sharp decrease in the mean size of both limpet species (7 mm in P. aspera and 5 mm in P. candei crenata). These results might be indicative of overharvesting of both species in Tenerife. The conservation of the two studied species needs to be accomplished by the strict fulfillment of current protective strategies, as well as the creation of marine protected areas where intertidal harvesting is totally banned all over the year.


Effects of brief post-sample cues signaling presence or absence of reinforcers in delayed matching-to-sample.
When short-term memory is assessed in the delayed matching-to-sample (DMTS) procedure, performance is better when cues signal larger reinforcer magnitudes or higher reinforcer probabilities for correct responding. Previous studies demonstrating signaled-magnitude or signaled-probability effects presented cues for a prolonged period during the sample stimulus and/or retention interval. The present study asked whether a signaled-probability effect would occur with brief post-sample cues that signaled the presence or absence of reinforcement. Five pigeons responded in a DMTS task in which sample stimuli were sometimes followed by a 0.5-s cue signaling that reinforcers would either be available or not available in the current trial, and the retention interval varied from 0.5 s to 20 s. A reliable signaled-probability effect was found when reinforcers were arranged independently and for all correct responses, whereas a smaller, less systematic effect was found when reinforcers were arranged dependently and probabilistically. These findings highlight the importance of reinforcement contingencies and contingency discriminability in remembering, and add to the evidence showing that cues signaling differential reinforcement in DMTS may affect processes during the retention interval and comparison phase, rather than attention to the sample stimulus.


Health providers' perspectives on contraceptive use in rural Northwest Tanzania: A qualitative study.
In Tanzania, contraceptive use is limited, particularly in rural communities and even among women who would like to delay childbearing. This paper aims to present health providers' perspectives on populations seeking contraception and barriers that could be addressed to increase access to and uptake of contraception, given their interface with large portions of their communities. We conducted 18 in-depth interviews with providers stationed at health dispensaries in six rural villages in northwest Tanzania. Two investigators independently coded interviews using a stepwise process to achieve consensus on prevalent topics. Three topics emerged from our analysis: (1) nature of clients seeking contraception; (2) barriers to uptake of contraception; and (3) the role of secrecy in obtaining and using contraception. Health providers reported that married women with children were the most frequent users of contraception, alongside some single women, men, sex workers, and students. Barriers to contraception included lack of supplies and trained staff, misconceptions and fears, stigma, and unsupportive partners. Providers observed that contraception was often used secretly. They reported surreptitious visits and described clients' preferential use of discreet methods. Providers respected and supported clients' desires to keep visits confidential. Our data suggest maintaining high stocks of discreet contraceptive methods and deploying more trained staff to dispensaries could increase availability and access to contraceptives. At the community level, more education campaigns are warranted to address barriers, especially those related to stigma. Our work highlights the need for additional contraceptive methods that are easy to administer and discreet for women who must maintain secrecy. Future studies of the effectiveness of interventions and new contraceptives should obtain healthcare providers' perspectives, as they can provide important insights to service provision.


TARUP technique. Advantages of minimally invasive robot-assisted abdominal Wall surgery.
The use of robot-assisted minimally invasive surgery in ventral/incisional hernia repair has increased exponentially in recent years. This increase is probably related to the advantages of robotic surgery, among which are better visualization, the implementation of articulated instruments and better ergonomics for the surgeon. The TARUP (Robotic Transabdominal Retromuscular Umbilical Prosthetic Hernia Repair) technique combines the benefits of minimally invasive surgery, in terms of less wound-related morbidity, also allowing the placement of a mesh in a retromuscular position facilitated by the use of the robotic platform.


Low-molecular-weight lignin-rich fraction in the extract of cultured Lentinula edodes mycelia attenuates carbon tetrachloride-induced toxicity in primary cultures of rat hepatocytes.
The extract of cultured Lentinula edodes mycelia (LEM) is a medicinal food ingredient that has hepatoprotective effects. In this study, we fractionated the LEM extract to explore novel active compounds related to hepatoprotection by using primary cultures of rat hepatocytes exposed to carbon tetrachloride (CCl(4)). The LEM extract and the fractions markedly inhibited the release of alanine aminotransferase (ALT) from hepatocytes damaged by CCl(4) into the culture medium. The strongest hepatocyte-protective activity was seen in a fraction (Fr. 2) in which a 50% ethanol extract was further eluted with 50% methanol and separated using reverse-phase HPLC. Fr. 2 had an average molecular weight of 2753, and the main components are lignin (49%) and saccharides (36%, of which xylose comprises 41%). Therefore, Fr. 2 was presumed to be a low-molecular-weight compound consisting mainly of lignin and xylan-like polysaccharides. The hepatocyte-protective activity was observed even after digestion of xylan-like polysaccharides in Fr.2 and confirmed with low-molecular-weight lignin (LM-lignin) alone. In addition, Fr. 2, the xylan-digested Fr. 2 and LM-lignin showed higher superoxide dismutase (SOD)-like activity than the LEM extract. These results suggested that the effective fraction in the LEM extract related to hepatocyte protection consisted mainly of LM-lignin, and its antioxidant activity partially contributes to the hepatocyte-protective activity of the LEM extract.


Evaluations of workplace smoking cessation programs: a critique.
This article reviews 21 published evaluations of workplace smoking cessation programs. Its purpose is to assess the quality of these evaluations and outline recommendations that may benefit such smoking cessation efforts. Issues that should be considered during the planning and evaluation of these smoking cessation programs include research design, behavior measurement and verification, employee recruitment strategies, nonsmoking behavior maintenance, and ethics.


Detection and molecular characterization of astro and bocaviruses in dogs in Minnesota.
Canine astrovirus (CAstV) and canine bocavirus (CBoV) are involved in cases of mild, and sometimes severe, gastroenteritis in dogs. Fecal samples from two dead dogs with gastroenteritis were received at the University of Minnesota Veterinary Diagnostic Laboratory to determine the cause of death. Small round viruses of 20-35 nm diameter were observed by negative contrast electron microscopy. The samples were subjected to Illumina MiSeq sequencing. Both samples were strongly positive for CAstV; all viral reads were related to CAstV. In addition, sample number 1 had a few reads of CBoV. Two complete sequences of CAstV were identified (6625 and 6627 nt in length) with 95% nt identity. RT-PCR and PCR were used to confirm CAstV and CBoV infections in successive samples of canine gastroenteritis. Sanger sequencing was done on nucleic acids from positive samples. Of a total of ten samples, CAstV and CBoV infections were confirmed in six and eight animals, respectively. Four animals had mixed infection with both viruses. All sequences of ORF1b gene of CAstVs showed closest clusters in phylogenetic tree with 96-100% nucleotide and amino acids identity. On the other hand, identity between VP2 gene of different CBoV strains in this study ranged from 93%- 100%. All strains were located close to each other except the divergent MT078234 strain, which was arranged in a separate branch and was closer to reference strain JN648103/USA/2010. This study highlights the importance of electron microscopy and next generation sequencing for early detection and characterization of viruses associated with dog gastroenteritis.


Color Doppler ultrasonography evaluation for chemotherapy treatment response of osteogenic sarcoma.
The aim of this study was to evaluate the vascular parameters of the proximal peripheral arteries of limbs by color Doppler ultrasonography (CDUS) in individuals with osteogenic sarcoma (OGS) after neoadjuvant chemotherapy and their relation to the tumor necrosis rate. We recruited 50 individuals with osteogenic sarcoma who were scheduled for neoadjuvant chemotherapy before elective surgery from 2003 to 2010. Once enrolled, we evaluated these 50 subjects using color Doppler sonography to identify vascular parameters of tumor vessels before and after neoadjuvant therapy. The vascular parameters of the proximal peripheral arteries of limbs (peak systolic velocity [PSV], end-diastolic velocity [EDV], resistive index [RI]) and tumor neovascularity were compared before and after neoadjuvant chemotherapy using CDUS. Before chemotherapy, the PSV, EDV and RI differed significantly between the diseased and contralateral normal limbs (p < 0.001). Among the factors relating to the tumor necrosis rate before chemotherapy, the EDV of the diseased limb (p = 0.047) and tumor neovascularity (p = 0.027) showed significant differences. After chemotherapy, the PSV of the diseased limb (p = 0.022) and the difference in PSV between the diseased and contralateral limbs (p = 0.003) showed significant differences. The vascular parameters of the proximal peripheral arteries of limbs owing to tumor burden differ significantly between the diseased and contralateral normal limbs. For individuals with osteogenic sarcoma who still have a higher difference in PSV between the diseased and contralateral limbs after chemotherapy, another course of chemotherapy after surgery and close follow-up should be considered.


Organic solid waste upgrading under natural gas for valuable liquid products formation: Pilot demonstration of a highly integrated catalytic process.
An integrated catalytic process for natural-gas-assisted OSW upgrading is fully demonstrated at a pilot scale, which combines the methanolysis, methano-refining and catalytic liquefaction processes through careful process design and catalyst tailoring. Three types of agricultural and forestry wastes including pelleted wood chip, crushed rice straw and crushed corn stover are used as representatives of OSW for at least a 1-month continuous operation. The products are comprehensively analyzed and the indices for quality control in terms of basic, compositional, and fuel properties, as well as elemental and distillation analyses, are monitored and proved to be satisfactory for practical use. Economic assessment and life cycle analysis are also performed. It is validated that the OSW upgrading process under a natural gas atmosphere exhibits favorable feasibility, stability, operational margins and environmental friendliness. This exploration manifests an alternative route for simultaneous energy supply and waste management with great economic and environmental advantages.


Refractive lens exchange with the array multifocal intraocular lens.
To study the safety and efficacy of refractive lens exchange as a refractive surgery modality in the presbyopic population. Oregon Eye Institute, Eugene, Oregon, USA. This retrospective review of patient charts included patient selection, preoperative evaluation, management of astigmatism, surgical technique, postoperative visual outcome, and complications. The study included 68 eyes comprising 32 bilateral and 4 unilateral refractive lens exchanges. All patients having bilateral refractive lens exchange achieved an uncorrected binocular visual acuity of 20/40 and J5 or better 1 to 3 months postoperatively. More than 90% achieved an uncorrected binocular visual acuity of 20/30 and J4 and nearly 60%, of 20/25 and J3. Refractive lens exchange was a safe and effective refractive surgery modality in presbyopic patients.


AEG-1 overexpression is essential for maintenance of malignant state in human AML cells via up-regulation of Akt1 mediated by AURKA activation.
Acute myeloid leukemia (AML) remains highly fatal, highlighting the need for improved understanding of signal pathways that can lead to the development of new therapeutic regimens targeting common molecular pathways shared across different AML subtypes. Here we demonstrate that astrocyte elevated gene-1 (AEG-1) is one of such pathways, involving in cell cycle and apoptosis regulation and contributing to enhanced proliferation and chemoresistance in HL-60 and U937 AML cells. The pleiotropic effects of AEG-1 on AML were found to correlate with two novel target genes, Aurora kinase A (AURKA) and Akt1. Down-regulation of AEG-1 by short-hairpin RNA (shRNA) could not only decrease AURKA expression both on mRNA and protein levels but also decrease the levels of pAkt473 and pAkt308 (the active forms of phosphorylated Akt), similar effect as using AURKA inhibitor Tozasertib (VX680). Furthermore, the AEG-1 shRNA-induced malignant phenotype changes could be mitigated by forced overexpression of AURKA through increased Akt1 activation and phosphorylation in AML cells. On the other hand, although exogenous expression of AEG-1 could increase both AURKA and Akt expression levels the simultaneous use of AURKA inhibitor Tozasertib blocked AEG-1's role of up-regulation of Akt expression in ECV304 cells, suggesting that AURKA might be a key mediator of AEG-1 in regulating Akt activation, and a key effector of AEG-1 in maintaining the malignant state of AML. Moreover, knockdown AEG-1 expression also changed the expression levels of PTEN, survivin and stathmin, the genes that have been reported to be involved in the development of several other malignant tumors. Our results provide evidence for AEG-1's carcinogenesis role in AML and reveal a novel functional link between AEG-1 and AURKA on Akt1 activation. AEG-1 can be an important candidate as a drug design target within AURKA signal pathway for more specific killing of AML cells while sparing normal cells.


Stability and pinning synchronization of delayed memristive neural networks with fractional-order and reaction-diffusion terms.
Global asymptotic stability and synchronization are explored in this paper for fractional delayed memristive neural networks with reaction-diffusion terms (FDRDMNNs) in sense of Riemann-Liouville. First, we introduce diffusion into the existing model of fractional delayed memristive neural networks. Next, in terms of Green's theorem and inequality technique, a less conservative criterion for the asymptotic stability of FDRDMNNs is given by endowing Lyapunov direct method. Then, the appropriate pinning feedback controllers and adaptive controllers are designed to achieve the synchronization of the FDRDMNNs, and two sufficient conditions for global asymptotic synchronization are acquired. In addition, the results based on algebraic inequalities enhance some existing ones. The numerical simulations finally verify the validity of the derived results.


Induction of T-cell proliferation by an Ia+ monocytic tumor clone.
Ia+ immature malignant monocyte clones were isolated from retrovirus-induced lymphomas. These lymphomas contained a predominant population of Ly-1+ T cells. In order to explain this anomaly, the functional capacity of one of these clones, ORA I-a, was assessed. The results indicated that ORA I-a could present protein antigen to syngeneic and semisyngeneic antigen-primed lymph node T cells. Allogeneic stimulation, however, could not be induced. Furthermore, ORA I-a-conditioned medium could augment mitogen-dependent and -independent thymocyte proliferation. These studies suggest that the unique populations of malignant antigen-presenting cells can interact with distinct T-cell subpopulations. Functional analyses of these tumor cell lines may thus be useful in elucidating some of the cellular interactions which occur during the course of immunity.


Molecular genetics of type 2 von Willebrand disease.
Type 2 von Willebrand disease (VWD) is characterized by a wide heterogeneity of functional and structural defects. These abnormalities' cause either defective von Willebrand factor (VWF)-dependent platelet function in subtypes 2A, 2B, and 2M or defective VWF-factor VIII (FVIII) binding in subtype 2N. The diagnoses of types 2A, 2B, and 2M VWD may be guided by the observation of disproportionately low levels of ristocetin cofactor activity or collagen-binding capacity relative to VWF antigen. The abnormal platelet-dependent function is often associated with the absence of high molecular weight (HMW) multimers (type 2A, type 2B), but the HMW multimers may also be present (type 2M, some type 2B), and supranormal multimers may exist ("Vicenza" variant). The observation of a low FVIII-to-VWF:Ag ratio is a hallmark of type 2N VWD. in which the FVIII levels depend on the severity of the FVIII-binding defect. Today, the identification of mutations in particular domains of the pre-pro-VWF is helpful in classifying these variants and providing further insight into the structure-function relationship and the biosynthesis of VWF. Thus, mutations in the D2 domain, involved in the multimerization process, are found in patients with type 2A, formerly named IIC VWD. Mutations located in the D' domain or in the N terminus of the D3 domain define type 2N VWD. Mutations in the D3 domain characterize Vicenza and IIE patients. Mutations in the A1 domain may modify the binding of VWF multimers to platelets, either increasing (type 2B) or decreasing (type 2M, 2A/2M) the affinity of VWF for platelets. In type 2A VWD, molecular abnormalities identified in the A2 domain, which contains a specific proteolytic site, are associated with alterations in folding, impairing VWF secretion or increasing its susceptibility to proteolysis. Finally, a mutation localized in the carboxy-terminus CK domain, which is crucial for the dimerization of the VWF subunit, has been identified in a rare subtype 2A, formerly named IID.


[The educational continuum and the specialization in oral diseases and jaw surgery].
Throughout the world can be seen a strong development towards the requirement of both a dental and a medical degree for oral and maxillofacial surgeons. Such requirements call for a critical review of the various parts of the curriculum and the optimum educational continuity in the sequence dentistry--medicine--oral and maxillofacial surgery.


Extracellular annexin A5: functions of phosphatidylserine-binding and two-dimensional crystallization.
In normal healthy cells phosphatidylserine is located in the inner leaflet of the plasma membrane. However, on activated platelets, dying cells and under specific circumstances also on various types of viable leukocytes phosphatidylserine is actively externalized to the outer leaflet of the plasma membrane. Annexin A5 has the ability to bind in a calcium-dependent manner to phosphatidylserine and to form a membrane-bound two-dimensional crystal lattice. Based on these abilities various functions for extracellular annexin A5 on the phosphatidylserine-expressing plasma membrane have been proposed. In this review we describe possible mechanisms for externalization of annexin A5 and various processes in which extracellular annexin A5 may play a role such as blood coagulation, apoptosis, phagocytosis and formation of plasma membrane-derived microparticles. We further highlight the recent discovery of internalization of extracellular annexin A5 by phosphatidylserine-expressing cells.


Involvements of the ABC protein ABCF2 and α-actinin-4 in regulation of cell volume and anion channels in human epithelial cells.
After osmotic swelling, cell volume is regulated by a process called regulatory volume decrease (RVD). Although actin cytoskeletons are known to play a regulatory role in RVD, it is not clear how actin-binding proteins are involved in the RVD process. In the present study, an involvement of an actin-binding protein, α-actinin-4 (ACTN4), in RVD was examined in human epithelial HEK293T cells. Overexpression of ACTN4 significantly facilitated RVD, whereas siRNA-mediated downregulation of endogenous ACTN4 suppressed RVD. When the cells were subjected to hypotonic stress, the content of ACTN4 increased in a 100,000 × g pellet, which was sensitive to cytochalasin D pretreatment. Protein overlay assays revealed that ABCF2, a cytosolic member of the ABC transporter superfamily, is a binding partner of ACTN4. The ACTN4-ABCF2 interaction was markedly enhanced by hypotonic stimulation and required the NH(2) -terminal region of ABCF2. Overexpression of ABCF2 suppressed RVD, whereas downregulation of ABCF2 facilitated RVD. We then tested whether ABCF2 has a suppressive effect on the activity of volume-sensitive outwardly rectifying anion channel (VSOR), which is known to mediate Cl(-) efflux involved in RVD, because another ABC transporter member, CFTR, was shown to suppress VSOR activity. Whole-cell VSOR currents were largely reduced by overexpression of ABCF2 and markedly enhanced by siRNA-mediated depletion of ABCF2. Thus, the present study indicates that ACTN4 acts as an enhancer of RVD, whereas ABCF2 acts as a suppressor of VSOR and RVD, and suggests that a swelling-induced interaction between ACTN4 and ABCF2 prevents ABCF2 from suppressing VSOR activity in the human epithelial cells.


Production of aflatoxin byAspergillus parasiticus and its control.
The aim of the present work was to investigate the production of aflatoxin byAspergillus parasiticus and to find out the possible ways to control it. Of 40 food samples collected from Abha region, Saudi Arabia, only 25% were contaminated with aflatoxins. Oil-rich commodities had the highly contaminated commodities by fungi and aflatoxins while spices were free from aflatoxins.Bacillus megatertum andB cereus were suitable for microbiological assay of aflatoxins. Czapek's-Dox medium was found a suitable medium for isolation of fungi from food samples. The optimal pH for the growth ofA. parasiticus and its productivity of aflatoxin B1 was found at 6.0, while the best incubation conditions were found at 30°C for 10 days. D-glucose was the best carbon source for fungal growth, as well as aflatoxin production. Corn steep liquor, yeast extract and peptone were the best nitrogen sources for both fungal growth and toxin production (NH4)2HPO4 (1.55 gL(-1)) and NaNO2 (1.6 gL(-1)) reduced fungal growth and toxin production with 37.7% and 85%, respectively. Of ten amino acids tested, asparagine was the best for aflatoxin B1 production. Zn(2+) and Co(2+) supported significantly both fungal growth, as well as, aflatoxin B1 production at the different tested concentrations. Zn(2+) was effective when added toA. parasiticus growth medium at the first two days of the culture age. The other tested metal ions expressed variable effects depending on the type of ion and its concentration. Water activity (aw) was an important factor controlling the growth ofA. parasiticus and toxin production. The minimum aw for the fungal growth was 0.8 on both coffee beans and rice grains, while aw of 0.70 caused complete inhibition for the growth and aflatoxin B1 production. H2O2 is a potent inhibitor for growth ofA. parasiticus and its productivity of toxins. NaHCO3 and C6H5COONa converted aflatoxin B1 to water-soluble form which returned to aflatoxin B1 by acidity. Black pepper, ciliated heath, cuminum and curcuma were the most inhibitory spices on toxin production. Glutathione, quinine, EDTA, sodium azide, indole acetic acid, 2,4-dichlorophenoxy acetic acid, phenol and catechol were inhibitory for both growth, as well as, aflatoxin B1 production. Stearic acid supported the fungal growth and decreased the productivity of AFB1 gradually. Lauric acid is the most suppressive fatty acid for both fungal growth and aflatoxin production, but oleic acid was the most potent supporter. Vitamin A supported the growth but inhibited aflatoxin B1 production. Vitamins C and D2 were also repressive particularly for aflatoxin production The present study included studying the activities of some enzymes in relation to aflatoxin production during 20-days ofA. parasiticus age in 2-days intervals. Glycolytic enzymes and pyruvate-generating enzymes seems to be linked with aflatoxin B1 production. Also, pentose-phosphate pathway enzymes may provide NADPH for aflatoxin B1 synthesis. The decreased activities of TCA cycle enzymes particularly from 4th day of growth up to 10th day were associated with the increase of aflatoxin B1 production. All the tested enzymes as well as aflatoxin B1 production were inhibited by either catechol or phenol.


The avoidance of small intestine injury in gynecologic cancer.
The evolution of systematized operative staging and radical surgical procedures in the management of gynecologic cancer has increased the complexities of integrating radiation therapy. High dose irradiation to large treatment volumes has been associated with an increased incidence of small intestine injury. This complication is morbid and often fatal. Although predisposing factors have been extensively studied, there has been a paucity of reports evaluating preventative measures. Between 1975 and 1980, 140 patients with gynecologic cancer were treated at the Valley Presbyterian Hospital in the Division of Radiation Therapy. Twenty-six patients with cervix cancer received definitive irradiation and seven received adjunct irradiation. Seventy-two with corpus cancer received adjunct irradiation, seven received definitive irradiation and three palliative irradiation. Eleven patients with ovarian cancer received adjunct irradiation and 15 palliative irradiation. Eight-five patients were at potential risk for small intestine injury and had treatment planning small intestine X rays. Fixation was observed in 7/39 (18%) without prior pelvic surgery and 30/46 (65%) with prior pelvic surgery. Information from the small intestine X rays were used in 41 patients to make 60 treatment modifications. Twenty-five of 140 (17%) had a reduction of total dose, 26/140 (18%) had exclusion of the small intestine by shrinking fields, or patient positioning and 13/140 (9%) had displacement of the small intestine by distention of the bladder. No patient developed small intestine injury. The disease free survival for cervix cancer was 27/33 (82%), corpus cancer 68/79 (86%) and ovarian cancer 5/11 (45%). Pelvic failure was observed in 19/123 patients who received definitive or adjunct irradiation. One patient with corpus cancer and three patients with ovarian cancer might have benefited from the use of a larger treatment volume or a higher total dose.


Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations.
To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic. An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel. Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended. The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19.


Efficacy and durability of posterior wall isolation with ethanol infusion into the vein of Marshall.
Ethanol infusion into the vein of Marshall (EIVOM) is expected to be an adjunctive therapy for mitral isthmus (MI) ablation. Additionally, EIVOM can widely ablate the epicardium via the branches that extend to the left atrial posterior wall (LAPW) and facilitate LAPW isolation. This study aimed to investigate the efficacy and durability of LAPW isolation with EIVOM. Our cohort consisted of 413 patients with atrial fibrillation (AF) who underwent both LAPW and MI ablations. EIVOM was first attempted in 177 (35%) patients with adequate VOMs. The VOM was infused with 5 mL of ethanol with a double coaxial guiding catheter technique. Both ablations were performed only by radiofrequency ablation (the RF group) in the remaining 236 (57%) patients. EIVOM with 5 mL of ethanol was completely achieved in 106 patients (the EIVOM group). The application duration of LAPW isolation did not differ significantly between the two groups (718 ± 276 vs. 709 ± 288 s; p = .78). LAPW debulking ablation was required in 64/106 (60%) and 176/236 (75%) patients in the EIVOM and RF groups, respectively (p < .05). However, AF- or atrial tachycardia-free survival analyses revealed no significant differences between the two groups (log-rank p = .70). Among the cases of recurrence, 17 and 38 patients underwent subsequent ablation sessions; LAPW was reconnected in 9/17 (53%) and 25/38 (53%) patients (p = .36) in the EIVOM and RF groups, respectively. EIVOM reduced the number of cases that required LAPW debulking ablation but did not improve the durability of LAPW isolation or clinical outcomes.


Aminoacylation complex structures of leucyl-tRNA synthetase and tRNALeu reveal two modes of discriminator-base recognition.
Leucyl-tRNA synthetase (LeuRS) specifically recognizes the characteristic long variable arm and the discriminator base, A73, of tRNA(Leu) in archaea and eukarya. The LeuRS 'editing domain' hydrolyzes misformed noncognate aminoacyl-tRNA. Here we report the crystal structure of the archaeal Pyrococcus horikoshii LeuRS-tRNA(Leu) complex. The protruding C-terminal domain of LeuRS specifically recognizes the bases at the tip of the long variable arm. The editing domain swings from its tRNA-free position to avoid clashing with the tRNA. Consequently the tRNA CCA end can bend and reach the aminoacylation active site. The tRNA 3' region assumes two distinct conformations that allow A73 to be specifically recognized in different ways. One conformation is the canonical 'aminoacylation state.' The other conformation seems to be the 'intermediate state,' where the misaminoacylated 3' end has partially relocated to the editing domain.


Somatic Copy Number Amplification and Hyperactivating Somatic Mutations of EZH2 Correlate With DNA Methylation and Drive Epigenetic Silencing of Genes Involved in Tumor Suppression and Immune Responses in Melanoma.
The epigenetic modifier EZH2 is in the center of a repressive complex controlling differentiation of normal cells. In cancer EZH2 has been implicated in silencing tumor suppressor genes. Its role in melanoma as well as target genes affected by EZH2 are poorly understood. In view of this we have used an integrated systems biology approach to analyze 471 cases of skin cutaneous melanoma (SKCM) in The Cancer Genome Atlas (TCGA) for mutations and amplifications of EZH2. Identified changes in target genes were validated by interrogation of microarray data from melanoma cells treated with the EZH2 inhibitor GSK126. We found that EZH2 activation by mutations, gene amplification and increased transcription occurred in about 20% of the cohort. These alterations were associated with significant hypermethylation of DNA and significant downregulation of 11% of transcripts in patient RNASeq data. GSK126 treatment of melanoma lines containing EZH2 activation reversed such transcriptional repression in 98 candidate target genes. Gene enrichment analysis revealed genes associated with tumor suppression, cell differentiation, cell cycle inhibition and repression of metastases as well as antigen processing and presentation pathways. The identified changes in EZH2 were associated with an adverse prognosis in the TCGA dataset. These results suggest that inhibiting of EZH2 is a promising therapeutic avenue for a substantial fraction of melanoma patients.


Real-Time Walk Light Detection with a Mobile Phone.
Crossing an urban traffic intersection is one of the most dangerous activities of a blind or visually impaired person's travel. Building on past work by the authors on the issue of proper alignment with the crosswalk, this paper addresses the complementary issue of knowing when it is time to cross. We describe a prototype portable system that alerts the user in real time once the Walk light is illuminated. The system runs as a software application on an off-the-shelf Nokia N95 mobile phone, using computer vision algorithms to analyze video acquired by the built-in camera to determine in real time if a Walk light is currently visible. Once a Walk light is detected, an audio tone is sounded to alert the user. Experiments with a blind volunteer subject at urban traffic intersections demonstrate proof of concept of the system, which successfully alerted the subject when the Walk light appeared.


Budding yeast Mms22 and Mms1 regulate homologous recombination induced by replisome blockage.
Yeast cells lacking MMS22 or MMS1 are hypersensitive to agents that perturb replisome progression but the cellular functions of these genes are unknown. In this study we investigate the involvement of budding yeast MMS22 and MMS1 in homologous recombination (HR). Recombination between sister chromatids or between homologous chromosomes induced by agents that block replisomes was severely defective in cells lacking MMS22 or MMS1. In contrast, HR induced by double-strand breaks was not affected by the absence of these genes. Major defects in MMS-induced HR were also observed in cells lacking the cullin RTT101, the histone acetyltransferase RTT109 and in cells lacking the histone chaperone ASF1, all of which interact genetically with MMS22 and MMS1. Finally, we show that cells lacking either MMS22 or MMS1 are defective in recovery from MMS-induced replisome stalling. These results identify Mms22 and Mms1 as S-phase specific recombination-promoting factors.