Scaling of the resolving power and sensitivity for planar FAIMS and mobility-based discrimination in flow- and field-driven analyzers.
Continuing development of the technology and applications of field asymmetric waveform ion mobility spectrometry (FAIMS) calls for better understanding of its limitations and factors that govern them. While key performance metrics such as resolution and ion transmission have been calculated for specific cases employing numerical simulations, the underlying physical trends remained obscure. Here we determine that the resolving power of planar FAIMS scales as the square root of separation time and sensitivity drops exponentially at the rate controlled by absolute ion mobility and several instrument parameters. A strong dependence of ion transmission on mobility severely discriminates against species with higher mobility, presenting particular problems for analyses of complex mixtures. While the time evolution of resolution and sensitivity is virtually identical in existing FAIMS systems using gas flow and proposed devices driven by electric field, the distributions of separation times are not. The inverse correlation between mobility (and thus diffusion speed) and residence time for ions in field-driven FAIMS greatly reduces the mobility-based discrimination and provides much more uniform separations. Under typical operating conditions, the spread of elimination rates for commonly analyzed ions is reduced from >5 times in flow-driven to 1.6 times in field-driven FAIMS while the difference in resolving power decreases from approximately 60% to approximately 15%.


Differentiating keratoacanthoma from squamous cell carcinoma by the use of apoptotic and cell adhesion markers.
Keratoacanthomas (KA) are well-differentiated squamoproliferative skin lesions that grow rapidly and regress spontaneously. In contrast, squamous cell carcinomas (SCC) can have variable differentiation, inexorably progress and on occasion metastasize. Distinguishing between KA and SCC using haematoxylin and eosin-stained sections from an initial biopsy can often be difficult. There is also some debate as to whether KA is simply a variety of well-differentiated SCC or a distinct entity. Initial biopsy sections from 25 cases of SCC and 20 of KA were labelled with markers for both the initiation (the cytolytic receptor P2X7) and end-stage (terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling) of apoptosis, telomerase-associated protein (TP1) and the cell adhesion protein E-cadherin. As this was a retrospective study, the clinical outcome of each case was known. This resulted in a unique labelling pattern of each marker for SCC and KA, allowing a differential diagnosis between the two conditions. The simplest marker to use for this purpose was anti-P2X7. Sections from five cases that were initially very difficult to diagnose were correctly identified as SCC using this method. These results support the view that KA has a different pathogenesis and biochemistry from that of SCC, and is a distinct entity. Anti-P2X7 labelling, using routine immunohistochemical techniques, provides a method for differentially diagnosing these conditions.


Structural basis for the NAD binding cooperativity and catalytic characteristics of sperm-specific glyceraldehyde-3-phosphate dehydrogenase.
Catalytic properties of enzymes used in biotechnology can be improved by eliminating those regulatory mechanisms that are not absolutely required for their functioning. We exploited mammalian glyceraldehyde-3-phosphate dehydrogenase as a model protein and examined the structural basis of the NAD(+) cooperative binding exhibited by its homologous isoenzymes: the somatic enzyme (GAPD) and the recombinant sperm-specific enzyme (dN-GAPDS). Moreover, we obtained a mutant dN-GAPDS, which misses the cooperativity, but exhibits a twofold increase in the specific activity instead (92 and 45 μmol NADH/min per mg protein for the mutant and the wild type proteins, respectively). Such an effect was caused by the disruption of the interdomain salt bridge D311-H124, which is located close to the active site of the enzyme. The thermal stability of the mutant protein also increased compared to the wild type form (heat absorption peak values were 70.4 and 68.6 °C, respectively). We expect our findings to be of importance for the purposes of biotechnological applications.


Pharmacological Approach to Smoking Cessation: An Updated Review for Daily Clinical Practice.
Tobacco use is one of the major public health concerns and it is the most preventable cause of morbidity and mortality worldwide. Smoking cessation reduces subsequent cardiovascular events and mortality. Smoking is a real chronic disorder characterized by the development of an addiction status mainly due to nicotine. This condition makes the smokers generally unable to quit smoking without help. Different strategies are available to treat smoking dependence that include both non-pharmacological (behavioral counselling) and pharmacological therapies. Currently, it is well accepted that smoking cessation drugs are effective and safe in real-world settings. Nicotine replacement therapy (NRT), varenicline, bupropion and cytisine are the main pharmacological strategies available for smoking cessation. Their efficacy and safety have been proved even in patients with chronic cardiovascular disease. Each of these drugs has peculiar characteristics and the clinician should customize the smoking cessation strategy based on currently available scientific evidence and patient's preference, paying particular attention to those patients having specific cardiovascular and psychiatric comorbidities. The present document aims to summarize the current viable pharmacological strategies for smoking cessation, also discussing the controversial issue regarding the use of alternative tobacco products, in order to provide useful practical indications to all physicians, mainly to those involved in cardiovascular prevention.


Risk of ARI among Non-exclusively Breastfed Under-Five Passive Smoker Children: A Hospital-Based Cross-sectional Study of Nepal.
As Nepal witnesses high burden of both acute respiratory infection (ARI) and passive smoking among under-five children, studies on effect modification of exclusive breastfeeding on passive smoking and ARI carry huge significance. With Nepal holding no evidence in this regard, findings would be useful to promote a cost-effective intervention: exclusive breastfeeding. This study was therefore conceived as an effort to bring to light the modifying effect that exclusive breastfeeding may have on the association between household passive smoking and ARI among under-five children. One hundred and ninety-eight parents of under-five children from Kanti Children's Hospital, Kathmandu, Nepal, participated in this descriptive, cross-sectional study carried out in October 2012. Data collected from a semi-structured questionnaire were subjected to univariate, bivariate, and multivariable analysis in R version 3.1.2. Non-exclusively breastfed children with presence of anyone smoking at their house [aOR = 4.8, 95% confidence interval (CI): 1.7-13.2] and smoking in presence of children (aOR = 6.4, 95% CI: 1.1-38.3) had higher chances of ARI; nevertheless, this remained insignificant among the exclusively breastfed ones. Having a separate kitchen in the house showed protective effect against ARI among exclusively breastfed children (aOR = 0.2, 95% CI: 0.1-0.6). Children whose mothers spent at least 2 h per day in the kitchen had a higher chance of developing ARI, regardless of being exclusively breastfed (aOR = 4.5, 95% CI: 1.5-13.1) or non-exclusively breastfed (aOR = 4.5, 95% CI: 1.4-14.2) compared to those who spent <2 h per day. Non-exclusive breastfeeding may increase the chances of deleterious effects of household passive smoking, such as ARI, among under-five children. As these findings are not conclusive, studies with better design and larger samples are warranted to confirm the effect.


Association between blocking folate receptor autoantibodies and subfertility.
The association between blocking folate receptor (FR) autoantibodies and subfertility was investigated in a longitudinal study of women attempting to become pregnant. Seventeen women with subfertility (failure to conceive during 12 menstrual cycles) and 25 control women (women who conceived and went on to have normal pregnancy outcomes) were studied. Subfertility risk was 12 times higher in women with blocking FR autoantibodies compared with those without (odds ratio, 12; 95% confidence interval, 1.9-129.6).


Three-dimensional morphogenesis of MDCK cells induced by cellular contractile forces on a viscous substrate.
Substrate physical properties are essential for many physiological events such as embryonic development and 3D tissue formation. Physical properties of the extracellular matrix such as viscoelasticity and geometrical constraints are understood as factors that affect cell behaviour. In this study, we focused on the relationship between epithelial cell 3D morphogenesis and the substrate viscosity. We observed that Madin-Darby Canine Kidney (MDCK) cells formed 3D structures on a viscous substrate (Matrigel). The structures appear as a tulip hat. We then changed the substrate viscosity by genipin (GP) treatment. GP is a cross-linker of amino groups. Cells cultured on GP-treated-matrigel changed their 3D morphology in a substrate viscosity-dependent manner. Furthermore, to elucidate the spatial distribution of the cellular contractile force, localization of mono-phosphorylated and di-phosphorylated myosin regulatory light chain (P-MRLCs) was visualized by immunofluorescence. P-MRLCs localized along the periphery of epithelial sheets. Treatment with Y-27632, a Rho-kinase inhibitor, blocked the P-MRLCs localization at the edge of epithelial sheets and halted 3D morphogenesis. Our results indicate that the substrate viscosity, the substrate deformation, and the cellular contractile forces induced by P-MRLCs play crucial roles in 3D morphogenesis.


Growth factor modulation of melanoma growth stimulatory activity mRNA expression in human malignant melanoma cells correlates with cell growth.
This report demonstrates that the expression of melanoma growth stimulatory activity (MGSA) mRNA can be modulated in a positive fashion in the Hs294T human melanoma cell line by PDGF and MGSA. There is close correlation between MGSA expression and the pattern of cell growth in Hs294T cells.


Glucose variability: a new risk factor for cardiovascular disease.
Glucose variability (GV) is increasingly considered an additional index of glycemic control. Growing evidence indicates that GV is associated with diabetic vascular complications, thus being a relevant point to address in diabetes management. GV can be measured using various parameters, but to date, a gold standard has not been identified. This underscores the need for further studies in this field also to identify the optimal treatment. We reviewed the definition of GV, the pathogenetic mechanisms of atherosclerosis, and its relationship with diabetic complications.


The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region.
We are developing a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active site of HCV NS3 proteases, in relation to their catalytic activity. In our previous work, the 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) yielded divergent, gradual and genotype-dependent, 4D conformational instability measures, which strongly correlate with the known disparate catalytic activities among genotypes. Here, the correlation of our 4D geometrical measure is extended to intra-genotypic alterations in NS3 protease activity, due to sequence variations in the NS4A activating cofactor. The correlation between the 4D measure and the enzymatic activity is qualitatively evident, which further validates our methodology, leading to the development of an accurate quantitative metric to predict protease activity in silico. The results suggest plausible "communication" pathways for conformational propagation from the activation subunit (the NS4A cofactor binding site) to the catalytic subunit (the catalytic triad). The results also strongly suggest that the well-sampled (via convergence quantification) structural dynamics are more connected to the divergent catalytic activity observed in HCV NS3 proteases than to rigid structures. The method could also be applicable to predict patients' responses to interferon therapy and better understand the innate interferon activation pathway.


RNA interference-mediated silencing of the syntaxin 5 gene induces Golgi fragmentation but capable of transporting vesicles.
It has been suggested that syntaxin 5 (Syx5) participates in vesicular transport. We examined the effects of Syx5 down-regulation on the morphology of the Golgi apparatus and the transport of vesicles in mammalian cells. Knockdown of the Syx5 gene resulted in Golgi fragmentation without changing the level of endoplasmic reticulum (ER)-resident proteins, other Golgi-SNAREs (soluble N-ethylmaleimide-sensitive factor-attachment protein receptors), and coatmer proteins. Strikingly, a major decrease in Syx5 expression barely affected the anterograde transport of vesicular stomatitis virus G (VSVG) protein to the plasma membrane. These results suggest that Syx5 is required for the maintenance of the Golgi structures but may not play a major role in the transport of vesicles carrying VSVG between the ER and the Golgi compartment.


Intracranial epithelioid hemangioendothelioma.
Epithelioid hemangioendothelioma (EHE) is an uncommon soft-tissue vascular neoplasm. Although a well-defined entity outside the neuraxis, its intracranial occurrence is rare. Literature review revealed 35 reported cases till date. The authors report a case of intracranial EHE in a 15-year-old girl, who presented with a short history and unusual radiology. Following radical removal, the lesion recurred within 1 month and progressed to terminal stages. This tumor is thought to have an indolent intermediate malignancy potential and such rapid progression has not been reported so far.


Plasma exchange therapy for thrombotic thrombocytopenic purpura in pediatric patients with liver transplantation.
Sporadic cases of thrombotic thrombocytopenic purpura (TTP) have been reported in bone marrow and solid organ transplant patients receiving cyclosporine (CsA). We reported our experience with TTP using plasma exchange (PE) therapy in patients with liver transplantation (OLT). Between March, 1993, and May, 2007, 400 patients underwent OLT, including 146 pediatric living-donor liver transplantation (LDLT). Four pediatric patients developed TTP after OLT: three were males and one female of mean age at the time of transplantation of 7.8 +/- 3.6 years. The four recipients had the following indications for OLT: two glycogen storage disease, one biliary atresia, and one fulminant hepatic failure. Four patients initially received triple drug immunosuppression consisting of CsA, azathioprine, and steroids. Four (1%) patients developed TTP after OLT. All four patients were pediatric in the age group. The mean age at the time of TTP diagnosis was 8.0 +/- 3.2 years, with a mean postoperative interval to TTP of 78.8 +/- 114.2 days. The mean baseline platelet count was 7.0 +/- 7.1 x 10,000. The eventual platelet count was 21.1 +/- 20.8 x 10,000 after PE. These patients received PE 6.0 +/- 4.2. The mean baseline serum creatinine was 0.8 +/- 0.8 mg/dL. The mean peak serum creatinine was 2.3 +/- 2.3 mg/dL. The mean serum CsA level was 717.5 +/- 106.0 ng/mL before TTP diagnosis. Four patients were diagnosed by blood peripheral smears. The causes of TTP were CsA-associated in three patients and venoocclusive disease (VOD) in one patient. Three patients improved their platelet counts after PE therapy. Two patient changed from CsA to FK 506, one underwent reduced CsA dosage, and one stopped CsA. Three patients died of recurrent VOD, infection, and intrapulmonary hemorrhage. Only one patient survived. The incidence of TTP in our series was lower. It only developed in pediatric patients. The causes of TTP were associated with CsA and/or VOD. The mortality was high after the TTP diagnosis. We concluded that TTP was a potentially fatal condition, but an early diagnosis with prompt institution of therapy with invasive PE therapy may reduce its mortal consequences.


Old people in the emergency room: age-related differences in emergency department use and care.
Little is known about how the care received in emergency departments (ED) by the elderly population differs from that received by younger people. We prospectively abstracted ED records of 1620 consecutive patients visiting a large community hospital ED over a 22-day period in 1984 for demographic and medical variables. Charts of patients presenting with five specific complaints (dyspnea, chest pain, abdominal pain, syncope, and motor vehicle accidents) were also analyzed for process of care variables and, for patients hospitalized, the accuracy of the ED diagnosis. Older people (ie, those greater than or equal to 65 years of age) do not seem to be overutilizers of the ED for minor complaints, in fact, they tend to be more acutely ill on presentation than younger people. Older people were more likely to be hospitalized (46% v 10%, P less than .001), to arrive by ambulance (35% v 10%, P less than .001), and to have an identified source of primary care (95% v 64%, P less than .01). Older people stayed longer in the ED than younger people if they were eventually released home but shorter if admitted to the hospital. Test ordering patterns for specific complaints varied by patient age (eg, older patients had more electrocardiograms performed for chest pain and fewer urinalyses for abdominal pain than younger patients). Therapy for specific complaints showed less age effect. Although generally more diagnostic tests were performed on older patients, the ED diagnosis tended to be more accurate for younger patients. Our data indicate that the process of ED care may be substantially different for the elderly population and have implications for future planning and financing of medical care.


Relationship between naphthol AS-D chloroacetate esterase and prostaglandin synthase.
The close topographical correlation between naphthol AS-D chloroacetate esterase-positive macrophages and prostaglandin synthase-rich macrophages in the thymus of normal and cyclosporin-treated rats was observed. It seems possible that chloroacetate esterase is an enzyme related to metabolism of arachidonic acid and/or production of its active metabolites.


Barley plasma membrane intrinsic proteins (PIP Aquaporins) as water and CO2 transporters.
We identified barley aquaporins and demonstrated that one, HvPIP2;1, transports water and CO2. Regarding water homeostasis in plants, regulations of aquaporin expression were observed in many plants under several environmental stresses. Under salt stress, a number of plasma membrane-type aquaporins were down-regulated, which can prevent continuous dehydration resulting in cell death. The leaves of transgenic rice plants that expressed the largest amount of HvPIP2;1 showed a 40% increase in internal CO2 conductance compared with leaves of wild-type rice plants. The rate of CO2 assimilation also increased in the transgenic plants. The goal of our plant aquaporin research is to determine the key aquaporin species responsible for water and CO2 transport, and to improve plant water relations, stress tolerance, CO2 uptake or assimilation, and plant productivity via molecular breeding of aquaporins.


A preliminary study of the innate immune memory of Kupffer cells induced by PEGylated nanoemulsions.
The accelerated blood clearance (ABC) phenomenon describes a dilemma of polyethylene glycol (PEG) applied in drug delivery system (DDS) caused by its immunogenicity, that results in the enhanced blood clearance rate and increased hepatic and splenic accumulation after secondary injection of PEGylated nanocarriers. However, the ABC index, as the judgement of ABC phenomenon, only describes the accelerated blood clearance rate, but ignores the enhanced hepatic and splenic accumulation. Therefore, we proposed the hepatic accumulation (HA) index and the splenic accumulation (SA) index as supplements for assessing the ABC phenomenon, to emphasize the contribution of liver and spleen, especially the liver, possessing the most population of tissue resident macrophages. By altering the first injection site from the tail vein to the liver portal vein, there was no impact on anti-PEG IgM production, and the secondary hepatic accumulation of PEGylated nanoemulsions (PE) was observed to be proportionate to the first PE stimulation strength on the liver. We also determined that Kupffer cells (KCs) were the main contributor to this enhancement. On this basis, we revealed a definite phenomenon that PE could induce innate immune memory in KCs, by enhancing the phagocytosis of KCs toward PE during the secondary stimulation. The PE-stimulated KCs could carry this memory to the naïve rats through adoptive transfer, resulting in increased hepatic accumulation in the recipient rats without antibody production. Studies examining the phagocytosis of KCs in vivo, ex vivo and in vitro revealed that the memory of KCs against PE triggered by first-stimulated PE could be maintained independently of other cells or components until 21 days after the first stimulation, and possessing specificity to PEG, which was invalid to long-circulating GE (GM1 modified nanoemulsions). The discovery of immune memory in KCs induced by PE highlights the importance of focusing on the relationship between the innate immune system and PEGylated nanocarriers during the development of DDS to improve medication safety in the clinic.


Dose and rate-dependent effects of adenosine on atrial action potential duration in humans.
Adenosine provokes atrial fibrillation (AF) in some patients with paroxysmal supraventricular tachycardia (PSVT). Which patients are more susceptible to develop atrial fibrillation after the administration of adenosine to terminate PSVT is unknown. We prospectively measured atrial action potential duration (APD) at incremental doses of 3, 6, and 12 mg of adenosine at paced cycle lengths (CLs) of 600, 500, and 400 ms in 25 patients. Bolus injection of adenosine decreased APD at 90% repolarization in a dose- and rate-dependent manner. During paced CLs of 600, 500, and 400 ms, decreases of 8%, 13%, and 19% (p < 0.05), respectively, were found after bolus administration of 3 mg of adenosine. After 6 mg of adenosine, the APD shortened by 12%, 19%, (p < 0.05), and 27% (p < 0.01), respectively. After 12 mg of adenosine, the APD shortened by 15%, 27% (p < 0.05), and 38% (p < 0.01), respectively. Transient AF occurred in 4 of 25 (16%) patients, all during paced CLs of 400 ms, and after adenosine 6 mg in one patient and 12 mg in three patients. Adenosine shortens atrial action potential duration in a dose- and rate-dependent manner. Whether patients with faster rates during PSVT and those given higher doses of adenosine are more prone to develop atrial fibrillation remains to be determined.


Early prediction model of brain death in out-of-hospital cardiac arrest patients: a single-center retrospective and internal validation analysis.
A shortage of donor organs amid high demand for transplantable organs is a worldwide problem, and an increase in organ donation would be welcomed by the global healthcare system. Patients with brain death (BD) are potential organ donors, and early prediction of patients with BD may facilitate the process of organ procurement. Therefore, we developed a model for the early prediction of BD in patients who survived the initial phase of out-of-hospital cardiac arrest (OHCA). We retrospectively analyzed data of patients aged < 80 years who experienced OHCA with a return of spontaneous circulation (ROSC) and were admitted to our hospital between 2006 and 2018. We categorized patients into either a non-BD or BD group. Demographic and laboratory data on ED admission were used for stepwise logistic regression analysis. Prediction scores of BD after OHCA were based on β-coefficients of prognostic factors identified in the multivariable logistic model. Overall, 419 OHCA patients with ROSC were admitted to our hospital during the study period. Seventy-seven patients showed BD (18.3%). Age and etiology of OHCA were significantly different between the groups. Logistic regression analysis confirmed that age, low-flow time, pH, and etiology were independent predictors of BD. The area under the receiver operating characteristic curve for this model was 0.831 (95% confidence interval, 0.786-0.876). We developed and internally validated a new prediction model for BD after OHCA, which could aid in the early identification of potential organ donors for early donor organ procurement.


Resistin and visfatin in steatotic and non-steatotic livers in the setting of partial hepatectomy under ischemia-reperfusion.
This study examined whether the regulation of resistin and visfatin could reduce damage and improve regeneration in both steatotic and non-steatotic livers undergoing partial hepatectomy under ischemia-reperfusion, a procedure commonly applied in clinical practice to reduce bleeding. Resistin and visfatin were pharmacologically modulated in lean and obese animals undergoing partial hepatectomy under ischemia-reperfusion. No evident role for these adipocytokines was observed in non-steatotic livers. However, obese animals undergoing liver surgery showed increased resistin in liver and plasma, without changes in adipose tissue, together with visfatin downregulation in liver and increment in plasma and adipose tissue. Endogenous resistin maintains low levels of visfatin in the liver by blocking its hepatic uptake from the circulation, thus regulating the visfatin detrimental effects on hepatic damage and regenerative failure. Indeed, the administration of anti-resistin antibodies increased hepatic accumulation of adipocyte-derived visfatin, exacerbating damage and regenerative failure. Interestingly, treatment with anti-visfatin antibodies protected steatotic livers, and similar results were obtained with the concomitant inhibition of resistin and visfatin. Thus, when visfatin was inhibited, the injurious effects of anti-resistin antibodies disappeared. Herein we show that upregulation of visfatin increased NAD levels in the remnant steatotic liver, whereas visfatin inhibition decreased them. These later observations suggest that visfatin may favour synthesis of NAD instead of DNA and induces alterations in amino acid metabolism-urea cycle and NO production, overall negatively affecting liver viability. Our results indicate the clinical potential of visfatin blocking-based therapies in steatotic livers undergoing partial hepatectomy with ischemia-reperfusion.


Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors.
Central nervous system (CNS) irradiation can cause sensorineural hearing loss. The relationship between the dose to the cochlea and the development of hearing loss is unknown. Conformal radiation therapy (CRT) techniques facilitate accurate cochlear dosimetry. We modeled hearing threshold levels (HTL) after CRT in children with localized primary brain tumors (ependymoma, low- or high-grade astrocytoma, craniopharyngioma, or CNS germinoma) by using cochlear dose and clinical variables. We evaluated 72 children (median age, 9.5 years) with audiograms before and every 6 months after CRT (median follow-up, 16.6 months; range, 4.3-42.6 months). We used a mixed-effects model to predict change in hearing for each ear as a function of time, cochlear dose, and clinical variables. Hearing was affected the greatest in patients with CSF shunts and pre-CRT ototoxic chemotherapy, enhanced by cochlear dose, and was more prominent on the right side. Hearing impairment after CRT alone occurred at low and intermediate frequencies in patients with shunts and supratentorial tumors when the cochlear dose exceeded 32 Gy. Patients with shunts and central supratentorial tumors developed intermediate-frequency hearing loss after CRT alone regardless of dose. Hearing loss during the first 4 years after CRT alone is uncommon, although patients with shunts and supratentorial tumors appear to be at increased risk for low- and intermediate-frequency effects. CSF shunting and increased cochlear dose enhance the effect of ototoxic chemotherapy. If possible, the average cochlear dose should be <32 Gy over a 6-week course of treatment until more specific dose data become available.


Headache in the Emergency Department: Avoiding Misdiagnosis of Dangerous Secondary Causes, An Update.
In the initial assessment of the headache patient, the emergency physician must consider several dangerous secondary causes of headache. A thorough history and physical examination, along with consideration of a comprehensive differential diagnosis may alert the emergency physician to the diagnosis of a secondary headache particularly when the history is accompanied by any of the following clinical features: sudden/severe onset, focal neurologic deficits, altered mental status, advanced age, active or recent pregnancy, coagulopathy, malignancy, fever, visual deficits, and/or loss of consciousness.


Interrupted inferior vena cava syndrome discovered incidentally after minimally invasive mitral valve repair in a 31-year-old female patient: A case report.
Femoral cannulation is a technique used in minimally invasive cardiac surgery (MICS) for accessing the heart through the femoral artery and vein. However, the presence of an interruption in the inferior vena cava (IVC) can pose challenges during the procedure. Understanding the patient's venous anatomy is crucial to ensure successful cannulation. We present the case of a 31-year-old female patient scheduled for minimally invasive mitral valve repair. During the procedure, femoral vein cannulation was unsuccessful. Subsequent diagnostic Computed Tomography (CT) revealed an interrupted IVC with azygos continuation. The interruption of the IVC can make cannulation through the femoral vein difficult or impossible due to the absence of the femoral vein or the presence of a collateral, necessitating alternative approaches. Preoperative imaging, such as CT, plays a significant role in identifying IVC interruptions and guiding surgical planning. Our case highlights the challenges associated with IVC interruptions during femoral cannulation in MICS. Preoperative imaging is essential for identifying anatomical variations and determining the most appropriate cannulation approach.


Apolipoprotein E synthesis in peripheral tissues of nonhuman primates.
The tissue distribution of apolipoprotein (apo) E synthesis in the cynomolgus monkey, Macaca fascicularis, was determined via short-term organ culture with radiolabeled amino acid. Tissue extracts were reacted with antiserum to apo-E, and immunoprecipitates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Newly synthesized apo-E was detected in liver, adrenal, testis, lung, spleen, mesenteric lymph node, and kidney. Peripheral and hepatic apo-E showed the same electrophoretic mobility. High resolution two-dimensional gel analysis showed that newly synthesized apo-E exists in two major isoforms in each tissue examined. Comparison of isoform patterns and mixing experiments showed that newly synthesized apo-E isoforms have identical charge properties in each tissue examined. These data indicate that numerous peripheral tissues synthesize apo-E that is indistinguishable from liver apo-E by the criteria tested. Measurements of relative synthetic capacities illustrate that apo-E is a moderately abundant protein product of a variety of peripheral tissues although quantitative differences in apo-E synthesis occur. Apo-E mRNA from cynomolgus monkey liver and human Hep G2 cells co-migrated with an electrophoretic mobility corresponding to approximately 1200 nucleotides. Apo-E mRNA from liver, brain, thymus, kidney, testis, lymph node, and spleen was the same size. Primer extension analysis yielded a cDNA product representing complete copying of the 5' untranslated region of human Hep G2 apo-E mRNA. A cDNA of identical size was produced with cynomolgus monkey apo-E mRNA from liver, spleen, brain, lymph node, kidney, lung, and thymus. These data suggest that transcription of the apo-E gene is initiated at or near the same site in each tissue examined.


Magnitude and Pace of Improvement in Performance of Hospitals Treating Mechanically Ventilated Children in the United States: Analysis From Two National Databases.
To use two national databases to quantify the pace and magnitude of improvement in hospital performance (as measured by mortality) across hospitals caring for critically ill children in the United States. We used empirical Bayes shrinkage estimators to obtain shrinkage estimators of observed/expected mortality ratios for each hospital assuming a Gamma Poisson posterior distribution. Revised mortality rates for each hospital were obtained from the shrunken incidence ratios. Pediatric Health Information System participating hospital and Kids' Inpatient Database participating hospital. Patients less than or equal to 18 years old who received invasive mechanical ventilation during their hospital stay at a Pediatric Health Information System participating hospital (2005-2015) or a Kids' Inpatient Database participating hospital (1997-2012) were included. None. A total of 486,838 patients from 48 Pediatric Health Information System hospitals and 798,840 patients from 947 Kids' Inpatient Database hospitals were included. For the Pediatric Health Information System hospitals, the median shrunken adjusted mortality decreased from 11.66% in 2005 to 7.11% in 2015; for the Kids' Inpatient Database hospitals, it decreased from 5.79% in 1997 to 3.86% in 2012. By 2015, more than 95% of the Pediatric Health Information System hospitals performed better than or as well as the best 25% of the hospitals in 2005. By 2012, 33.7% of Kids' Inpatient Database hospitals performed better than or as well as the best 25% of the hospitals in 1997. This study provides insight into the magnitude of improvement in patient mortality in hospitals caring for critically ill children in the United States. This study quantifies hospital performance in pediatric critical care over time, and it provides benchmarks against which individual hospitals can assess their own performance. In future pediatric epidemiologic studies, we should identify outcomes other than mortality to quantify improvement in hospital performance.


Inter-tibiofibular graft for traumatic segmental bone defect of the tibia.
The present study sought to assess the interest of inter-tibiofibular graft (ITFG), alternatively called posterolateral bone graft, in traumatic segmental tibial bone defect. Twenty-eight ITFGs were performed in 125 tibial reconstructions for traumatic bone defect. Patient's records were reviewed retrospectively in a multicenter study. Tibial reconstruction with and without ITFG was compared for bone healing and patient's return to full weight-bearing status. There were no failures of bone healing in the ITFG group, versus 14 (14%) in the non-ITFG group. Graft-to-consolidation delays were shorter with first-line ITFG, at a mean 10 months (range, 3-20 months) versus 16.5 months (range, 3-63 months) in the non-ITFG group (P<0.05). Weight-bearing was likewise more quickly resumed, with full weight-bearing at a mean 9 months (range, 3-19 months) versus 15 months (range, 1-34 moths) respectively (P<0.05). Return to work was also quicker, at a mean 15 months (range, 4-28 months) versus 27 months (range, 8-56 months) respectively (P<0.05). This study confirmed the interest of ITFG in tibial bone defect reconstruction. ITFG may singly be used for small defects less than 4 cm, or in conjunction with another tibial reconstruction technique; ITFG in the present series achieved consolidation in all cases and significantly shortened the times to return to full weight-bearing status and to work. III: retrospective case-control study.


Expression of transferrin binding protein in the capillaries of the brain in the developing chick embryo.
Transferrin-binding protein (TfBP) has been shown to be a novel protein, structurally related to the chicken heat shock protein 108. The physiological function of this protein, however, has not yet been established. Antiserum to TfBP selectively stains transferrin- and iron-rich oligodendrocytes and choroidal epithelium in the adult and embryonic chick brain, suggesting a role for this protein in transferrin and iron storage in these cells. In this study, we further demonstrate TfBP-immunoreactivity (IR) in the blood vessels of the embryonic chick central nervous system. A strong TfBP-IR was present in blood vessels from E6, declined from E10 and was absent by E18. Thus, the expression of the TfBP in the blood vessels precedes its expression in the oligodendrocytes. At the subcellular level, TfBP-IR was confined to the cytoplasm of capillary pericytes while the Tf-receptor IR was associated with the capillary endothelium of the brain. The up-regulated expression of TfBP, together with the Tf-receptor of the brain capillaries, suggests that pericytes may be associated with the high iron uptake required for the metabolic demands of the developing brain.


Structural and kinetic contributions of the oxyanion binding site to the catalytic activity of acylaminoacyl peptidase.
It is widely accepted that the catalytic activity of serine proteases depends primarily on the Asp-His-Ser catalytic triad and other residues within the vicinity of this motif. Some of these residues form the oxyanion binding site that stabilizes the tetrahedral intermediate by hydrogen bonding to the negatively charged oxyanion. In acylaminoacyl peptidase from the thermophile Aeropyrum pernix, the main chain NH group of Gly369 is one of the hydrogen bond donors forming the oxyanion binding site. The side chain of His367, a conserved residue in acylaminoacyl peptidases across all species, fastens the loop holding Gly369. Determination of the crystal structure of the H367A mutant revealed that this loop, including Gly369, moves away considerably, accounting for the observed three orders of magnitude decrease in the specificity rate constant. For the wild-type enzyme ln(k(cat)/K(m)) vs. 1/T deviates from linearity indicating greater rate enhancement with increasing temperature for the dissociation of the enzyme-substrate complex compared with its decomposition to product. In contrast, the H367A variant provided a linear Arrhenius plot, and its reaction was associated with unfavourable entropy of activation. These results show that a residue relatively distant from the active site can significantly affect the catalytic activity of acylaminoacyl peptidase without changing the overall structure of the enzyme.


Developmental lead exposure induces tactile defensiveness in rhesus monkeys (Macaca mulatta).
Tactile defensiveness in children is associated with difficult social relations, emotional dysregulation, and inattention. However, there are no studies of lead exposure and tactile defensiveness in children or animals in spite of the fact that lead exposure is also associated with inattention and emotional dysregulation. In this study we tested whether lead exposure induces tactile defensiveness in rhesus monkeys. We tested 61 monkeys from a 3 (no lead, 1-year lead, 2-year lead) x 2 (succimer chelation or not) factorial experiment for tactile defensiveness at 4 years of age. Lead-treated monkeys had been orally administered lead in a daily milk solution from 8 days of life to either 1 or 2 years of age to produce blood lead levels of 35-40 mg/dL. Succimer chelation therapy or placebo was administered at 1 year of age. We measured tactile defensiveness using six repeated trials of each of three textures as a swipe to the cheek and neck. Lead-exposed monkeys showed higher negative responses to repeated tactile stimulation compared with controls. Blood lead during the first 3 months of life was positively correlated with the negative response on the tactile defensiveness test. There was an interaction of lead exposure x succimer chelation x trials, but it is not clear that succimer chelation was beneficial with respect to tactile defensiveness. This is the first report to implicate lead as a potential cause of tactile defensiveness. Research should examine whether lead exposure is associated with tactile defensiveness in children.


Free peritoneal tumour cells are an independent prognostic factor in curatively resected stage IB gastric carcinoma.
Several studies have shown that the cytological detection of free peritoneal tumour cells (FPTCs) in patients with gastric cancer indicates the presence of metastatic disease. The immunocytochemical detection of FPTCs, especially in early-stage tumours, has not been examined comprehensively. Peritoneal lavage was performed in 351 patients before curative resection of a gastric carcinoma between 1987 and 2001, and an adequate sample was obtained from 346 patients. FPTCs were detected immunocytochemically using Ber-EP4 antibody. Median follow-up time was 70 months. FPTCs were detected in the lavage fluid of 74 patients (21.4 per cent) and correlated with increasing pathological tumour depth (pT) and lymph node (pN) status (P < 0.001). The 5-year overall survival of patients with FPTCs was significantly worse than that of patients without FPTCs (35 versus 71.9 per cent; P < 0.001). FPTCs were present in 14 (8.5 per cent) of 164 patients with stage IA or IB tumours. Although the detection of FPTCs had no prognostic significance for stage IA tumours, the presence of FPTCs in those with stage IB tumours was associated with a worse prognosis (P < 0.001). Multivariate analysis identified the presence of FPTCs as an independent prognostic factor in the whole cohort and in the stage IB subgroup. Detection of FPTCs is associated with poor prognosis even in patients with early-stage gastric cancer and should be used for risk-group stratification.


Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose.
To investigate the effect of high-dose cisplatin (40 mg/m2 daily for 5 days), 51Cr-EDTA clearance was used as a measure of glomerular filtration rate (GFR). 51Cr-EDTA clearance decreased significantly from 109 +/- 3 ml/min * 1.73 m2 to 68 +/- 3 ml/min * 1.73 m2 after three cycles of cisplatin and remained at this decreased level during the observation period (24 months). To determine the reliability of creatinine as a measure of GFR, we compared the simultaneous clearance of creatinine to that of 51Cr-EDTA. A good correlation between 51Cr-EDTA clearance and creatinine clearance was observed before and 3 months after termination of treatment, but no correlation was found during treatment. S-creatinine decreased significantly during treatment, probably due to muscle wasting. We conclude that s-creatinine and creatinine clearance are unsuitable measures of glomerular function during high-dose cisplatin treatment. All patients developed proteinuria during treatment. The changes in clearance ratios of beta-2-microglobulin/albumin and IgG/albumin show that the proteinuria observed during cisplatin infusion is predominantly of tubular origin, whereas the proteinuria between the treatment periods is mainly of glomerular origin.


Is amyloid fibrillation related to 3D domain swapping for the C-terminal domain of SARS-CoV main protease?
The C-terminal domain of SARS-CoV main protease (Mpro-C) can form 3D domain-swapped dimer by exchanging the α1-helices fully buried inside the protein hydrophobic core, under non-denaturing conditions. Here, we report that Mpro-C can also form amyloid fibrils under the 3D domain-swappable conditions in vitro, and the fibrils are not formed through runaway/propagated domain swapping. It is found that there are positive correlations between the rates of domain swapping dimerization and amyloid fibrillation at different temperatures, and for different mutants. However, some Mpro-C mutants incapable of 3D domain swapping can still form amyloid fibrils, indicating that 3D domain swapping is not essential for amyloid fibrillation. Furthermore, NMR H/D exchange data and molecular dynamics simulation results suggest that the protofibril core region tends to unpack at the early stage of 3D domain swapping, so that the amyloid fibrillation can proceed during the 3D domain swapping process. We propose that 3D domain swapping makes it possible for the unpacking of the amyloidogenic fragment of the protein and thus accelerates the amyloid fibrillation process kinetically, which explains the well-documented correlations between amyloid fibrillation and 3D domain swapping observed in many proteins.


Differences in AD-related pathology profiles across APOE groups.
The apolipoprotein (APOE) e4 allele is a known risk factor for Alzheimer's disease (AD), while the e2 allele is thought to be protective against AD. Few studies have examined the relationship between brain pathologies, atrophy, and white matter hyperintensities (WMHs) and APOE status in those with the e2e4 genotype and results are inconsistent for those with an e2 allele. We analyzed Alzheimer's Disease Neuroimaging participants that had APOE genotyping and at least one of the following metrics: regional WMH load, ventricle size, hippocampal (HC) and entorhinal cortex (EC) volume, amyloid level (i.e., AV-45), and phosphorylated tau (pTau). Participants were divided into one of four APOE allele profiles (E4=e4e4 or e3e4; E2=e2e2 or e2e3; E3=e3e3; or E24=e2e4, Fig.1). Linear mixed models examined the relationship between APOE profiles and each pathology (i.e., regional WMHs, ventricle size, hippocampal and entorhinal cortex volume, amyloid level, and phosphorylated tau measures). while controlling for age, sex, education, and diagnostic status at baseline and over time. APOE ε4 is associated with increased pathology while ε2 positivity is associated with reduced baseline and lower accumulation of pathologies and rates of neurodegeneration. APOE ε2ε4 is similar to ε4 (increased neurodegeneration) but with a slower rate of change. The strong associations observed between APOE and pathology in this study show the importance of how genetic factors influence structural brain changes. These findings suggest that ε2ε4 genotype is related to increased declines associated with the ε4 as opposed to the protective effects of the ε2. These findings have important implications for initiating treatments and interventions. Given that people who have the ε2ε4 genotype can expect to have increased atrophy, they must be included (alongside those with an ε4 profile) in targeted interventions to reduce brain changes that occur with AD.


Rheumatoid Arthritis Patients Have Better Outcomes Than Non-Rheumatoid Arthritis Patients When Hospitalized for Ischemic Stroke: Analysis of the National Inpatient Sample.
The aims of this study were to compare the outcomes of patients primarily admitted for ischemic stroke with and without a secondary diagnosis of RA. Data were abstracted from the National Inpatient Sample (NIS) 2016 and 2017 database. The NIS was searched for hospitalizations for adult patients with ischemic stroke as principal diagnosis with and without RA as secondary diagnosis using International Classification of Diseases, 10th Revision codes. The primary outcome was inpatient mortality. Hospital length of stay (LOS), total hospital charges, odds of receiving tissue plasminogen activator, and mechanical thrombectomy were secondary outcomes of interest. Multivariate logistic and linear regression analyses were used accordingly to adjust for confounders. There were more than 71 million discharges included in the combined 2016 and 2017 NIS database. Of 525,570 patients with ischemic stroke, 8670 (1.7%) had RA. Hospitalizations for ischemic stroke with RA had less inpatient mortality (4.7% vs. 5.5%; adjusted odds ratio, 0.66; 95% confidence interval, 0.52-0.85; p = 0.001), shorter LOS (5.1 vs 5.7 days, p < 0.0001), lower mean total hospital charges ($61,626 vs. $70,345, p < 0.0001), and less odds of undergoing mechanical thrombectomy (3.9% vs. 5.1%; adjusted odds ratio, 0.55; 95% confidence interval, 0.42-0.72; p < 0.0001) compared with those without RA. Hospitalizations for ischemic stroke with RA had less inpatient mortality, shorter LOS, lower total hospital charges, and less likelihood of undergoing mechanical thrombectomy compared with those without RA. However, the odds of receiving tissue plasminogen activator were similar between both groups. Further studies to understand its mechanism would be helpful.


Simultaneous extraction and determination of albendazole and triclabendazole by a novel syringe to syringe dispersive liquid phase microextraction-solidified floating organic drop combined with high performance liquid chromatography.
A syringe to syringe dispersive liquid phase microextraction-solidified floating organic drop was introduced and used for the simultaneous extraction of trace amounts of albendazole and triclabendazole from different matrices. The extracted analytes were determined by high performance liquid chromatography along with fluorescence detection. The analytical parameters affecting the microextraction efficiency including the nature and volume of the extraction solvent, sample volume, sample pH, ionic strength and the cycles of extraction were optimized. The calibration curves were linear in the range of 0.1-30.0 μg L(-1) and 0.2-30.0 μg L(-1) with determination coefficients of 0.9999 and 0.9998 for albendazole and triclabendazole respectively. The detection limits defined as three folds of the signal to noise ratio were found to be 0.02 μg L(-1) for albendazole and 0.06 μg L(-1) for triclabendazole. The inter-day and intra-day precision (RSD%) for both analytes at three concentration levels (0.5, 2.0 and 10.0 μg L(-1)) were in the range of 6.3-10.1% and 5.0-7.5% respectively. The developed method was successfully applied to determine albendazole and triclabendazole in water, cow milk, honey, and urine samples.


Prenatal recognition of 4p- syndrome.
A fetus with the rare 4p- syndrome was detected by chromosome analysis of amniotic cell culture, and the pregnancy terminated. The fetus showed a number of the physical stigmata of the syndrome.


Efficacy of a self-management program for childhood asthma--a prospective controlled study.
Asthma training programs for parents and children have been developed to increase both the self-management skills of asthmatic children and compliance with medical regimes. In order to evaluate two training programs for asthmatic children aged 7-14, 81 patients were randomly assigned to three groups. Group 1 consisted of 27 patients and their parents who participated in a five-day standardized family-oriented clinical asthma training program. They had monthly follow-up meetings with the training team for a period of six months. Group 2 (n = 29) had the same clinical training without follow-up interventions; a control group (n = 25) received regular medical treatment according to the international guidelines at the asthma clinics without a training program and served as control group. Questionnaires regarding self-management aspects, coping and anxiety were filled out by patients, parents, family doctors and the training team prior to as well as twelve months after the training. The results indicate that Training group 1 benefitted most with respect to active asthma self-management, Training group 2 to some degree while the control group showed no significant effects. The differences after one year between the three groups regarding physical parameters such as lung-function and days missed in school did not reach the level of significance. Our results indicate that the long-term efficacy of self management courses for asthmatic children is enhanced by regular follow-up training sessions.


Design and evaluation of a novel portable erythema-melanin-meter.
Objective evaluation of the pigmentation index (PI) and the eythema index (EI) of human skin is a prerequisite for successful optimization of laser- and intense-pulsed-light (IPL)-based treatment modalities in dermatology. We describe a three-wavelength technique for determining PI and EI as well as its particular implementation using LEDs operating at wavelengths of 560, 650, and 710 nm and a large-area photodiode. The instrument has been evaluated both in vitro and in vivo. In vitro, good correlation between the measured indices and results obtained with commercially available techniques has been observed. In addition, linearity of the PI with melanin concentration in the phantom medium up to 7 x 10(-3) nm(-1) (defined as a slope of the optical density spectrum) has been established. In vivo, feasibility of using the technique for predicting the minimal erythema dose (MED), minimal phototoxic dose (MPD), and the threshold of epidermal damage in a photothermal treatment has been demonstrated. The data suggest that the technique has a substantial potential as a method of pre-treatment diagnostics for photochemical and photothermal procedures.


Neuronal activity in the subcortically denervated hippocampus: a chronic model for epilepsy.
Spontaneous and evoked field potentials and cellular discharges were studied in the subcortically denervated hippocampus of the freely moving rat. The fimbria fornix, the ventral hippocampal commissure, and the supracallosal afferent fibers were removed by aspiration, and recordings were made 3-5 months after the lesion. Two types of spontaneous interictal spikes were observed. Type 1 interictal spike had identical depth distribution to physiological sharp waves but they were shorter in duration (less than 40 ms), larger in amplitude (greater than 2.5 mV) and population spikes were riding on the main deflection. Type 2 interictal spikes were negative in the stratum oriens and positive in the pyramidal layer and stratum radiatum of both CA1 and CA3. The amplitude of both types of interictal spikes could exceed 6 mV. We suggest that interictal spikes were initiated randomly in different subpopulations of the CA2-3 region and the location of the initiating population burst determined the polarity and amplitude of the extracellular interictal spike. Repetitive stimulation of the perforant path (5 Hz, 6 s) evoked markedly uniform afterdischarges in both intact and fimbria fornix-deprived rats. The threshold of afterdischarges was significantly lower, the seizure spread to the contralateral hippocampus was slower, and secondary afterdischarges lasted significantly longer in the lesioned rats. We suggest that under physiological conditions the electrical stability of the hippocampus is ensured by the feed-forward inhibitory action of subcortical afferents. Removal of tonic inhibitory influences and/or sprouting of local axon collaterals allows extreme synchronization and reverberation of information in the entorhinal-hippocampal-entorhinal cortex circuitry. The presence of interictal spikes and increased susceptibility to seizures for several months after the lesion offers the fimbria-fornix-deprived hippocampus a useful chronic preparation to study the mechanisms of limbic epilepsy.


Prevention of pediatric pulmonary problems: the importance of maternal smoking.
Although many factors are associated with lower respiratory illnesses in children, few can be identified as likely direct causal influences. Maternal smoking has been strongly associated with respiratory morbidity in early life. The relationship is consistent in different studies, and is dose-related. It is also resistant to attempts at statistical control for factors that might confound the association. The effect seems most marked from maternal smoking during pregnancy. Stopping young women taking up cigarette smoking is a priority preventive medical need.


Social modeling in the school environment, student characteristics, and smoking susceptibility: a multi-level analysis.
To examine how social models in the school environment and individual student characteristics are related to smoking susceptibility. Using data from the School Smoking Profile Project, multi-level logistic regression analysis was used to identify school and student characteristics related to smoking susceptibility among 6679 never smokers from 29 secondary schools in Ontario, Canada. If a nonsmoking student attended a school where there was student smoking on the school periphery, he or she was less likely to be susceptible to smoking (OR 0.71, 95% CI 0.57-0.89). A significant contextual interaction between the smoking on the school periphery and friends' disapproval of smoking was identified (beta = 0.68 [0.23], p < .01]; students with friends who disapprove of smoking were more likely to be susceptible to smoking if they attended a school with student smoking on the school periphery. Nonsmoking students who attend a school with student smoking on the school periphery are at an increased risk for being susceptible to smoking if they have friends who disapprove of smoking. Future school-based smoking prevention programs might benefit from targeting both individual students and entire schools with programming activities.


Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort. We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ε4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D). Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2-4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = -0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs. Q2-4) also had lower scores on tests of visual memory (β ± SE = -0.47 ± 0.18; p = 0.008), executive function (β ± SE = -0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = -0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models. Lower RBC DHA levels are associated with smaller brain volumes and a "vascular" pattern of cognitive impairment even in persons free of clinical dementia.


Randomized trial comparing the efficacy between different types of paclitaxel-eluting stents: the comparison of efficacy between COroflex PLEASe ANd Taxus stent (ECO-PLEASANT) randomized controlled trial.
Paclitaxel-eluting stents (PESs) have been shown to inhibit neointimal hyperplasia after percutaneous coronary intervention. Coroflex Please (B Braun, Melsungen, Germany) is a newly developed PES. We compared the clinical and angiographic efficacy of Coroflex Please with Taxus Liberte (Boston Scientific, Natick, MA) in a real-world practice. We performed a prospective, open-label, randomized, controlled study that enrolled 945 patients undergoing percutaneous coronary interventions in 18 centers in Korea. The primary end point was clinically driven target vessel revascularization at 9 months. The baseline characteristics were mostly similar and comparable between 2 groups. At 9 months, the incidence of clinically driven target vessel revascularization was 14.6% for Coroflex and 6.4% for Taxus, which was significantly different (hazard ratio 2.43, 95% CI 1.50-3.94, noninferiority P value = 1.000). This is well corroborated by the difference of in-stent late loss between 2 stents (0.71 ± 0.64 mm vs 0.52 ± 0.50 mm, P < .001) by 9-month follow-up angiography (n = 415 vs 215). Among secondary clinical end points, stent thrombosis (definite and probable) for 1 year was 2.2% in Coroflex and 1.3% in Taxus (P = .317). Also, myocardial infarction for 9 months was higher in Coroflex group than that in Taxus (4.9% vs 1.6%, P = .012), which was partly contributed by the higher incidence of periprocedural myocardial infarction in Coroflex arm (2.2% vs 0.3%, P = .028). Coroflex Please was inferior to Taxus Liberte with regard to clinical and angiographic efficacy.


Speed/position sensor fault tolerant control in adjustable speed drives - A review.
The position sensor is one of the most used devices in Adjustable Speed Drives (ASDs). Its use is mandatory in electric machines vector control. In this paper, an interest was addressed to this field. Indeed, a bibliographical review, about Fault Detection and Isolation (FDI) and Fault Tolerant Control (FTC) in ASDs, is presented. Thus, the paper deals with position sensor FDI and sensorless control-based FTC in ASDs. Moreover, this issue is mainly addressed to position sensor faults in ASDs. This paper is based on a wide literature review referring to scientific papers and manufacturer׳s technical documents. In total, 186 references in the open literature, dating back to 1981, have been investigated in order to perform this study.


Identification of novel cystinuria mutations in pediatric patients.
Cystinuria is a common inherited disorder of renal reabsorption of cystine and the dibasic amino acids. So far, mutations in two genes (SLC3A1 and SLC7A9) have been identified in cystinuria patients. Molecular searches for cystinuria mutations show that their distribution depends on the ethnic origin of the patients, but have not allowed the detection of 100% of variants. Pediatric patients representing a severe form of the disease appear to carry other mutations than those patients referred from urological centers. We analysed patients with an age of manifestation less than 15 years for mutations in the two cystinuria genes. We screened 17 patients for mutations in SLC3A1 and SLC7A9, 15 of whom were younger than 16 years at first stone formation. The search for mutations used PCR-based standard techniques, and was focused on point mutations and larger deletions and duplications in both genes. Apart from detection of mutations in approximately 70% of patients but identification of only 53% of alleles, we detected three novel mutations as well as three new polymorphisms. The detection rate in young cystinuria patients is lower than that in older patients, and there is a different pattern of variants. There is evidence for other (probably genetic) factors being involved in the pathophysiology of cystinuria.


De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.
We analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex-derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include "functional" synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk.


Angiographic patterns of involvement in renal and perirenal lymphoma.
Ten patients with renal lymphoma studied by selective angiography are reported. Seven patients had unilateral and 3 had bilateral involvement. A localized mass was seen in 6 patients and diffuse infiltration in 3. In 1 patient with bilateral nodular involvement, the angiographic findings resembled those of adult-type polycystic kidney disease. In all cases, renal lymphoma was suspected angiographically. The findings included hypovascular mass or masses with fine neovascularity, smooth and diffuse arterial encasement, and faint tumor staining.


Genome-wide meta-analyses identify five new risk loci for nonsyndromic orofacial clefts in the Chinese Han population.
Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome-wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome-wide meta-analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. We identify 47 risk loci with genome-wide pmeta -value <5.0 × 10-8 , 5 risk loci (1p32.1, 3p14.1, 3p14.3, 3p21.31, and 13q22.1) of which are new. All of the 47 susceptibility loci conjointly account for 44.12% of the NSOFCs' heritability in the Chinese Han population. Our results improve the comprehending of genetic susceptibility to NSOFCs and provide new views into the genetic etiology of craniofacial anomalies.


The hydroxylation of phenylalanine and tyrosine: a comparison with salicylate and tryptophan.
The hydroxylation of phenylalanine by the Fenton reaction and gamma-radiolysis yields 2-hydroxy-, 3-hydroxy-, and 4-hydroxyphenylalanine (tyrosine), while the hydroxylation of tyrosine results in 2,3- and 3,4-dihydroxyphenylalanine (dopa). Yields are determined as a function of pH and the presence or absence of oxidants. During gamma-radiolysis and the Fenton reaction the same hydroxylated products are formed. The final product distribution depends on the rate of the oxidation of the hydroxyl radical adducts (hydroxycyclohexadiene radicals) relative to the competing dimerization reactions. The pH profiles for the hydroxylations of phenylalanine and tyrosine show a maximum at pH 5.5 and a minimum around pH 8. The lack of hydroxylated products around near pH 8 is due to the rapid oxidation of dopa to melanin. The relative abilities of iron chelates (HLFe(II) and HLFe(III) to promote hydroxyl radical formation from hydrogen peroxide are nitrilotriacetate (nta) greater than ethylenediaminediacetate (edda) much greater than hydroxyethylethylenediaminetriacetate greater than citrate greater than ethylenediaminetetraacetate greater than diethylenetriaminepentaacetate greater than adenosine 5'-triphosphate greater than pyrophosphate greater than adenosine 5'-diphosphate greater than adenosine 5'-monophosphate. The high activity of iron-nta and -edda chelates is explained by postulating the formation of a ternary Fe(III)-L-dopa complex in which dopa reduces Fe(III). The hydroxylations of phenylalanine and tyrosine are similar to that of salicylate (Z. Maskos, J. D. Rush, and W. H. Koppenol, 1990, Free Radical Biol. Med. 8, 153-162) and tryptophan (preceding paper) in that oxidants augment the formation of hydroxylated products by catalyzing the dismutation of hydroxyl radical adducts to the parent compound and a stable hydroxylated product. A comparison of salicylate and the amino acids tryptophan, phenylalanine, and tyrosine clearly shows that salicylate is the best indicator of hydroxyl radical production.


Infantile inflammatory myofibroblastic tumors: clinicopathological and molecular characterization of 12 cases.
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.


Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts.
For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = -0.13, false discovery rate-corrected p = 4.17 × 10-3; rg_thickness = -0.13, false discovery rate-corrected p = 4.00 × 10-2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.


Upper and lower gastrointestinal motor and sensory dysfunction after human spinal cord injury.
This chapter describes the results of investigations of the upper and lower gastrointestinal tract in subjects with complete and incomplete spinal cord injury. In one study, gastric emptying was investigated and found delayed. The delay was tentatively attributed to a colo-gastric inhibitory reflex triggered by inappropriate colonic emptying. In another study, anorectal motor and sensory functions were measured. Decreased tone of the internal anal sphincter, exaggerated recto-anal reflexes following rectal distension and spontaneous high-amplitude rectal contractions at low distension volumes were among the findings of the study. Some of the subjects, classified as having a complete injury according to usual clinical criteria (American Spinal Injury Association, ASIA), reported sensation of distension of the rectum. This raises the issue of the need for better methods for the clinical assessment of sensory transmission in the spinal cord. Promising results obtained with functional magnetic resonance imaging of the brain during rectal stimulation in a small group of paraplegics, with complete injuries by ASIA criteria, showed evidence of activation of several brain regions.


Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines.
The synthesis of new 4-amino substituted pyrazolo[3,4-d]pyrimidines along with their activity in cell-free enzymatic assays on Src and Abl tyrosine kinases is reported. Some compounds emerged as good dual inhibitors of the two enzymes, showed antiproliferative effects on two Bcr-Abl positive leukemia cell lines K-562 and KU-812, and induced apoptosis, as demonstrated by the PARP assay. Docking studies have been also performed to analyze the binding mode of compounds under study and to identify the structural determinants of their interaction with both Src and Abl.


Work Around the Clock: How Work Hours Induce Social Jetlag and Sleep Deficiency.
A growing body of evidence has placed an increasing emphasis on how sleep affects health. Not only does insufficient sleep make one subjectively feel worse, but is associated with chronic diseases that are considered epidemics in industrialized nations. This is partly caused by the growing need for prolonged work and social schedules, exemplified by shift work, late-night weekends, and early morning work/school start times (social jetlag). Here, we consider fundamental relationships between the circadian clock and biologic processes and discuss how common practices, such as shift work and social jetlag, contribute to sleep disruption, circadian misalignment, and adverse health outcomes.


Caveolin-1 suppresses tumor formation through the inhibition of the unfolded protein response.
Caveolin-1 (CAV1), is a broadly expressed, membrane-associated scaffolding protein that acts both, as a tumor suppressor and a promoter of metastasis, depending on the type of cancer and stage. CAV1 is downregulated in human tumors, tumor cell lines and oncogene-transformed cells. The tumor suppressor activity of CAV1 is generally associated with its presence at the plasma membrane, where it participates, together with cavins, in the formation of caveolae and also has been suggested to interact with and inhibit a wide variety of proteins through interactions mediated by the scaffolding domain. However, a pool of CAV1 is also located at the endoplasmic reticulum (ER), modulating the secretory pathway in a manner dependent on serine-80 (S80) phosphorylation. In melanoma cells, CAV1 expression suppresses tumor formation, but the protein is largely absent from the plasma membrane and does not form caveolae. Perturbations to the function of the ER are emerging as a central driver of cancer, highlighting the activation of the unfolded protein response (UPR), a central pathway involved in stress mitigation. Here we provide evidence indicating that the expression of CAV1 represses the activation of the UPR in vitro and in solid tumors, reflected in the attenuation of PERK and IRE1α signaling. These effects correlated with increased susceptibility of cells to ER stress and hypoxia. Interestingly, the tumor suppressor activity of CAV1 was abrogated by site-directed mutagenesis of S80, correlating with a reduced ability to repress the UPR. We conclude that the tumor suppression by CAV1 involves the attenuation of the UPR, and identified S80 as essential in this context. This suggests that intracellular CAV1 regulates cancer through alternative signaling outputs.


Erysothrine, an alkaloid extracted from flowers of Erythrina mulungu Mart. ex Benth: evaluating its anticonvulsant and anxiolytic potential.
In this study, we isolated the alkaloid erysothrine from the hydroalcoholic extract of flowers from E. mulungu and screened for its anticonvulsant and anxiolytic actions based on neuroethological and neurochemical experiments. Our results showed that the administration of erysothrine inhibited seizures evoked by bicuculline, PTZ, NMDA and most remarkably, kainic acid. Also, erysothrine induced an increase in the number of entries but not in the time spent in the open arms of the EPM. However, we did not notice any alterations in the light-dark choice or in the open-field tests. In preliminary neurochemistry tests, we also showed that erysothrine (0.001-10 μg/mL) did not alter the GABA or glutamate synaptossomal uptake and binding. Altogether, our results describe an alkaloid with anticonvulsant activity and mild anxiolytic activity that might be considered well tolerated as it does not alter the general behavior of the animals in the used doses.


Activation of AMP-activated protein kinase in cerebella of Atm-/- mice is attributable to accumulation of reactive oxygen species.
Ataxia telangiectasia (A-T) is an inherited disease, the most prominent feature of which is ataxia caused by degeneration of cerebellar neurons and synapses. The mechanisms underlying A-T neurodegeneration are still unclear, and many factors are likely to be involved. AMP-activated protein kinase (AMPK) is a sensor of energy balance, and research on its function in neural cells has gained momentum in the last decade. The dual roles of AMPK in neuroprotection and neurodegeneration are complex, and they need to be identified and characterized. Using an Atm (ataxia telangiectasia mutated) gene deficient mouse model, we showed here that: (a) upregulation of AMPK phosphorylation and elevation of reactive oxygen species (ROS) coordinately occur in the cerebella of Atm-/- mice; (b) hydrogen peroxide induces AMPK phosphorylation in primary mouse cerebellar astrocytes in an Atm-independent manner; (c) administration of the novel antioxidant monosodium luminol (MSL) to Atm-/- mice attenuates the upregulation of both phosphorylated-AMPK (p-AMPK) and ROS, and corrects the neuromotor deficits in these animals. Together, our results suggest that oxidative activation of AMPK in the cerebellum may contribute to the neurodegeneration in Atm-/- mice, and that ROS and AMPK signaling pathways are promising therapeutic targets for treatment of A-T and other neurodegenerative diseases.


The role of growth factors in haemopoietic development: clinical and biological implications.
Mature blood cells of all lineages are derived from a single class of cell, the haemopoietic stem cell. Stem cells are pluripotent and capable of almost limitless self-renewal. In the bone marrow they form part of a hierarchy that includes progenitor cells, which are more restricted in the lineages their progeny can adopt, and precursor cells, which are committed to differentiation. The mechanisms that regulate progression through this hierarchy are not fully understood, but evidence suggests that both bone marrow stromal cells and soluble growth factors have a role in controlling haemopoiesis. Four growth factors act on progenitor cells to promote their survival, proliferation, differentiation, and maturation: interleukin-3 (IL-3), granulocyte/macrophage-colony stimulating factor (GM-CSF), granulocyte-CSF (G-CSF), and macrophage-CSF (M-CSF). They can also activate the function of mature cells. Considerable overlap is found in the target cells for these four growth factors. We have found that growth factors acting in synergy can recruit more primitive cells than had previously been appreciated. These factors can also determine the lineage that the progeny of multipotential progenitors will adopt. Thus, colony-stimulating factors (CSFs) have the potential to regulate the development of primitive haemopoietic cells in vivo. The properties of CSFs have made them useful in treating malignant disease: G-CSF, in particular, has been used to reduce the period of neutropaenia that follows cytotoxic therapy for various malignancies. The success of these early trials gives ground for cautious optimism about the clinical use of these compounds.


Macrophage membrane-coated nanovesicles for dual-targeted drug delivery to inhibit tumor and induce macrophage polarization.
Immunosuppressive M2 macrophages in the tumor microenvironment (TME) can mediate the therapeutic resistance of tumors, and seriously affect the clinical efficacy and prognosis of tumor patients. This study aims to develop a novel drug delivery system for dual-targeting tumor and macrophages to inhibit tumor and induce macrophage polarization. The anti-tumor effects of methyltransferase like 14 (METTL14) were investigated both in vitro and in vivo. The underlying mechanisms of METTL14 regulating macrophages were also explored in this study. We further constructed the cyclic (Arg-Gly-Asp) (cRGD) peptide modified macrophage membrane-coated nanovesicles to co-deliver METTL14 and the TLR4 agonist. We found that METTL14 significantly inhibits the growth of tumor in vitro. METTL14 might downregulate TICAM2 and inhibit the Toll-like receptor 4 (TLR4) pathway of macrophages, meanwhile, the combination of METTL14 and the TLR4 agonist could induce M1 polarization of macrophages. Macrophage membrane-coated nanovesicles are characterized by easy modification, drug loading, and dual-targeting tumor and macrophages, and cRGD modification can further enhance its targeting ability. It showed that the nanovesicles could improve the in vivo stability of METTL14, and dual-target tumor and macrophages to inhibit tumor and induce M1 polarization of macrophages. This study anticipates achieving the dual purposes of tumor inhibition and macrophage polarization, and providing a new therapeutic strategy for tumors.


Indigenous customized sponge shunt for a recurrent brainstem cyst.
Various treatment modalities are available for treatment of cystic lesions of the brainstem. However, cyst refilling and recurrences are very common. This article describes a young boy who presented with an intra-axial brainstem cyst following radiation for a pilocytic astrocytoma. The cyst was decompressed surgically once but it soon refilled. The use of a novel customized synthetic sponge acting as a shunt for the treatment of a cystic brainstem lesion is discussed. The sponge was fashioned like a dumbbell and inserted across the fenestration in the cyst wall. The dumbbell design made it self-retaining. The characteristics of the sponge permitted continuous capillary drainage, with a low risk of occlusion. There was a dramatic decrease in the cyst size on follow-up scans, with resolution of clinical deficits. A customized sponge shunt can serve as an easily available and effective internal shunt for intra-axial craniospinal cysts.


Novel biomimetic polymersomes as polymer therapeutics for drug delivery.
Novel amphiphilic diblock copolymers, cholesterol-end-capped poly(2-methacryloyloxyethyl phosphorylcholine) (CMPC), which have poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) as hydrophilic segment and cholesterol as hydrophobic segment, was specially designed as drug delivery systems. Fluorescence probe technique and transmission electron microscope (TEM) characterizations indicated that this novel amphiphilic copolymer formed micelles structure in water and the critical micelle concentration (CMC) was determined to be 1.57 x 10(-7) mol/l. A commercial obtained polymeric amphiphiles, Cholesterol end capped PEO (CPEO), which had a similar structure with CMPC, was used as a control in the cytotoxicity test. While CPEO showed obvious cytotoxicity, cytotoxicity of this novel amphiphiles was not observed as indicated by cell culture. Anti-cancer drug adriamycin (ADR) was incorporated into the micelles by oil-in-water method. The size of the drug-containing micelles was less than 200 nm, and the size distribution of the drug-containing micelles showed a narrow and monodisperse unimodal pattern. The release rate of ADR from the nanosphere was slow and the release continued over 7 days and the release rate decreased with the increase of molecular weights of the copolymer and the amount of the drug entrapped. These experimental results suggested that the nanoparticles prepared from CMPC block copolymers could be a good candidate for injectable drug delivery carrier.


High prevalence of human papillomavirus type 66 in low-grade cervical lesions of Mexican women.
Our aim was to analyze the prevalence of high-risk human papillomavirus (HR-HPV) and its association with risk factors related to cervical lesions. We used 362 cervical samples from a transversal study to detect nineteen types from the high-risk HPV clade by highly sensitive PCR. Unexpectedly, we found a very high prevalence of HPV type 66 (32.8%), particularly in low-grade squamous intraepithelial lesions. A significant association of HPV66 with previously sexually transmitted disease was observed (p < 0.05). Our results strongly suggest that HPV66 might be indicative of cervical lesions that will not progress to cancer. HPV genotyping by methods that grouped type 66 with other HR-HPV clade types should be interpreted with caution.


The clinical outcomes and predictive factors for in-hospital mortality in non-neutropenic patients with candidemia.
Recent epidemiologic studies have showed that candidemia is an important nosocomial infection in hospitalized patients. The majority of candidemia patients were non-neutropenic rather than neutropenic status. The aim of this study was to determine the clinical outcome of non-neutropenic patients with candidemia and to measure the contributing factors for mortality. A total of 163 non-neutropenic patients with candidemia during January 2010 to December 2013 were retrospectively enrolled. The patients' risk factors for mortality, clinical outcomes, treatment regimens, and Candida species were analyzed. The overall mortality was 54.6%. Candida albicans was the most frequent Candida species (n = 83; 50.9% of patients). Under multivariate analyses, hemodialysis (OR, 4.554; 95% CI, 1.464-14.164) and the use of amphotericin B deoxycholate (OR, 8.709; 95% CI, 1.587-47.805) were independent factors associated with mortality. In contrast, abdominal surgery (OR, 0.360; 95% CI, 0.158-0.816) was associated with a better outcome. The overall mortality is still high in non-neutropenic patients with candidemia. Hemodialysis and use of amphotericin B deoxycholate were independent factors associated with mortality, whereas prior abdominal surgery was associated with a better outcome.


Erythema nodosum induced by the synergism of acupuncture therapy and flu-like infection.
A 32-year-old female patient developed erythema nodosum-like lesions at needle prick sites after acupuncture therapy. Over the next few days, she developed similar new lesions over the extremities, trunk and face along with flu-like symptoms. There were neither genital ulcerations nor eye lesions. A skin biopsy specimen from an extremity lesion showed the characteristic findings of erythema nodosum. Treatment with oral potassium iodide at a dose of 750 mg/day was effective, and there has not been any recurrence to date. We diagnosed this case as erythema nodosum induced by a synergism between acupuncture therapy and a flu-like infection.


Prevention by rebamipide of acute reflux esophagitis in rats.
Proinflammatory factors, including neutrophil-derived oxygen free radicals and inflammatory cytokines, have recently been implicated in the pathogenesis of reflux esophagitis. Rebamipide has been widely used as an anti-ulcer agent. The aim of the present study was to assess the protective effect of rebamipide against acute reflux esophagitis in rats. Esophagitis was induced in rats by ligation at the limiting ridge and the lower portion of the duodenum. Vehicle or rebamipide were given as a single dose intraduodenally. Lesion index (LI), thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, mRNA and protein of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were markedly increased; pretreatment with rebamipide, however, significantly reduced both macroscopic and microscopic injuries and increases in inflammatory mediators. The results of this study indicate that rebamipide protects against the occurrence of esophagitis and has highly promising potential as a new therapeutic agent for reflux esophagitis.


Orotic acid overproduction in experimental cirrhosis of rats.
Ammonia clearance, portal blood ammonia, and amino acid concentrations were studied during induction of cirrhosis by carbon tetrachloride in rats. Exposure to CCl4 vapors twice weekly for 7-16 weeks doubled orotic acid excretion. If exposure was discontinued for 7 days, the orotic acid excretion decreased despite the presence of cirrhosis proven histologically. Replacement of dietary casein with soybean protein eliminated the CCl4-induced orotic aciduria in growing rats but not in adults. Supplementation of casein with 1.5% arginine did not prevent CCl4-induced orotic aciduria. [14C]Orotate uptake into RNA and DNA of liver was not impaired. Perfusion of livers of cirrhotic animals with ammonia concentrations between 0.2 and 3.0 mM revealed no significant decreases in urea synthesis rates due to cirrhosis and no increase in the tendency to make orotic acid at a given ammonia concentration. However, ammonia uptake by cirrhotic livers was significantly reduced, resulting in higher ammonia concentrations in the effluent when there was moderate-to-severe cirrhosis. Portal blood samples taken from rats exposed to CCl4 had higher ammonia concentrations as cirrhosis worsened. The results lend support to the "intact hepatocyte" hypothesis of cirrhosis which attributes metabolic abnormalities to intrahepatic shunts.


[Selection interviews at Hanover Medical School (MHH): determinants of student selection in medical studies].
In order to incorporate social and communicative skills in its student admissions process, Hanover Medical School (MHH) has conducted selection interviews (in combination with the high-school GPA) to choose 60 % of its freshmen in medical studies. The present article analyses if applicants' performances in the interviews were the determining criterion of student selection, despite a higher weighting of school grades in the admission process. Furthermore, this article checks whether the grading of the interviews was independent of the applicants' gender, age, origin and educational background. For a sample of more than 3,000 successful and unsuccessful participants in the MHH student admission process in the years 2010-2017, we employ variance analysis and logistic regression analysis to determine those factors that have contributed to the chances of being offered a place at the MHH after a successful interview. The scores received in the selection interview were the sole determinant of being offered a place at the MHH; neither the applicants'age nor their gender or origin biased the decisions of the selection committees. The grading of the interview was also not affected by school GPAs. The selection interviews at the MHH have been costly in terms of both financial and human resources. However, this selection method has been popular among students and lecturers alike, not least because its elements fit the MHH's focus on early bedside teaching and social skills of prospective physicians. However, there is no evidence that selection interviews are effective in predicting academic success. The present article has shown that the selection interviews acted up to the principles defined by the MHH: very homogenous high school GPAs were complemented by differentiated interview assessments that did not discriminate by sociodemographic characteristics. It is, however, unclear if the MHH will resume the interviews after the end of a federally mandated halt to stand-alone selection methods at medical schools in Germany.


Effects of statins on the incidence and outcomes of acute kidney injury in critically ill patients: a systematic review and meta-analysis.
In critically ill patients, acute kidney injury (AKI) is a common complication with very high mortality rates. Several studies indicated that statin therapy, primarily due to its so-called pleiotropic effects, may beneficially affect the course of the disease, otherwise leading to significant clinical complications. However, both the original research as well as available meta-analyses on these associations report equivocal results. This leaves open a question whether pre- and perioperative statins might prevent AKI and improve overall prognosis in patients undergoing surgery. Following a systematic search of the literature, we performed a meta-analysis of selected clinical studies investigating the impact of statin treatment on the development and the clinical outcomes of AKI among subjects undergoing surgeries. The pooled odds ratios (OR) with 95% confidence intervals (CI) for the development of AKI and AKI-associated mortality, as well as the pooled mean differences (MD) and 95% CI for mean intensive care unit (ICU) stay and overall hospital length of stay were calculated for statin users compared to non-users. Our results showed a highly significant association between statin use and the decrease in mortality of patients with AKI (OR = 0.73, 95% CI: 0.69-0.77; p<0.001). The development of AKI (OR = 0.92, 95% CI: 0.63-1.33; p = 0.659) as well as the ICU stay (MD = -0.02, 95% CI: -0.06 - 0.02; p = 0.321) were not significantly affected, while the overall hospital length of stay (MD = -0.49, 95% CI: -0.91 -0.07; p = 0.020) was reduced. Subgroup analysis showed that both pre- and postoperative statin use were not associated with the risk of AKI. Our analysis showed a significant association between statin therapy and overall mortality of critically ill surgical patients diagnosed with AKI, while at the same time the use of statins did not affect the length of their stay in ICU.


Positive Airway Pressure Therapy in Sleep-Disordered Breathing.
Obstructive sleep apnea (OSA) is a highly prevalent condition with major neurocognitive and cardiovascular health effects. Positive airway pressure (PAP) therapy prevents the collapse of the pharyngeal airway to improve hypoxemia, hypercapnia, and sleep fragmentation caused by OSA. While adherence to PAP therapy has been thought to be a barrier to use, consistent usage is likely much higher than commonly thought. In addition, many strategies have been developed to assist providers in improving their patients' PAP adherence.


Changes in cerebral tissue oxygen saturation during anaesthetic-induced hypotension: an interpretation based on neurovascular coupling and cerebral autoregulation.
There is currently no consensus regarding how to intervene in anaesthetic-induced hypotension. Whether or not the balance between cerebral oxygen supply and demand is maintained lacks adequate elucidation. It is thus intriguing to explore how cerebral tissue oxygen saturation is affected by anaesthetic-induced hypotension. Thirty-three patients scheduled for elective non-neurosurgical procedures were included in this study. Physiological measurements were performed immediately before induction with propofol and fentanyl and after tracheal intubation. Mean (SD) Bispectral index decreased from 84.3 (9.3) to 24.4 (8.0) (p<0.001). Mean arterial pressure decreased from 84.4 (10.6) mmHg to 53.6 (11.4) mmHg (p<0.001). However, cerebral tissue oxygen saturation remained stable (67.0 (9.4) % vs 67.5 (7.8) %, p=0.6). These results imply that the fine balance between cerebral oxygen supply and demand is not disrupted by anaesthetic-induced hypotension. An interpretation based on neurovascular coupling and cerebral autoregulation is proposed.


Effect of butyrate on aromatase cytochrome P450 levels in HT29, DLD-1 and LoVo colon cancer cells.
Epidemiological studies suggest that colonic production of butyrate and estrogen may be involved in human susceptibility to colorectal cancer (CRC). Estrone (E1) can be produced by the aromatase pathway during the conversion of androstenedione (A) to E1. Therefore, we studied the effect of sodium butyrate (NaBu) on the CYP19A1 transcript and protein levels and on the conversion of A to E1 in HT29, DLD-1 and LoVo CRC cells. We found that NaBu significantly downregulated CYP19A1 transcript and protein levels, a phenomenon that was associated with reduced conversion of A to E1 in HT29, DLD-1 and LoVo cells. Our studies demonstrated that, although butyrate exhibited a protective role in CRC development, this compound may reduce aromatase activity and the production of E1 in colon cancer cells.