Tumor-derived exosomes in hypoxic microenvironment: release mechanism, biological function and clinical application.
Hypoxia is a key feature of solid tumors and is related to disease aggressiveness and adverse outcomes. It is recognized that the two-way communication between cancer cells and their microenvironment is critical to cancer progression. Increasing evidences show that the cellular communication and crosstalk between tumor cells and their microenvironment is not limited to secreted molecules, but also includes exosomes secreted by tumor cells. Exosomes are nano-scale extracellular vesicles (30-100 nm in diameter), which carry the molecular characteristics and cargo of the source cell, participating in intercellular communication through autocrine, paracrine and near-crine pathways. Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than normoxia conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Therefore, in this review, we summarize and discuss the latest research on the physiological mechanism of hypoxia regulating the secretion of exosomes, and the involvement of hypoxic exosomes in cancer progression and immune escape processes, and expounds the potential for targeting hypoxia-induced exosomes for cancer therapy strategies.


Response of the aging hamster lung to elastase injury.
The effect of age on the induction of emphysema in hamsters was investigated by administering porcine pancreatic elastase endotracheally to old (18 months of age) and young (4 months of age) hamsters; age-matched untreated animals served as controls. Lung volumes, quasi-static deflation volume pressure relations, and mean linear intercept, an index of alveolar size, were measured. Elastase-treated young hamsters demonstrated an increased volume of air in the lungs at a transpulmonary pressure of 25 cm H2O and an increased mean linear intercept. The lungs of old elastase-treated animals showed less pronounced changes than those of young hamsters in lung volume at transpulmonary pressure of 25 cm H2O and in mean linear intercept. Untreated old hamsters had a larger lung volume at a transpulmonary pressure of 25 cm H2O and an 85% increase in total lung collagen. Age-related alterations in connective tissues may account for the increased resistance of old lungs to injury by pancreatic elastase.


Behcet's Disease with Absent HLA Serotyping and Pathergy Test.
Behcet's disease is a multisystemic vasculitis of unknown etiopathogenesis characterized by recurrent acute inflammation. A 30-year male presented with progressive blurred vision in both eye for one month associated with photophobia, redness and ocular pain. On presentation best corrected visual acuity was 6/9 both eyes. Bilateral ocular examination of anterior segment demonstrated occasional cells. Treatment history of multiple joint pain along with oral aphthous ulcers. Erythematous papulopustular lesion over face, neck, trunk and genital ulcers were being treated. Irrespective of negative human leucocyte antigen B51 and pathergy, patient was diagnosed as Behcet's disease on the basis of clinical criteria and started with topical steroid and cycloplegic. At one-month, ocular symptoms were relieved. Behcet's disease is a rare, autoimmune disease, which lacks universal pathognomonic test and investigations, therefore diagnosis is primarily done with international criteria for Behcet's disease. Multidisciplinary approach certainly helps in early diagnosis and eliminating morbidity.


Long-lasting reflux episodes in gastroesophageal reflux and its complications in children.
The aim of the study was to test the hypothesis that long-lasting reflux episodes (episodes longer than 5 minutes and longest reflux episode) are more and are longer in patients with complicated gastroesophageal reflux (GER), such as reflux esophagitis, etc. In a prospective study 120 children (age 2 months to 14 years) were evaluated for the presence of GER and its complications (respiratory disease, reflux esophagitis). Out of them 51 were without GER (control group). With functional GER were 17, respiratory disease and GER had 21, and RE 16. Diagnosis of GER was established by computed 24 hour pH monitoring (C24hpHM) using Digitrapper Mark III, Synectics, Sweden. GER was positive if pH<4 was >5% of investigated time. Number of reflux episodes (NRE), episodes longer than 5 minutes (EL5), the longest reflux episodes (LRE), reflux index (RI) and duration of investigation were considered for the purpuse of this study. There was no significant statistical difference for the duration of procedure between the groups (Kruskal-Wallis test p>0.05). There was significant statistical difference for all parameters between control group and group with RE (Kruskal-Wallis test p<0.05). In RE patients there was significantly higher number of EL5, and longer duration of LRE compared with uncomplicated GER, functional GER, and GER with respiratory disease (Kruskal-Wallis test p<0.05). Between respiratory disese and functional GER there was no significant statistical difference. There was significant statistical difference between mild and severe RE for EL5 and LRE (Kruskal-Wallis test p<0.05). We confirmed that long lasting reflux episodes (EL5, LRE) are significantly higher in number and longer duration in children with RE, and together with acid reflux area, and impaired esophageal clearance contribute to development of RE.


Can surveillance systems identify and avert adverse drug events? A prospective evaluation of a commercial application.
Computerized monitors can effectively detect and potentially prevent adverse drug events (ADEs). Most monitors have been developed in large academic hospitals and are not readily usable in other settings. We assessed the ability of a commercial program to identify and prevent ADEs in a community hospital. and Measurement We prospectively evaluated the commercial application in a community-based hospital. We examined the frequency and types of alerts produced, how often they were associated with ADEs and potential ADEs, and the potential financial impact of monitoring for ADEs. Among 2,407 patients screened, the application generated 516 high priority alerts. We were able to review 266 alerts at the time they were generated and among these, 30 (11.3%) were considered substantially important to warrant contacting the physician caring for the patient. These 30 alerts were associated with 4 ADEs and 11 potential ADEs. In all 15 cases, the responsible physician was unaware of the event, leading to a change in clinical care in 14 cases. Overall, 23% of high priority alerts were associated with an ADE (95% confidence interval [CI] 12% to 34%) and another 15% were associated with a potential ADE (95% CI 6% to 24%). Active surveillance used approximately 1.5 hours of pharmacist time daily. A commercially available, computer-based ADE detection tool was effective at identifying ADEs. When used as part of an active surveillance program, it can have an impact on preventing or ameliorating ADEs.


Muscarinic ACh receptor activation causes transmitter release from isolated frog vestibular hair cells.
In the frog, vestibular efferent fibers innervate only type-II vestibular hair cells. Through this direct contact with hair cells, efferent neurons are capable of modifying transmitter release from hair cells onto primary vestibular afferents. The major efferent transmitter, acetylcholine (ACh), is known to produce distinct pharmacological actions involving several ACh receptors. Previous studies have implicated the presence of muscarinic ACh receptors on vestibular hair cells, although, surprisingly, a muscarinic-mediated electrical response has not been demonstrated in solitary vestibular hair cells. This study demonstrates that muscarinic receptors can evoke transmitter release from vestibular hair cells. Detection of this release was obtained through patch-clamp recordings from catfish cone horizontal cells, serving as glutamate detectors after pairing them with isolated frog semicircular canal hair cells in a two-cell preparation. Although horizontal cells alone failed to respond to carbachol, application of 20 microM carbachol to the two-cell preparation resulted in a horizontal cell response that could be mimicked by exogenous application of glutamate. All of the horizontal cells in the two-cell preparation responded to 20 microM CCh. Furthermore, this presumed transmitter release persisted in the presence of d-tubocurarine at concentrations that block all known hair cell nicotinic ACh receptors. The effect on the detector cell, imparted by the carbachol application to the hair cell-horizontal cell preparation, was blocked both by 2-amino-5-phosphonopentanoic acid, a selective N-methyl-D-aspartate antagonist, and the muscarinic antagonist, atropine. Thus vestibular hair cells from the frog semicircular canal can be stimulated to release transmitter by activating their muscarinic receptors.


Prisoner reentry: a public health or public safety issue for social work practice?
A significant literature identifies the policy, economic, health, and social challenges that confront released prisoners. This literature also describes the public health and public safety risks associated with prisoner reentry, provides recommendations for improving the reentry process, and describes the effectiveness of prison-based programs on recidivism rates. Public health and public safety risks are particularly significant in communities where large numbers of prisoners are released and few evidence-based services exist. The purpose of this article is to describe the public health and public safety risks that released prisoners experience when they reenter communities, and to discuss the social justice issues relevant for social work practice.


The anti-hyperlipidemic effect and underlying mechanisms of barley (Hordeum vulgare L.) grass polysaccharides in mice induced by a high-fat diet.
Hyperlipidemia is a pathological disorder of lipid metabolism that can cause fatty liver, atherosclerosis, acute myocardial infarction, and other diseases, seriously endangering people's health. Polysaccharides have been shown to have lipid-lowering potential. In the current study, the anti-hyperlipidemia effect and potential mechanisms of a polysaccharide (BGP-Z31) obtained from barley grass harvested at the stem elongation stage in high-fat diet (HFD)-treated mice were investigated. Results showed that supplementation with BGP-Z31 (200 and 400 mg kg-1) not only suppressed obesity, organ enlargement, and fat accumulation caused by HFD, but also regulated dyslipidemia, relieved liver function injury, and ameliorated the oxidative stress level. Meanwhile, BGP-Z31 increased the concentrations of acetic acid, propionic acid, butyric acid, and isovaleric acid in HFD-induced mice. Gut microbiota analysis demonstrated that BGP-Z31 had no obvious effect on the gut microbiota diversity in mice treated with HFD, but it positively remodeled the intestinal flora structure by elevating the relative abundances of Bacteroides, Muribaculaceae, and Lachnospiraceae and lowering the Firmicutes/Bacteroides value and the relative abundance of Desulfovibrionaceae. Therefore, our data suggested that BGP-Z31 can be used as a promising nutritional supplement for dietary intervention in hyperlipidemia.


Neuropathology of human spinal cord injury sustained in sports-related activities.
The neuropathology of 20 cases of traumatic human spinal injury is described. Cases were classified as having "complete" or "incomplete" spinal cord injuries based upon the neuropathological findings. Special attention was directed to those cases with neuropathological evidence of continuity of long tract axons across the lesion but that were obtained from individuals with clinically complete sensory and motor loss. Clinical and neuropathological data were obtained from the Western Australian Spinal Cord Injury Database and were selected from those cases involving sports-related injuries. From the total of 20 cases of spinal injury, 6 exhibited neuropathologically and clinically complete cord injuries, 4 were neuropathologically incomplete yet clinically complete, and 4 were neuropathologically and clinically incomplete (one being motor complete yet sensory incomplete). The clinical/neuropathological correlation was indeterminate in 6 cases because of death at or shortly after the accident. The neuropathological findings varied with the severity of trauma and the length of survival. In those cases examined less than 3 months postinjury, there was typically swelling of the cord from vasogenic edema with petechial hemorrhage and myelomalacia. Central hemorrhagic necrosis was common as was hyperemia with free red cells present among disrupted tissue. Activated astrocytes and polymorphs or macrophages were observed and early stages of glial cell scar formation were evident. Wallerian degeneration was evident in motor tracts caudal to the level of insult and in sensory tracts rostral to the lesion. Cases examined 3-6 months postinjury often revealed multilocular cysts with gliotic walls often extending several millimeters above and below the primary locus of injury. In the "chronic" cases (i.e., those surviving more than 6 months), there was evidence of varying degrees of preserved long tract parenchyma, nerve root regeneration, and Schwann cell remyelination of long tract axons. The degree of sparing of long motor and sensory tract parenchyma generally correlated well with the clinical observations of residual function. In four cases, however, there was a residuum of motor or sensory tract axons that appeared to have been spared injury, but the clinical data reported chronically complete sensory and motor loss. The presence of clinically complete yet neuropathologically incomplete injury was more often associated with crush or flexion injuries than with extension or compression trauma. The preserved parenchyma in these types of lesion may provide the anatomical substrate for restorative intervention.


Synthesis of DNA in isolated nuclei from differentiated mammalin epidermal cells.
Epidermal spinous and granular cells from the newborn rat neither replicate their nuclear DNA nor proliferate in vitro under conditions which support both processes in basal cells. However, as shown by autoradiography, (3H)thymidine and (14C)bromodeoxyuridine do label nuclei removed from spinous cells but not from granular cells. CsCl density gradient centrifugation of DNA obtained from early differentiated nuclei which had been exposed in vitro to (14C)bromodeoxyuridine, indicated that a considerable level of the tracer was present in the nucleic acid and suggested that replication of the genome had occurred. Therefore, spinous cells appear to retain the capability of reproducing nuclear DNA. Since differentiated cells appear to have the "diploid" level of DNA, these observations point to the replication of DNA as a possible locus of the mitotic inhibition which is coincident with epidermal differentiation.


Is Left Atrial Size a Predictor of Mortality after Coronary Artery Bypass Surgery? A Single Center Study.
To investigate the left atrial (LA) size as an independent predictor of mortality following coronary artery bypass surgery (CABG). This single center study evaluated determinants of mortality in 1070 patients who underwent isolated CABG from 2005-2014. Clinical, laboratory and demographic data were obtained from medical records. Collinearity between enlarged LA size (diameter ≥ 4 cm) and covariates was identified. The adjusted effects of enlarged LA size on 30-day mortality post CABG were tested using multiple logistic regression models. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were reported. The mean age was 59 ± 9.8 years, and 238 patients were female. Two multivariate logistic regression models were evaluated. In Model A, mitral regurgitation (MR), ejection fraction, intensive care unit length-of-stay and variables found to be collinear with LA size as predictors of mortality were excluded. In model B, the collinear variables were included. By multivariate analysis (Model A), the statistically significant independent predictors of 30-day mortality after CABG were: enlarged LA size (OR 4.82, 95% CI 2.16-10.79), emergency CABG (OR 3.54, 95% CI 1.75-7.18), prolonged inotropic support (OR 2.79, 95% CI 1.38-5.6), diuretic use ≥ 1 month (OR 1.29, 95% CI 1.3-8.42), and use of clopidogrel within a week before surgery (OR 3.27, 95% CI 1.28-8.36. In Model B, enlarged LA and moderate MR were identified as independent predictors of 30-day mortality. Increased LA size is a strong independent predictor of mortality after isolated CABG.


PoPoolationTE2: Comparative Population Genomics of Transposable Elements Using Pool-Seq.
The evolutionary dynamics of transposable elements (TEs) are still poorly understood. One reason is that TE abundance needs to be studied at the population level, but sequencing individuals on a population scale is still too expensive to characterize TE abundance in multiple populations. Although sequencing pools of individuals dramatically reduces sequencing costs, a comparison of TE abundance between pooled samples has been difficult, if not impossible, due to various biases. Here, we introduce a novel bioinformatic tool, PoPoolationTE2, which is specifically tailored for the comparison of TE abundance among pooled population samples or different tissues. Using computer simulations, we demonstrate that PoPoolationTE2 not only faithfully recovers TE insertion frequencies and positions but, by homogenizing the power to identify TEs across samples, it provides an unbiased comparison of TE abundance between pooled population samples. We anticipate that PoPoolationTE2 will greatly facilitate the analysis of TE insertion patterns in a broad range of applications.


Hematology of the keeled box turtle (Cuora mouhotii).
A healthy adult, intact female keeled box turtle (Cuora mouhotii) was found to have a marked heterophilic leukocytosis using normal hematologic parameters established for the eastern box turtle (Terrapene carolina carolina), a related chelonian species. This animal was monitored with serial complete blood counts (CBCs) over the next 15 years despite remaining asymptomatic for an infectious condition. Retrospective CBC data were compiled from 38 presumably healthy keeled box turtles to establish hematologic values for comparison in this species. Using this species-specific data, over the 15-year period, the female keeled box turtle had two times where the white blood cell (WBC) count was greater than 2 standard deviations (SD) above the mean, six times where the WBC count was greater than 1 SD above the mean, six times where the PCV was greater than 2 SD above the mean, and eight times where the PCV was greater than 1 SD above the mean. Infection and inflammation are the most common causes of leukocytosis in reptiles; however, given the clinical presentation of this patient, it was postulated that these clinicopathologic changes could be secondary to a stress response. Establishing reference intervals and understanding how stress impacts CBC parameters are important for evaluating the health status of keeled box turtles kept in captivity and for assessing the effects of environmental changes on the health status of wild populations of this endangered chelonian species.


Obstructive Giant Inflammatory Polyp of the Colon in Ulcerative Colitis.
Inflammatory polyps, also known as pseudo-polyps, are a common benign condition affecting 10-20% of patients with inflammatory bowel disease. Chronic, repeated inflammation and ulceration associated with healing lead to the formation of polyp-like structures in the colon. Although there are no common symptoms accompanying these pseudo-polyps, they can present with anemia, weight loss, diarrhea, intussusception, palpable mass, abdominal pain, discomfort, and melena, not to mention bowel obstruction that happens infrequently. Finally, it is important to recognize giant inflammatory polyps as they may occasionally be mistaken for colon cancer, leading to unnecessary surgical interventions. We present the case of a 38-year-old woman who was diagnosed with ulcerative colitis 10 years back, treated with oral mesalamine for five years, and had no follow-up after this period. She came to our clinic complaining of recurrent obstructive symptoms for a few months. Examination shows tenderness in the left lower quadrant with normal vital signs and bowel sounds.


[Investigation of the essence of chilliness and cold limbs of yang deficiency syndrome in Chinese medicine based on the adaptability of body to cold stimulation].
Chinese medicine (CM) theories attach great importance to the interaction between the human body and the environment. From this entry point, based on a great number of related CM literatures and knowledge of modern medicine, this paper investigated the essence of chilliness and cold limbs of yang deficiency syndrome. The differences on cognition and solution to this problem between CM theory and modern medicine theory were also analyzed. Firstly, the close relationship between the CM concepts of yang deficiency, "external cold", and winter was put forward after a review of yang deficiency in CM scripture Huangdi Neijing. Chilliness and cold limbs of yang deficiency patients was believed to be highly similar to the body state of "external cold" of healthy people in winter. Secondly, the state of "external cold" was described as a reduction of body surface blood flow (heat) with references to the adaptability to cold stimulation. Then according to a collection of physiological and pathological factors which may cause such reduction, we proposed that the essence of chilliness and cold limbs of yang deficiency patients may probably be the state of reduction of body surface blood flow (heat) due to some pathological factors already known as heart failure, poor circulation, and thyroid dysfunction. Thirdly, by using the method of "syndrome differentiation through formula effects assessment", this recognition was confirmed because the pharmacological activities of cardiotonic or peripheral vasodilating, or surface temperature increasing were found in a great number of single medicines and prescriptions applied to yang deficiency syndrome in CM.


All-oral direct-acting antiviral therapy against hepatitis C virus (HCV) in human immunodeficiency virus/HCV-coinfected subjects in real-world practice: Madrid coinfection registry findings.
We evaluated treatment outcomes in a prospective registry of human immunodeficiency virus/hepatitis C virus (HCV)-coinfected patients treated with interferon-free direct-acting antiviral agent-based therapy in hospitals from the region of Madrid between November 2014 and August 2016. We assessed sustained viral response at 12 weeks after completion of treatment and used multivariable logistic regression to identify predictors of treatment failure. We evaluated 2,369 patients, of whom 59.5% did not have cirrhosis, 33.9% had compensated cirrhosis, and 6.6% had decompensated cirrhosis. The predominant HCV genotypes were 1a (40.9%), 4 (22.4%), 1b (15.1%), and 3 (15.0%). Treatment regimens included sofosbuvir (SOF)/ledipasvir (61.9%), SOF plus daclatasvir (14.6%), dasabuvir plus ombitasvir/paritaprevir/ritonavir (13.2%), and other regimens (10.3%). Ribavirin was used in 30.6% of patients. Less than 1% of patients discontinued therapy owing to adverse events. The frequency of sustained viral response by intention-to-treat analysis was 92.0% (95% confidence interval, 90.9%-93.1%) overall, 93.8% (92.4%-95.0%) for no cirrhosis, 91.0% (88.8%-92.9%) for compensated cirrhosis, and 80.8% (73.7%-86.6%) for decompensated cirrhosis. The factors associated with treatment failure were male sex (adjusted odds ratio, 1.75; 95% confidence interval, 1.14-2.69), Centers for Diseases Control and Prevention category C (adjusted odds ratio, 1.65; 95% confidence interval, 1.12-2.41), a baseline cluster of differentiation 4-positive (CD4+) T-cell count <200/mm3 (adjusted odds ratio, 2.30; 95% confidence interval, 1.35-3.92), an HCV RNA load ≥800,000 IU/mL (adjusted odds ratio, 1.63; 95% confidence interval, 1.14-2.36), compensated cirrhosis (adjusted odds ratio, 1.35; 95% confidence interval, 0.96-1.89), decompensated cirrhosis (adjusted odds ratio, 2.92; 95% confidence interval, 1.76-4.87), and the use of SOF plus simeprevir, SOF plus ribavirin, and simeprevir plus daclatasvir. In this large real-world study, direct-acting antiviral agent-based therapy was safe and highly effective in coinfected patients; predictors of failure included gender, human immunodeficiency virus-related immunosuppression, HCV RNA load, severity of liver disease, and the use of suboptimal direct-acting antiviral agent-based regimens. (Hepatology 2018;68:32-47).


Design, synthesis, and biological evaluation of benzo[b]thiophene 1,1-dioxide derivatives as potent STAT3 inhibitors.
As a member of the signal transducer and activator of transcription (STAT) family, STAT3 plays a critical role in several biological pathways such as cell proliferation, migration, survival, and differentiation. Due to abnormal continuous activation in tumors, inhibition of STAT3 has emerged as an attractive approach for the treatment of various cancer cells. Herein, we report a series of novel STAT3 inhibitors based on benzo[b]thiophene 1,1-dioxide scaffold and evaluated their anticancer potency. Among them, compound 8b exhibited the best activity against cancer cells. Compound 8b induced apoptosis and blocked the cell cycle. Meanwhile, 8b reduced intracellular ROS content and caused the loss of mitochondrial membrane potential. Further research revealed that 8b significantly blocked STAT3 phosphorylation and STAT3-dependent dual-luciferase reporter gene experiments showed that compound 8b has a marked inhibition of STAT3-mediated Firefly luciferase activity. Molecular modeling studies revealed compound 8b occupied the pocket well with the SH2 domain in a favorable conformation.


Dimensional interaction in distance judgment.
Participants decided under speed stress whether or not the horizontal distances between pairs of frontal locations exceeded a criterion distance. The error rate reflected parallel effects of the horizontal and vertical distance between the locations. Whereas dimensional interaction in perceptual judgment has previously been attributed either to the perception of the stimulus or to the response decision concerning the stimulus, here dimensional interaction was attributed to the process of distance assessment regarding the test locations. Under the proposed account, the horizontal distance between the locations could not be assessed independently of the vertical distance. Only the overall distance between the locations could be assessed. However, because the horizontal and vertical positions of the locations could be independently assessed, the horizontal distance between the locations was available to the extent that the vertical positions of the locations were weighted so as to minimize vertical distance prior to the assessment of overall distance. In support of this account, parallel effects of horizontal and vertical distance were not observed when participants decided whether or not pairs of locations had the same horizontal position.


Fully automated side branch detection in intravascular optical coherence tomography pullback runs.
Side branches in the atherosclerotic lesion region are important as they highly influence the treatment strategy selection and optimization. Moreover, they are reliable landmarks for image registration. By providing high resolution delineation of coronary morphology, intravascular optical coherence tomography (IVOCT) has been increasingly used for side branch analysis. This paper presents a fully automated method to detect side branches in IVOCT images, which relies on precise segmentation of the imaging catheter, the protective sheath, the guide wire and the lumen. 25 in-vivo data sets were used for validation. The intraclass correlation coefficient between the algorithmic results and manual delineations for the imaging catheter, the protective sheath and the lumen contour positions was 0.997, 0.949 and 0.974, respectively. All the guide wires were detected correctly and the Dice's coefficient of the shadow regions behind the guide wire was 0.97. 94.0% of 82 side branches were detected with 5.0% false positives and the Dice's coefficient of the side branch size was 0.85. In conclusion, the presented method has been demonstrated to be accurate and robust for side branch analysis.


Gene polymorphisms implicated in influencing susceptibility to venous and arterial thromboembolism: frequency distribution in a healthy German population.
Evolvement and progression of cardiovascular diseases affecting the venous and arterial system are influenced by a multitude of environmental and hereditary factors. Many of these hereditary factors consist of defined gene polymorphisms, such as single nucleotide polymorphisms (SNPs) or insertion-deletion polymorphisms, which directly or indirectly affect the hemostatic system. The frequencies of individual hemostatic gene polymorphisms in different normal populations are well defined. However, descriptions of patterns of genetic variability of a larger extent of different factors of hereditary hypercoagulability in single populations are scarce. The aim of this study was i) to give a detailed description of the frequencies of factors of hereditary thrombophilia and their combinations in a German population (n = 282) and ii) to compare their distributions with those reported for other regions. Variants of coagulation factors [factor V 1691G>A (factor V Leiden), factor V 4070A>G (factor V HR2 haplotype), factor VII Arg353Gln, factor XIII Val34Leu, beta-fibrinogen -455G>A, prothrombin 20210G>A], coagulation inhibitors [tissue factor pathway inhibitor 536C>T, thrombomodulin 127G>A], fibrinolytic factors [angiotensin converting enzyme intron 16 insertion/deletion, factor VII-activating protease 1601G>A (FSAP Marburg I), plasminogen activator inhibitor 1-675 insertion/deletion (5G/4G), tissue plasminogen activator intron h deletion/insertion], and other factors implicated in influencing susceptibility to thromboembolic diseases [apolipoprotein E2/E3/E4, glycoprotein Ia 807C>T, methylenetetrahydrofolate reductase 677C>T] were included. The distribution of glycoprotein Ia 807C>T deviated significantly from the Hardy-Weinberg equilibrium, and a comparison with previously published data indicates marked region and ethnicity dependent differences in the genotype distributions of some other factors.


Unraveling polyketide synthesis in members of the genus Aspergillus.
Aspergillus species have the ability to produce a wide range of secondary metabolites including polyketides that are generated by multi-domain polyketide synthases (PKSs). Recent biochemical studies using dissected single or multiple domains from PKSs have provided deep insight into how these PKSs control the structural outcome. Moreover, the recent genome sequencing of several species has greatly facilitated the understanding of the biosynthetic pathways for these secondary metabolites. In this review, we will highlight the current knowledge regarding polyketide biosynthesis in Aspergillus based on the domain architecture of non-reducing, highly reducing, and partially reducing PKSs, and PKS-non-ribosomal peptide synthetases.


Broadcasting behavior change: a comparison of the effectiveness of paid and unpaid media to increase folic acid awareness, knowledge, and consumption among Hispanic women of childbearing age.
Awareness about folic acid's effectiveness in reducing the risk of certain birth defects has increased among women in the United States; however, few Hispanic women are consuming enough folic acid daily. A 1998 survey conducted by the Gallup Organization for the National March of Dimes Birth Defects Foundation found that English-speaking Hispanic women had lower folic acid awareness (53% vs. 72%) and lower daily consumption (29% vs. 33%) than non-Hispanic White women. In 1999, the Centers for Disease Control and Prevention (CDC) conducted baseline surveys with Spanish-speaking Hispanic women in selected U.S. markets to measure folic acid awareness, knowledge, and consumption. A Spanish-language public service announcement (PSA) volunteer campaign and a paid Spanish-language media and community education campaign were conducted in 2000 and 2002, respectively. Comparisons of postcampaign surveys indicate that the paid media campaign was significantly more effective than the PSA campaign in increasing folic acid awareness, knowledge, and consumption among Spanish-speaking Hispanic women.


Diffusion of Alexa Fluor 488-conjugated dendrimers in rat aortic tissue.
In this study, the distribution of labeled dendrimers in native and aneurysmal rat aortic tissue was examined. Adult male rats underwent infrarenal aorta perfusion with generation 5 (G5) acetylated Alexa Fluor 488-conjugated dendrimers for varying lengths of time. In a second set of experiments, rats underwent aortic elastase perfusion followed by aortic dendrimer perfusion 7 days later. Aortic diameters were measured prior to and postelastase perfusion, and again on the day of harvest. Aortas were harvested 0, 12, or 24 h postperfusion, fixed, and mounted. Native aortas were harvested and viewed as negative controls. Aortic cross-sections were viewed and imaged using confocal microscopy. Dendrimers were quantified (counts/high-powered field). Results were evaluated by repeated measures ANOVA and Student's t-test. We found that in native aortas, dendrimers penetrated the aortic wall in all groups. For all perfusion times, fewer dendrimers were present as time between dendrimer perfusion and aortic harvest increased. Longer perfusion times resulted in increased diffusion of dendrimers throughout the aortic wall. By 24 h, the majority of the dendrimers were through the wall. Dendrimers in aneurysmal aortas, on day 0 postdendrimer perfusion, diffused farther into the aortic wall than controls. In conclusion, this study documents labeled dendrimers delivered intra-arterially to native rat aortas in vivo, and the temporal diffusion of these molecules within the aortic wall. Increasing perfusion time and length of time prior to harvest resulted in continued dendrimer diffusion into the aortic wall. These preliminary data provide a novel mechanism whereby local inhibitory therapy may be delivered locally to aortic tissue.


Oral minoxidil treatment for hair loss: A review of efficacy and safety.
Although topical minoxidil is an effective treatment option for hair loss, many patients are poorly compliant because of the necessity to apply the medication twice a day, undesirable hair texture, and scalp irritation. In recent years, oral minoxidil at low dose has been proposed as a safe alternative. This study reviewed articles in which oral minoxidil was used to treat hair loss to determine its efficacy and safety as an alternative to topical minoxidil. PubMed searches were performed to identify articles discussing oral minoxidil as the primary form of treatment for hair loss published up to April 2020. A total of 17 studies with 634 patients were found discussing the use of oral minoxidil as the primary treatment modality for hair loss. Androgenetic alopecia was the most studied condition, but other conditions included telogen effluvium, lichen planopilaris, loose anagen hair syndrome, monilethrix, alopecia areata, and permanent chemotherapy-induced alopecia. Larger randomized studies comparing the efficacy/safety of different doses with standardized objective measurements will be needed to clarify the best treatment protocol. Oral minoxidil was found to be an effective and well-tolerated treatment alternative for healthy patients having difficulty with topical formulations.


Vaccine therapy for renal cell carcinoma.
Several potential vaccines have been evaluated for the treatment of patients with renal cell carcinoma (RCC). They include dendritic cells pulsed with tumor lysate, a dendritic cell-tumor cell hybrid, irradiated tumor cells admixed with adjuvants, and a heat shock protein-peptide complex. Promising results have been obtained in several early clinical trials, but issues of tumor immunosuppression and lack of identified tumor-associated antigens must be addressed before vaccine therapy can be applied successfully in advanced RCC. In this patient population, vaccine therapy will likely be required in combination with other forms of immunotherapy, such as interleukin-2 and thalidomide. In contrast, vaccine therapy alone may be sufficient for high-risk patients in the adjuvant setting.


Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial.
Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.


PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.
Purinosomes serve as metabolons to enhance de novo purine synthesis (DNPS) efficiency through compartmentalizing DNPS enzymes during stressed conditions. However, the mechanism underpinning purinosome assembly and its pathophysiological functions remains elusive. Here, we show that K6-polyubiquitination of the DNPS enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) by cullin-5/ankyrin repeat and SOCS box containing 11 (Cul5/ASB11)-based ubiquitin ligase plays a driving role in purinosome assembly. Upon several purinosome-inducing cues, ASB11 is upregulated by relieving the H3K9me3/HP1α-mediated transcriptional silencing, thus stimulating PAICS polyubiquitination. The polyubiquitinated PAICS recruits ubiquitin-associated protein 2 (UBAP2), a ubiquitin-binding protein with multiple stretches of intrinsically disordered regions, thereby inducing phase separation to trigger purinosome assembly for enhancing DNPS pathway flux. In human melanoma, ASB11 is highly expressed to facilitate a constitutive purinosome formation to which melanoma cells are addicted for supporting their proliferation, viability, and tumorigenesis in a xenograft model. Our study identifies a driving mechanism for purinosome assembly in response to cellular stresses and uncovers the impact of purinosome formation on human malignancies.


Appropriate Use Criteria in Musculoskeletal Imaging.
In the United States, health care costs are spiraling upward at an unsustainable rate. Concurrently, medical specialties, legislatures, and the population each recognize the need to prove that current medical practices are effective, measured by outcomes. These forces necessitate a change in radiology's role, from emphasizing interpretation and reporting to maintaining and demonstrating quality and value. An important part of this task involves establishing the appropriateness of imaging tests by application of objective data and expert opinion in an effort to optimize resource utilization and modality selection. We explore the justifications for establishing appropriateness use criteria, various paradigms that have been applied to their creation, inherent limitations of appropriateness rules based on imperfect data, and challenges associated with their widespread implementation and utilization. An appendix of key terms that may be unfamiliar to radiologists is included for future reference.


Application of neuropsychology and imaging to brain injury and use of the integrative cognitive rehabilitation psychotherapy model.
An early approach to cognitive rehabilitation therapy (CRT) was developed based on A. R. Luria's theory of brain function. Expanding upon this approach, the Integrative Cognitive Rehabilitation Psychotherapy model (ICRP) was advanced. To describe the ICRP approach to treatment of clients post brain injury and provide a comprehensive list of evaluation tools to determine the client's abilities and needs. Finally, to provide a link between CRT and functional imaging studies designed to improve rehabilitation efforts. History of cognitive rehabilitation and neuropsychological testing is reviewed and description of cognitive, academic, psychiatric, and substance abuse tools are provided. Cognitive and emotional treatment techniques are fully described. Additionally, a method of determining the client's stage of recovery and pertinent functional imaging studies is detailed. Authors have been able to provide a set of tools and techniques to use in comprehensive treatment of clients with brain injury. Inclusive treatment which is outlined in the ICRP model is optimal for the client's recovery and return to a full and satisfying life post brain injury. The model provides a framework for neuropsychologists to integrate issues that tend to co-occur in clients living with brain injury into a unified treatment plan.


Depressive symptoms and untreated dental caries in older independently living South Brazilians.
The importance of psychological reactions in modifying oral health behaviors and salivary immunity has been shown previously, but few studies assessed whether psychological reactions are associated with caries in populations. Thus, the aim of this study was to examine the association of depressive symptoms with untreated caries using a hierarchal approach. In this cross-sectional study, a random sample of 390 South Brazilians aged 60 years or more was evaluated using a structured questionnaire assessing sociodemographic, behavior, health and depressive symptoms (Geriatric Depression Scale) data. Oral examinations were carried out in order to assess: (1) dental status, using the DMFT index; (2) dental plaque, using the Visible Plaque Index, and (3) unstimulated saliva flow, using the spit method. A hierarchical model based on the framework of caries was carried out to assess whether depressive symptoms were associated with prevalent untreated dental caries (or D >0). Depressive symptoms, number of teeth and plaque accumulation were significant predictors of caries with respect to the D >0 outcome. Our findings suggest that depressive symptoms may act as determinants of caries, adding to the body of knowledge supporting the importance of psychological reactions in oral health/disease processes.


Arachidonic acid pathway alterations in cerebrospinal fluid of dogs with naturally occurring spinal cord injury.
Canine intervertebral disc πherniation causes a naturally-occurring spinal cord injury (SCI) that bears critical similarities to human SCI with respect to both injury pathomechanisms and treatment. As such, it has tremendous potential to enhance our understanding of injury biology and the preclinical evaluation of novel therapies. Currently, there is limited understanding of the role of arachidonic acid metabolites in canine SCI. The CSF concentrations of PLA2 and PGE2 were higher in SCI dogs compared to control dogs (p = 0.0370 and 0.0273, respectively), but CSF LCT4 concentration in SCI dogs was significantly lower than that in control dogs (p < 0.0001). Prostaglandin E2 concentration in the CSF was significantly and positively associated with increased severity of SCI at the time of sampling (p = 0.041) and recovery 42 days post-injury (p = 0.006), as measured by ordinal behavioral scores. Arachidonic acid metabolism is altered in dogs with SCI, and these data suggest that these AA metabolites reflect injury severity and recovery, paralleling data from other model systems.


Mechanisms Involved in Hypersensitivity Reactions to Polysulfone Hemodialysis Membranes.
Several cases of patients with anaphylactic or systemic hypersensitivity reactions to polysulfone (PS) hemodialysis (HD) membranes and tolerance to cellulose triacetate (CTA) membranes have recently been reported. To investigate the mechanisms involved in PS hypersensitivity, basophil, T cell, and complement activation were analyzed in acute-phase samples from two patients with systemic reactions to PS-based membranes. Basophil and T cell activation, as well as higher serum tryptase levels were detected in acute-phase samples compared with basal levels. Complement levels (C3 and C4) were decreased in acute-phase samples from PS-allergic patients to a higher extent than in samples from control donors taken at the same time points, indicating complement activation during the acute reactions. An experimental external circuit was established on pediatric membranes after rinsing with low or high priming volumes of saline solution, to analyze basophils, T cells, and complement activation in blood samples from 10 PS-allergic and 8 nonallergic HD patients upon contact with PS-based or CTA membranes. Predialysis and postdialysis samples were collected. Basophils from PS-allergic patients exhibited increased degranulation, and T cells showed significantly increased activation after contact with PS-based membranes primed with low volumes of saline. No activation was detected in leukocytes from nonallergic patients under the same experimental conditions. Membrane priming with high volumes of saline abrogated activation of basophils and T cells. However, basophils from allergic donors showed significantly higher responses to Fcεc stimulation after contact with PS membranes. Basophil degranulation and elevated serum tryptase levels in allergic patients during acute reactions support the systemic activation of mast cells and basophils during hypersensitivity reactions to PS-based membranes. A leachable component of the membranes might be responsible for cell activation in some patients.


Mesenchymal neoplasms of the tubular gut and adjacent structures: experience with EUS-guided fine-needle aspiration cytopathology.
Unlike epithelial malignancies, mesenchymal neoplasms arising within the tubular gut are less often encountered in endoscopic ultrasound-guided (EUS) fine-needle aspiration biopsies (FNABs). Nonetheless, preoperative diagnosis of such neoplasms has important therapeutic and prognostic value. We report our experience with this category of neoplasms from the past decade. We performed a 10-year retrospective search at our respective institutions to identify EUS-guided FNAB cases of mesenchymal neoplasms arising from the tubular gut wall and closely adjacent structures. Cytopathologic diagnoses were compared to corresponding surgical pathology (SP) when available. Cases with either no confirmatory cell block (CB) immunohistochemical (IHC) staining, or no SP were excluded. Two-hundred eighty-two cases (M:F = 1:1; age range: 25-94 years, mean age = 60 years) of EUS-guided FNAB from the tubular gut met our criteria. Onsite adequacy was performed on nearly all cases. Case numbers: 209 gastrointestinal stromal tumors (GIST), 58 smooth muscle neoplasms, and 15 miscellaneous neoplasms. Of these, 188 (67%) had SP follow-up. We found that 258 (91%) aspirates had a correct specific diagnosis, 3 (1%) were nondiagnostic, 18 (6%) had indeterminate diagnoses, and 3 (1%) had incorrect diagnoses (2 leiomyosarcomas mistaken as leiomyoma, and 1 fibrosclerotic lesion mistaken as inflammatory pseudotumor). Of 94 cases with no SP, all had a specific cytologic diagnosis based on confirmatory IHC staining from the CB including 61 GISTs, 29 smooth muscle neoplasms, and 4 miscellaneous tumors. This study endorses the clinical utility of EUS-guided FNAB in the diagnosis of tubular gut mesenchymal neoplasms. A definitive and accurate diagnosis is possible in over 90% of cases, chiefly when cytomorphology is coupled with optimal cellularity and IHC from a concurrent CB. EUS-guided FNAB diagnosis of mesenchymal tubular gut neoplasms may play an important role in determining neoadjuvant therapy as targeted therapy evolves.


COVID-19 in congenital heart disease (COaCHeD) study.
COVID-19 has caused significant worldwide morbidity and mortality. Congenital heart disease (CHD) is likely to increase vulnerability and understanding the predictors of adverse outcomes is key to optimising care. Ascertain the impact of COVID-19 on people with CHD and define risk factors for adverse outcomes. Multicentre UK study undertaken 1 March 2020-30 June 2021 during the COVID-19 pandemic. Data were collected on CHD diagnoses, clinical presentation and outcomes. Multivariable logistic regression with multiple imputation was performed to explore predictors of death and hospitalisation. There were 405 reported cases (127 paediatric/278 adult). In children (age <16 years), there were 5 (3.9%) deaths. Adjusted ORs (AORs) for hospitalisation in children were significantly lower with each ascending year of age (OR 0.85, 95% CI 0.75 to 0.96 (p<0.01)). In adults, there were 24 (8.6%) deaths (19 with comorbidities) and 74 (26.6%) hospital admissions. AORs for death in adults were significantly increased with each year of age (OR 1.05, 95% CI 1.01 to 1.10 (p<0.01)) and with pulmonary arterial hypertension (PAH; OR 5.99, 95% CI 1.34 to 26.91 (p=0.02)). AORs for hospitalisation in adults were significantly higher with each additional year of age (OR 1.03, 95% CI 1.00 to 1.05 (p=0.04)), additional comorbidities (OR 3.23, 95% CI 1.31 to 7.97 (p=0.01)) and genetic disease (OR 2.87, 95% CI 1.04 to 7.94 (p=0.04)). Children were at low risk of death and hospitalisation secondary to COVID-19 even with severe CHD, but hospital admission rates were higher in younger children, independent of comorbidity. In adults, higher likelihood of death was associated with increasing age and PAH, and of hospitalisation with age, comorbidities and genetic disease. An individualised approach, based on age and comorbidities, should be taken to COVID-19 management in patients with CHD.


Gross efficiency and cycling economy are higher in the field as compared with on an Axiom stationary ergometer.
This study was designed to examine the biomechanical and physiological responses between cycling on the Axiom stationary ergometer (Axiom, Elite, Fontaniva, Italy) vs. field conditions for both uphill and level ground cycling. Nine cyclists performed cycling bouts in the laboratory on an Axiom stationary ergometer and on their personal road bikes in actual road cycling conditions in the field with three pedaling cadences during uphill and level cycling. Gross efficiency and cycling economy were lower (-10%) for the Axiom stationary ergometer compared with the field. The preferred pedaling cadence was higher for the Axiom stationary ergometer conditions compared with the field conditions only for uphill cycling. Our data suggests that simulated cycling using the Axiom stationary ergometer differs from actual cycling in the field. These results should be taken into account notably for improving the precision of the model of cycling performance, and when it is necessary to compare two cycling test conditions (field/laboratory, using different ergometers).


Cerebral generators involved in the pathogenesis of the restless legs syndrome.
The pathophysiology of periodic limb movements and sensory leg discomfort in the restless legs syndrome is unknown. With high-resolution functional magnetic resonance imaging, we localized for the first time cerebral generators associated with sensory leg discomfort and periodic limb movements in 19 patients with restless legs syndrome. During sensory leg discomfort there was mainly bilateral activation of the cerebellum and contralateral activation of the thalamus. During the combined periodic limb movement and sensory leg discomfort conditions, patients also showed activity in the cerebellum and thalamus. In contrast to the sensory leg discomfort condition alone, the combined condition was associated with additional activation in the red nuclei and brainstem close to the reticular formation. Voluntary imitation of periodic limb movements by patients and control subjects was not associated with brainstem activity, but with additional activation in the globus pallidus and motor cortex. These findings indicate that cerebellar and thalamic activation may occur because of sensory leg discomfort and that the red nucleus and brainstem are involved in the generation of periodic limb movements in patients with restless legs syndrome.


The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants' life: a systematic review.
The human gut is the habitat for diverse and dynamic microbial ecosystem. The human microbiota plays a critical role in functions that sustain health and is a positive asset in host defenses. Establishment of the human intestinal microbiota during infancy may be influenced by multiple factors including delivery mode. Present review compiles existing evidences on the effect of delivery mode on the diversity and colonization pattern of infants gut microbiota. Two investigators searched for relevant scientific publications from four databases (Pubmed, Medline, Embase, and Web of Science). The last search was performed on September 21, 2015, using key terms ((delivery mode OR caesarean delivery OR cesarean section OR vaginal delivery) AND (gut microbiota OR gut microbiome OR gut microflora OR intestinal microflora OR microbial diversity) AND (infants OR children)). All included studies described at least two types of gut microbiota in relation to delivery mode (caesarean section vs vaginal delivery) and used fecal samples to detect gut microbiota. Seven out of 652 retrieved studies met inclusion criteria, were included in systematic analysis. Caesarean Section (CS) was associated with both lower abundance and diversity of the phyala Actinobacteria and Bacteroidetes, and higher abundance and diversity of the phylum Firmicute from birth to 3 months of life. At the colonization level, Bifidobacterium, and Bacteroides genera seems to be significantly more frequent in vaginally delivered infants compared with CS delivered. These infants were more colonized by the Clostridium, and Lactobacillus genera. From the reports, it is tempting to say that delivery mode has less effect on colonization and diversity of Bifidobacteria, Bacteroides, Clostridium, and Lactobacillus genera from the age of 6 to 12 months of life. The diversity and colonization pattern of the gut microbiota were significantly associated to the mode of delivery during the first three months of life, however the observed significant differences disappears after 6 months of infants life. The healthy gut microbiota is considered to promote development and maturation of the immune system while abnormal gut is considered as the major cause of severe gastrointestinal infections during the infancy. Further studies should investigate the diversity and colonization levels of infant gut microbiota in relation to the mode of delivery and its broad impact on infants' health at each stage of life.


Occupational asthma caused by two herb materials, Dioscorea batatas and Pinellia ternata.
There have been very few cases of occupational allergies caused by herb materials. In this paper, we report a case of occupational asthma and rhinitis caused by two herb materials, Dioscorea batatas and Pinellia ternata, which are known as Sanyak and Banha respectively. The patient had strong positive responses to grass pollens and cat fur, as well as to Sanyak and Banha extracts on skin-prick tests. Bronchoprovocation tests showed a dual asthmatic response to Sanyak whereas only an early asthmatic response to Banha. Serum specific IgE and IgG4 antibodies to Sanyak were detected by enzyme-linked immunosorbent assay (ELISA) but there was no specific IgE antibody binding to Banha. In order to further characterize the allergenic component of these extracts, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and electroblotting studies were also performed. Three IgE binding components (29,000, 57,000, 63,000 Da) were detected within the Sanyak extracts, but no IgE-binding component was noted within the Banha extracts. It is suggested that Sanyak can induce IgE-mediated bronchoconstriction in an exposed worker. Further studies are needed to investigate the pathogenetic mechanism triggered by Banha.


Relationship between diabetic retinopathy, diabetic macular oedema and erectile dysfunction in type 2 diabetics.
To investigate the relationship of diabetic retinopathy and diabetic macular oedema with erectile dysfunction in patients with type 2 diabetes. Hospital-based, cross-sectional study. Three hundred twenty-four men with diabetes from the Diabetic Management Project were recruited. Participants underwent a comprehensive interview, a complete eye examination, fasting blood tests, and had retinal and macula assessments using fundus images and optical coherence tomography, respectively. Diabetic retinopathy was categorized as none, mild, moderate, severe non-proliferative and proliferative, and diabetic macular oedema as none, mild, moderate and severe. Erectile dysfunction was defined as problems achieving or maintaining an erection and was assessed using a self-reported questionnaire. Erectile dysfunction. The mean ± standard deviation age of 324 men with type 2 diabetes was 65.2 ± 11.1 years. Compared with patients without diabetic retinopathy, those with any retinopathy (odds ratio 2.06, 95% confidence interval 1.22-3.48, P = 0.007) had a twofold increased odds of having erectile dysfunction. Patients with severe non-proliferative diabetic retinopathy (odds ratio 4.39, 95% confidence interval 1.48-13.0, P = 0.008) and proliferative diabetic retinopathy (odds ratio 2.74, 95% confidence interval 1.44-5.19, P = 0.002) had fourfold and threefold increased odds of having erectile dysfunction, respectively, compared with those without diabetic retinopathy. Diabetic macular oedema, irrespective of presence or severity, was not independently associated with erectile dysfunction. The presence and severity of diabetic retinopathy but not diabetic macular oedema are independently associated with self-reported erectile dysfunction.


Exploitation and recovery of a sea urchin predator has implications for the resilience of southern California kelp forests.
Size-structured predator-prey interactions can be altered by the history of exploitation, if that exploitation is itself size-selective. For example, selective harvesting of larger sized predators can release prey populations in cases where only large individuals are capable of consuming a particular prey species. In this study, we examined how the history of exploitation and recovery (inside marine reserves and due to fisheries management) of California sheephead (Semicossyphus pulcher) has affected size-structured interactions with sea urchin prey in southern California. We show that fishing changes size structure by reducing sizes and alters life histories of sheephead, while management measures that lessen or remove fishing impacts (e.g. marine reserves, effort restrictions) reverse these effects and result in increases in density, size and biomass. We show that predation on sea urchins is size-dependent, such that the diet of larger sheephead is composed of more and larger sized urchins than the diet of smaller fish. These results have implications for kelp forest resilience, because urchins can overgraze kelp in the absence of top-down control. From surveys in a network of marine reserves, we report negative relationships between the abundance of sheephead and urchins and the abundance of urchins and fleshy macroalgae (including giant kelp), indicating the potential for cascading indirect positive effects of top predators on the abundance of primary producers. Management measures such as increased minimum size limits and marine reserves may serve to restore historical trophic roles of key predators and thereby enhance the resilience of marine ecosystems.


Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.


Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids.
Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists improve insulin sensitivity and lipemia partly through enhancing adipose tissue proliferation and capacity for lipid retention. The agonists also reduce local adipose glucocorticoid production, which may in turn contribute to their metabolic actions. This study assessed the effects of a PPARgamma agonist in the absence of glucocorticoids (adrenalectomy, ADX). Intact, ADX, and intact pair-fed (PF) rats were treated with the PPARgamma agonist rosiglitazone (RSG) for 2 wk. RSG increased inguinal (subcutaneous) white (50%) and brown adipose tissue (6-fold) weight but not that of retroperitoneal (visceral) white adipose tissue. ADX but not PF reduced fat accretion in both inguinal and retroperitoneal adipose depots but did not affect brown adipose mass. RSG no longer increased inguinal weight in ADX and PF rats but increased brown adipose mass, albeit less so than in intact rats. RSG increased cell proliferation in white (3-fold) and brown adipose tissue (6-fold), as assessed microscopically and by total DNA, an effect that was attenuated but not abrogated by ADX. RSG reduced the expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in all adipose depots. RSG improved insulin sensitivity (reduction in fasting insulin and homeostasis model assessment of insulin resistance, both -50%) and triacylglycerolemia (-75%) regardless of the glucocorticoid status, these effects being fully additive to those of ADX and PF. In conclusion, RSG partially retained its ability to induce white and brown adipose cell proliferation and brown adipose fat accretion and further improved insulin sensitivity and lipemia in ADX rats, such effects being therefore independent from the PPARgamma-mediated modulation of glucocorticoids.


[Typology of illness in aging--consequences for prevention concepts].
Conventional dichotomy or three-part classifications for disease and age are not very helpful for practical application. The article presents a typology of disease, which we developed further into four categories. It considers the relation between physiological processes of aging and pathological developments as well as the courses of disease in old age. Adequate prevention strategies can be derived. Category I (physiological changes in old age which are only possibly a disease) demonstrates the importance of the context in illness. Physiological processes of aging with a high plasticity can be influenced by prevention strategies. Category II (age-related disease with a long latency period) demonstrates the problem of early recognition and secondary prevention. The category III (disease with different physiological process in old age because of reduced homeostatic regulation and repair mechanism) is not receptive to preventative concepts, but only to tertiary prevention and rehabilitation. In the category IV (disease as a result of long term exposure, increasing with lifetime) population-based prevention strategies are sensible.


Synchronous mucosa-associated lymphoid tissue lymphoma and adenocarcinoma of the stomach.
The development of simultaneous primary gastric lymphoma and carcinoma is a rare event for which a possible etiopathogenetic role for Helicobacter pylori (HP) recently has been postulated. We report a series of eight such cases diagnosed from 1980 to 1995. In two cases, both tumors arose in a gastric stump, at 26 and 34 years, respectively, after gastric resection for a duodenal ulcer. Grossly, the lymphoma and carcinoma formed a single lesion in four cases (collision tumor); they were separated in the other four cases. Histologically, all the lymphomas fit into the category of B-cell mucosa-associated lymphoid tissue lymphoma; six of them were low-grade lymphomas and two were low-grade lymphomas with a high-grade component. The adenocarcinomas were intestinal-type in four cases, diffuse in three, and mixed in one. Regarding the depth of infiltration, four carcinomas were early gastric cancers and four were advanced. All the collision tumors contained an early gastric cancer. Our observations confirmed the association of HP with gastric lymphoma and carcinoma in 4 cases. Spiral bacteria with the features of Helicobacter heilmannii were found in one case. The occurrence of two different tumors in a gastric stump, which has not been reported previously, suggests that postgastrectomy gastritis might contribute to the development of both gastric lymphoma and carcinoma.


[Role transition from clinical nurse to case manager for Medical-aid beneficiaries: taking root in a barren land].
The purpose of this study was to explain the role transition process to nurse case managers (NCMs) for Medical-aid beneficiaries in Korea. Fourteen NCMs were interviewed regarding their experiences of becoming proficient in the new role of case manger. Data were analyzed through the application of grounded theory. 'Taking root in a barren land' was the core category explaining the role transition process of NCMs. They engaged in four stages: launching, trial and error, proficiency, and wait-and-see stages. NCMs showed not only fear but also passion for case management practice. Despite their passion and effort, NCMs went through a period of trial and error. After becoming skilled, NCMs went through a stage of wait-and-see often because of job insecurity related to temporary position or few opportunities for promotion. Factors influencing NCMs' role transition process included their understanding of client characteristics, belief in case management, and support from their colleagues and families. NCMs experience many challenges in the process of becoming proficient NCMs. To help with their role transition, there is a need for education programs, preceptorship programs, research on their roles and functions, and regulation for securing NCMs' employment and career stability.


Denial: The Greatest Barrier to the Opioid Epidemic.
"Why can't you be like my old doctor?" This essay explores my experiences as a new family physician in a rural town endemic with liberal opioid prescribing practices and opioid addiction. I detail my inner turmoil while overcoming resistance to change, the influence of these experiences on my professional growth, and my decision to offer medication-assisted treatment.


Use of the laryngeal mask for management of the compromised airway--a case report.
A 54-year old woman was scheduled for thoracotomy for excision of a tumor of the left upper lobe. Reduced thyromental distance and thyroid enlargement were identified by the preoperative physical examination and inability to visualize the larynx was encountered during direct laryngoscopy. A 37-Fr left sided double lumen tube was inserted in trachea with great difficulty after three failed attempts. One lung anesthesia underwent uneventfully and postoperatively it was decided to exchange the double lumen tube to a single lumen tracheal tube. After the extubation, five failed attempts of reintubation were performed. A laryngeal mask airway (LMA) size 3 was passed easily achieving an airtight airway. The patient underwent an uneventful prolonged (105 min) weaning via the LMA which was left in place until the patient regained full consciousness. Peripheral oxygen saturation remained greater than 95% throughout the airway manipulation. LMA insertion is an easy non-invasive technique and should be considered whenever airway management proves difficult.


Haemoglobin and serum iron responses to periodic intravenous iron-dextran infusions during maintenance haemodialysis.
Patients with chronic renal failure who were on maintenance haemodialysis, were given monthly 600 mg iron intravenously as iron-dextran complex to a body replacement total of 5-6 g iron. Those patients who had been on maintenance haemodialysis for a long period and had received numerous blood transfusions failed to show a rise in haemoglobin levels. Those patients who received iron from the commencement of maintenance dialysis, and who had not received blood transfusions, showed a significant increase in haemoglobin concentrations which has been maintained for more than 18 months after iron therapy ceased, despite a concurrent decrease in serum iron concentrations. Pre-treatment and post-treatment levels of serum iron are not of predictive value for the success of iron treatment, neither for the haemoglobin nor the serum iron response. A body replacement dose of iron given intravenously over a year benefits the majority of patients on maintenance haemodialysis and is recommended for the treatment of their anaemia.


Relationship estimation by Markov-process models in a sib-pair linkage study.
The results of sib-pair linkage studies may be compromised if a substantial number of putative sib pairs are not actually sib pairs. For classification of pairs in a sib-pair genome scan, I propose multipoint methods that are based on a Markov-process model of allele sharing along the chromosome. These methods can be implemented by standard algorithms that compute multipoint marker allele-sharing probabilities for sib pairs. When marker data from at least half the genome are used, misclassification rates are small. The methods will be implemented in an upcoming version of the computer software package S.A.G.E.


Value theory and the best interests standard.
The idea of a patient's best interests raises issues in prudential value theory -- the study of what makes up an individual's ultimate (nonmoral) good or well-being. While this connection may strike a philosopher as obvious, the literature on the best interests standard reveals almost no engagement of recent work in value theory. There seems to be a growing sentiment among bioethicists that their work is independent of philosophical theorizing. Is this sentiment wrong in the present case? Does value theory make a significant difference in interpreting best interests? In pursuing this question, I begin with a quick sketch of broad kinds of value theories, identifying representatives that are plausible enough to count as contenders. I then explore what each account suggests in (1) neonatal treatment decisions, and (2) decisions for patients in persistent vegetative states. I conclude that while these accounts converge somewhat in their interpretations of best interests, they also have importantly different implications.


Proliferation of Pneumocystis trophozoites in human lymph nodes and in nude mice lungs.
Pneumocystis infection in athymic nude mice lungs showed a particularly high trophozoite to cyst ratio. A similar observation was obtained from a study of a patient with lymph node infection with Pneumocystis. Eosinophilic foamy masses in these sites were observed by light microscopy. With the electron microscope, the masses were seen to be composed of large aggregates of trophozoites. Cystic forms (precyst, cyst and empty cyst) were extremely scarce in comparison with the huge numbers of trophozoites. These cystic forms were mostly undergoing degeneration. These observations indicate that the mode of proliferation in both situations was predominantly asexual, that is, proliferation by trophozoites, suggesting that certain conditions may enhance asexual reproduction or depress the formation of cysts.


Degeneration of the Eyes of Tyrosine-Deficient Chick Embryos.
Subjecting 4-day-old chick embryos to a yolk-sac perfusion medium lacking tyrosine resulted in arrest of retinal pigmentation and in degeneration of the neural retina. Phenylaldnine was ineffective in replacing tyrosine. Possibly retinal tyrosinase played a part in initiating the degenerative changes.


Kinetics of 13 new cholinesterase inhibitors.
Kinetics of hydrolysis of acetylcholine and acetylthiocholine by two types of acetylcholinesterase and butyrylcholinesterase inhibited by 13 new inhibitors (5 carbamates and 8 carbazates--hydrazinium derivatives) was measured in vitro in a batch reactor at 25 degrees C, pH 8, ionic strength 0.11 M and enzyme activity 3.5 U by four nondependent analytical methods. Sevin, rivastigmin (Exelon) and galantamin (Reminyl) served as comparative inhibiting standards. Kinetics of hydrolyses inhibited by all studied carbamates, sevin, carbazates (with exceptions) and rivastigmin (with exceptions) can be simulated by the competitive inhibition model with irreversible reaction between enzyme and inhibitor. Galantamin does not fulfil this model. In positive simulations, the value of inhibition (carbamoylation) rate constant k3 was calculated, describing the reaction velocity between the given enzyme and inhibitor. Physiologically important hydrolyses of acetylcholine catalyzed by acetylcholinesterase from electric eel or bovine erythrocytes and butyrylcholinesterase from horse plasma can be most quickly inhibited by carbamoylation of the mentioned enzymes by the 3-N,N-diethylaminophenyl-N'-(1-alkyl) carbamates 4 and 5. Probably this is due to a long enough hydrocarbon aliphatic substituent (hexyl and octyl) on the amidic nitrogen atom. The tested carbazates failed as inhibitors of cholinesterases. The regeneration ability of the inhibited enzymes was not measured.


Pseudophysaloptera enigmatica sp. nov. (Nematoda: Physalopteridae) from Dactylopsila trivirgata Gray, 1858 (Marsupialia: Petauridae) in Australia, with a review of the genus.
The nematode Pseudophysaloptera enigmatica sp. nov. is described from the stomach of Dactylopsila trivirgata Gray, 1858, in Queensland, Australia. The new species is distinguished from congeners by its size and features present on the tail of the male. P. enigmatica sp. nov. is considerably larger than virtually all congeners, and can be differentiated by the presence of spicules and the shape and distribution of caudal papillae in the male tail. This is the first record of the genus in Australia and in marsupials. A review of the genus is provided.


Controlled Polymerization of Acrylamide via One-Pot and One-Step Aqueous Cu(0)-Mediated Reversible-Deactivation Radical Polymerization.
Copper-catalyzed controlled polymerization of acrylamide (AM) has always been a challenge, which typically exhibits low monomer conversion and broad molecular weight distribution (MWD) or requires complex/multistep reaction procedures, due to the highly active nature of the AM radical and its side reactions. To overcome the above challenges, herein, we report the successful synthesis of well-defined polyacrylamide (PAM) via a facile one-pot and one-step aqueous Cu(0)-mediated reversible-deactivation radical polymerization (RDRP). The results of this strategy show that strong deactivation control is the key for the controllability of AM RDRPs, which depends on the equilibria of polymerization and mutual conversion of different copper species. With the fast-propagating monomer AM, extra addition of CuII into the reaction system is an effective way to enhance deactivation. Based on this kinetically controlled strategy, well-defined PAMs with narrow molecular weight distributions (MWDs) and varied molecular weights (Mws) were successfully achieved.


Transesophageal echocardiography. A technique for intraoperative monitoring.
Cardiac ischemia and myocardial infarction continue to be major causes of perioperative morbidity and mortality, despite aggressive intraoperative monitoring. Intraoperative TEE is evolving as a helpful noninvasive monitor in patients with coronary artery disease and valvular heart disease. Early detection of ischemia and evaluation of valve function with continuous imaging has allowed the use of TEE as a dynamic tool to optimize therapeutic management of cardiac dysfunction that was not always readily available by conventional invasive techniques. As new equipment and techniques are developed, this monitoring method will undoubtedly find even more frequent intraoperative use.


CENP-C binds the alpha-satellite DNA in vivo at specific centromere domains.
CENP-C is a fundamental component of the centromere, highly conserved among species and necessary for the proper assembly of the kinetochore structure and for the metaphase-anaphase transition. Although CENP-C can bind DNA in vitro, the identification of the DNA sequences associated with it in vivo and the significance of such an interaction have been, until now, elusive. To address this problem we took advantage of a chromatin-immunoprecipitation procedure and applied this technique to human HeLa cells. Through this approach we could establish that: (1) CENP-C binds the alpha-satellite DNA selectively; (2) the CENP-C region between amino acids 410 and 537, previously supposed to contain a DNA-binding domain, is indeed required to perform such a function in vivo; and (3) the profile of the alpha-satellite DNA associated with CENP-C is essentially identical to that recognized by CENP-B. However, further biochemical and ultrastructural characterization of CENP-B/DNA and CENP-C/DNA complexes, relative to their DNA components and specific spatial distribution in interphase nuclei, surprisingly reveals that CENP-C and CENP-B associate with the same types of alpha-satellite arrays but in distinct non-overlapping centromere domains. Our results, besides extending previous observations on the role of CENP-C in the formation of active centromeres, show, for the first time, that CENP-C can associate with the centromeric DNA sequences in vivo and, together with CENP-B, defines a highly structured organization of the alpha-satellite DNA within the human centromere.


Purification of human sperm by a discontinuous Percoll density gradient with an innercolumn.
Human sperm were highly purified through the use of a discontinuous Percoll density gradient placed in an inner column of a centrifuge tube. Six ml of 80% Percoll solution were poured into a centrifuge tube with an inner column containing successive 1.0-ml layers of 70, 60, and 40% Percoll solutions. Diluted semen was placed on top of the gradient, and the tube was centrifuged at 600 X g for 30 min using a swing-out rotor. After centrifugation, the majority of the progressive motile sperm were isolated in the sediment; they had a mean motility of 93 +/- 4.1% (n = 10). Other cellular components, including bacteria, remaining in the inner column. The level of bacterial contamination in the purified sperm fraction was below detection for most of the species quantified. The purified sperm were found to be more than 92 +/- 3.2% viable, as judged by dye exclusion, and abnormal sperm were reduced to 5.2 +/- 1.4%. Because of the use of the inner column, the contamination by seminal plasma was negligible in the purified sperm, as estimated by residual protein, fructose, and acid phosphatase activity.


Short communication: Survival of Vaccinia virus in inoculated cheeses during 60-day ripening.
Bovine vaccinia is a neglected zoonosis caused by Vaccinia virus (VACV) and has a major economic and public health effect in Brazil. Previous studies showed infectious VACV particles in milk from either experimentally or naturally infected cows and in fresh cheeses prepared with experimentally contaminated milk. Ripening is a process that leads to major changes in the physical and chemical characteristics of cheese, reducing contamination by spoilage, pathogenic microorganisms, or both. However, it is not known if VACV infectious particles persist after the ripening process. To investigate this issue, viral infectivity at different ripening times was studied in cheeses manufactured with milk experimentally contaminated with VACV strain Guarani P2 (GP2). Cheeses were analyzed at 1, 7, 14, 21, 45, and 60 d of ripening at 25°C. Viral DNA was quantified by real-time PCR, and VACV isolation and titration were performed in Vero cells. The whole experiment was repeated 4 times. Analysis of the mean viral DNA quantification and infectivity indicated a reduction of approximately 2 logs along the ripening process; however, infectious viral particles (1.7 × 102 pfu/mL) could still be recovered at d 60 of ripening. These findings indicate that the ripening process reduces VACV infectivity, but it was not able to inactivate completely the viral particles after 60 d.


Nonsyndromic double mesiodentes--hidden lambs among normal flock!
Mesiodens, a common supernumerary tooth, is found in the midline in anterior maxilla between the incisors. Its occurrence as multiples is termed as 'mesiodentes'. Double mesiodentes, a rare phenomenon, is seldom reported in literature and show a plethora of manifestations as described in the case report. They may not be apparent clinically, necessitating the use of imaging modalities and require careful evaluation to prevent complications. This paper presents a report of six double mesiodentes cases with negative family history for supernumerary teeth and absence of any syndromes. This is an effort to educate dentists about signs, symptoms, complications and management of mesiodentes.


Lymphatic Stomata in the Adult Human Pulmonary Ligament.
Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 μm in the left pulmonary ligaments and from 2.50 to 12.50 μm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm(2) in the left pulmonary ligaments and from 2 to 18 per mm(2) in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura.


Multi-loop nonlinear control design for performance improvement of LTI systems.
This paper puts forward a multi-loop nonlinear control (MLNC) strategy to overcome the limited performance of LTI controllers due to the so-called "waterbed" effect. According to "Bode's sensitivity integral", increasing the bandwidth or additional integral gain of LTI controller to improve the low-frequency disturbance attenuation irrefutably increases the sensitivity to high-frequency disturbances or measurement noise. Hence, it is impossible to attain the best of both worlds in the case of linear controllers. Therefore, with an aim to improve the transient and steady state performance of linear controllers, in this paper, a nonlinear control framework using circle criterion method and saturation nonlinearity, which adjusts the integral gain based on the error threshold, is discussed. The global asymptotic stability (GAS) of the MLNC strategy is theoretically proved using LaSalle's invariance principle and experimentally validated using measured frequency response function (FRF). Moreover, the performance of the MLNC strategy is compared with that of the multi-loop linear control (MLLC) strategy on a benchmark magnetic levitation system for tracking application. The cumulative power spectral density (CPSD) of tracking error, which is used as the performance index to assess the overall closed loop performance, accentuates that MLNC can yield better steady state and transient performance compared to MLLC scheme.


Association of postoperative furosemide use with a reduced blood transfusion rate in sagittal craniosynostosis surgery.
OBJECT A major challenge in sagittal craniosynostosis surgery is the high transfusion rate (50%-100%) related to blood loss in small pediatric patients. Several approaches have been proposed to prevent packed red blood cell (PRBC) transfusion, including endoscopic surgery, erythropoietin ortranexamic acid administration, and preoperative hemodilution. The authors hypothesized that a significant proportion of postoperative anemia observed in pediatric patients is actually dilutional. Consequently, since 2005, at CHU Sainte-Justine, furosemide has been administered to correct the volemic status and prevent PRBC transfusion. The purpose of this study was to evaluate the impact of postoperative furosemide administration on PRBC transfusion rates. METHODS This was a retrospective study of 96 consecutive patients with sagittal synostosis who underwent surgery at CHU Sainte-Justine between January 2000 and May 2012. The mean age at surgery was 4.9 ± 1.5 months (range 2.8-8.7 months). Patients who had surgery before 2005 constituted the control group. Those who had surgery in 2005 or 2006 were considered part of an implementation phase because furosemide administration was not routine. Patients who had surgery after 2006 were part of the experimental (or furosemide) group. Transfusion rates among the 3 groups were compared. The impact of furosemide administration on transfusion requirement was also measured while accounting for other variables of interest in a multiple logistic regression model. RESULTS The total transfusion rate was significantly reduced in the furosemide group compared with the control group (31.3% vs 62.5%, respectively; p = 0.009), mirroring the decrease in the postoperative transfusion rate between the groups (18.3% vs 50.0%, respectively; p = 0.003). The postoperative transfusion threshold remained similar throughout the study (mean hemoglobin 56.0 g/dl vs 60.9 g/dl for control and furosemide groups, respectively; p = 0.085). The proportion of nontransfused patients with recorded hemoglobin below 70 g/dl did not differ between the control and furosemide groups (41.7% vs 28.6%, respectively; p = 0.489). Surgical procedure, preoperative hemoglobin level, estimated blood loss, and furosemide administration significantly affected the risk of receiving a postoperative PRBC transfusion. When these variables were analyzed in a multiple logistic regression model, furosemide administration remained strongly associated with a reduced risk of being exposed to a blood transfusion (OR 0.196, p = 0.005). There were no complications related to furosemide administration. CONCLUSIONS A significant part of the postoperative anemia observed in patients who underwent sagittal craniosynostosis surgery was due to hypervolemic hemodilution. Correction of the volemic status with furosemide administration significantly reduces postoperative PRBC transfusion requirements in these patients.


MRI findings in Dyggve-Melchior-Clausen syndrome, a rare spondyloepiphyseal dysplasia.
We present the case of an 8-year-old female patient with bone dysplasia as part of Dyggve-Melchior-Clausen syndrome (DMCS). MRI was used to evaluate the case. In the spine, odontoid apophysis aplasia was found with no ossification nucleus, vertebrae with central hump, disk protrusions, hypertrophy of the posterior common vertebral ligament, and hidden spina bifida at the S4 level. Morphological anomalies were found in the hips both in the proximal femoral epiphysis, which was located excentrically and laterally to the femoral neck, and in the Y-cartilage, which was greatly enlarged. In the knees, anterior crossed ligaments were not seen, although there were some indirect signs that indicated congenital absence, including hypoplasia of the femoral trochlea and the intercondylar notch. There was bilateral medial patellar plicae and asymmetry in the height of the distal femoral and proximal tibial physes, as well as dysplasia of the facets of the patella. In comparison with radiography, MRI provides a much clearer definition of the aspects of bone dysplasia that are related to DMCS, including morphological changes in the soft tissue and cartilage of the spine, hips, and knees. MRI can enhance our understanding of the pathogenesis and evolution of deformities.


[Lyme arthritis].
Lyme disease is a multi-system inflammatory disease caused by spirochetes of the Borrelia burgdorferi. Among multiplicity manifestations of Lyme disease, musculoskeletal symptoms also occur. In the following article authors present epidemiology of Lyme disease, pathogenesis of antibiotic-refractory Lyme arthritis, symptoms, diagnosis and management of Lyme arthritis based on recent guidelines prepared by an expert panel of the infectious Diseases Society of America.


Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy.
Mesenchymal stem cells (MSCs) are a pleiotropic population of cells that are self-renewing and capable of differentiating into canonical cells of the mesenchyme, including adipocytes, chondrocytes, and osteocytes. They employ multi-faceted approaches to maintain bone marrow niche homeostasis and promote wound healing during injury. Biomedical research has long sought to exploit their pleiotropic properties as a basis for cell therapy for a variety of diseases and to facilitate hematopoietic stem cell establishment and stromal reconstruction in bone marrow transplantation. Early results demonstrated their usage as safe, and there was little host response to these cells. The discovery of their immunosuppressive functions ushered in a new interest in MSCs as a promising therapeutic tool to suppress inflammation and down-regulate pathogenic immune responses in graft-versus-host and autoimmune diseases such as multiple sclerosis, autoimmune diabetes, and rheumatoid arthritis. MSCs produce a large number of soluble and membrane-bound factors, some of which inhibit immune responses. However, the full range of MSC-mediated immune-modulation remains incompletely understood, as emerging reports also reveal that MSCs can adopt an immunogenic phenotype, stimulate immune cells, and yield seemingly contradictory results in experimental animal models of inflammatory disease. The present review describes the large body of literature that has been accumulated on the fascinating biology of MSCs and their complex effects on immune responses.


Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma has a worse prognosis than HPV-associated disease: a retrospective cohort study.
Vulvar squamous cell carcinoma (VSCC) can be subdivided by human papillomavirus (HPV) status into two clinicopathological entities. Studies on the prognostic significance of HPV in VSCC are discordant. We performed a retrospective analysis of overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) in 217 patients with VSCC. Cases were extracted from an era of more aggressive en-bloc radical dissections (1985-95) and more localized radical surgery through separate vulvar and groin excisions (1996-2005). p16 immunohistochemistry was used as a surrogate for HPV status. HPV status could be determined in 197 tumours, 118 HPV-independent and 79 HPV-associated tumours. Patients with HPV-associated tumours were younger (mean 58.8 versus 71.6 years for HPV-independent tumours, P < 0.0001) and more likely to have prior abnormal cervical cytology (41.1 versus 5.6% for HPV-independent tumours, P < 0.0001). In univariable analysis, patients with HPV-associated tumours had superior PFS [hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.18-0.70], DSS (HR: 0.19, 95% CI: 0.08-0.41) and OS (HR: 0.35, 95% CI: 0.21-0.59). This was driven by worse outcomes (PFS, DSS and OS) for patients with HPV-independent tumours compared with HPV-associated tumours who underwent surgery after 1995. After adjusting for age and stage in multivariable analysis, patients with HPV-associated tumours showed superior PFS (HR: 0.25, 95% CI: 0.07-0.77) and DSS (HR: 0.21, 95% CI: 0.04-0.78). VSCC can be stratified into two prognostically different diseases based on p16 immunostaining. HPV status was associated only with prognosis in the cohort that underwent surgery after 1995, suggesting that more conservative surgery may have led to worse outcomes for patients with HPV-independent tumours.


Correlation of V-src gene amplification with the tumorigenic phenotype in a Syrian hamster embryo cell line.
A preneoplastic cell line (10W) isolated after treatment of Syrian hamster embryo cells with asbestos was cotransfected with pSV2-neo DNA and Rous sarcoma virus DNA. Six of these colonies contained v-src DNA; however, none of the six initially expressed v-src RNA. Five of the clones failed to grow in soft agar (frequency, less than 10(-6)). One clone (61) grew in soft agar, but with a low frequency. Three of the clones (41, 61, and 62) were tumorigenic in nude mice and three were nontumorigenic. Cells cloned from soft agar or established from tumor explants expressed the v-src gene. The gene copy number of v-src, which was three to 10 in the original neoR clones, was increased approximately 10-fold in the soft agar-derived cell clones and tumor-derived cell lines. Cytogenetic analyses indicated that cells with amplified v-src contained double minute chromosomes. The results suggest that gene amplification influences the expression of the transfected oncogene and is a mechanism which can overcome the initial suppression of transcription of the v-src oncogene in the 10W cell line.


BIOETHICSLINE use by medical students: curriculum-integrated instruction and collection development implications.
BIOETHICSLINE uselogs were analyzed during months when second-year medical students were engaged in ethics coursework that included curriculum-integrated bibliographic instruction. Uselog data showed that peak activity occurred while students were preparing a required paper. Further uselog analysis indicated that students applied database features such as controlled vocabulary, the "explode" command, and a combination of multiple search concepts. In addition, the study examined journal use and interlibrary loan activity for a correlation with online search activity. Higher bioethics journal use and interlibrary loan statistics coincided with peak BIOETHICSLINE activity periods. Citation analysis of student bibliographies reflected the interdisciplinary nature of BIOETHICSLINE and the need for ethics, legal, and clinical information sources in a bioethics collection. This study suggests that the integration of bibliographic instruction and the coordination of collection development with students' curricular needs lead to increased and more competent use of information resources.