Robustness-Heterogeneity-Induced Ultrathin 2D Structure in Li Plating for Highly Reversible Li-Metal Batteries.
Anode interface modification is crucial for the stabilization of Li-metal batteries (LMBs), which have been considered as the most promising system for the electric vehicle market owing to their high energy density (500 W h kg-1). However, the biggest challenge for LMBs lies in the preservation of anode reversibility, including plated Li morphology control and dendritic Li inhibition during cycling. Here, we propose a nanostructure modulation strategy of Li grains and plating to activate the anode kinetics of LMBs without the compromise of anode stability. This modulation is triggered by the rapid deposition of ultrathin polydopamine coating on the Cu foil (PDA@Cu), which results in an unusual interlaced growth of vertical or lie-down two-dimensional Li nanoflakes on PDA. The high binding energy (>3 eV) between Li atoms and rich imino/carbonyl groups enables a superior lithiophilicity of PDA to homogenize the Li-ion flowing and Li-mass electroplating with negligible nucleation overpotential. The high Coulombic efficiency (98%) and low voltage hysteresis (∼20 mV) are stabilized for at least 300 cycles in the Li-PDA@Cu cell architecture. This PDA@Cu electrode can even tolerate much higher current densities of 5 and 10 mA cm-2 for 170 and 100 cycles, respectively. The interlaced network of Li nanosheets reinforces the electric contact and therefore charge transfer at the anode-electrolyte interface characterized by small interfacial resistance (<3 Ω cm2) and activation energy (0.28 eV). A viewpoint of robustness loss or mechanical heterogeneity in Li plating is discussed to disclose the evolution from column-like Li grains to porous Li sponges and then to compactly stacked Li nanoflakes with porosity shrinkage.


Resolution of DL-2-aminosuberic acid via protease-catalyzed ester hydrolysis.
Papain-catalyzed regioselective cleavage of alpha-methyl ester in Z-DL-Asu(OMe)-OMe leads to Z-L-Asu(OMe)-OH and Z-D-Asu(OMe)-OMe. Subsequent saponifications yield Z-L-Asu-OH and Z-D-Asu-OH. The enzymatic alpha-ester hydrolysis was also achieved by subtilisin BPN' in organic solvent with low water content.


Silencing Notch4 promotes tumorigenesis and inhibits metastasis of triple-negative breast cancer via Nanog and Cdc42.
Elucidation of individual Notch protein biology in specific cancer is crucial to develop safe, effective, and tumor-selective Notch-targeting therapeutic reagents for clinical use [1]. Here, we explored the Notch4 function in triple-negative breast cancer (TNBC). We found that silencing Notch4 enhanced tumorigenic ability in TNBC cells via upregulating Nanog expression, a pluripotency factor of embryonic stem cells. Intriguingly, silencing Notch4 in TNBC cells suppressed metastasis via downregulating Cdc42 expression, a key molecular for cell polarity formation. Notably, downregulation of Cdc42 expression affected Vimentin distribution, but not Vimentin expression to inhibit EMT shift. Collectively, our results show that silencing Notch4 enhances tumorigenesis and inhibits metastasis in TNBC, indicating that targeting Notch4 may not be a potential strategy for drug discovery in TNBC.


Lyophilization of cholesterol-free PEGylated liposomes and its impact on drug loading by passive equilibration.
The obstacles in translating liposome formulations into marketable products could be attributed to their physical instabilities upon long-term storage as aqueous dispersions. Lyophilization is the most commonly used technique to improve physical stability of liposomes. The development of stable, lyophilized liposomes is focused primarily on the cholesterol-containing liposomes or pure phosphatidylcholine-based liposomes, with minimal studies on cholesterol-free, pegylated (CF-PEG) liposomes which have emerged as an important class of liposome drug carriers. Hence, it is our interest to investigate the effect of lyophilization on CF-PEG liposomes, and specifically, on drug loading via the passive equilibration method. Three different sugar cryoprotectants were used at two different sugar-to-lipid molar ratios (S/L). Our results demonstrated that CF-PEG liposomes lyophilized with sucrose at S/L=5:1 yielded the best cryoprotective effect, as characterized by size, polydispersity indices, and microscopic examination upon liposome reconstitution. The lyophilized liposomes had low water content of 2.59 ± 0.18%. Of note, lyophilized CF-PEG liposomes exhibited two-fold increase in drug content when carboplatin was loaded via the passive equilibration method, and the in vitro drug release profile of these liposomes were not different from that of the non-lyophilized counterparts. Taken together, we envisioned that a stable, lyophilized empty CF-PEG liposome system could be coupled to hydrophilic drug loading via the passive equilibration method to produce a liposomal drug kit product.


Scoliosis in children with severe cerebral palsy: a population-based study of 206 children at GMFCS levels III-V.
To evaluate the prevalence of scoliosis and the rate of scoliosis progression in children with severe cerebral palsy (CP) at GMFCS levels III-V. Two hundred and six children (86 girls, 120 boys), born 2002-2008, were recruited from The Norwegian Quality and Surveillance Registry for Cerebral Palsy (NorCP). Inclusion criteria were bilateral CP and GMFCS levels III-V. Scoliosis was evaluated annually by examination of the spine by a physiotherapist. Radiographic examination was performed in children with moderate or severe scoliosis at clinical evaluation. The Cobb angle was used as a measure of curve magnitude. Scoliosis, defined as Cobb angle ≥ 10°, occurred in 121 children (59%). Severe scoliosis (Cobb angle ≥ 40°) developed in 80 of the 206 patients (39%) at a mean age of 10.9 years (range 5-16) and was more prevalent in children at GMFCS level V (62%) than at levels IV (19%) and III (6%). Initial Cobb angle, Cobb angle ≥ 30° at age 10 years, and GMFCS level V were independent risk factors for severe scoliosis. In children at GMFCS level V, the rate of scoliosis progression decreased with age from a mean of 9.7° per year at age 3-5 years to 2-3° per year in children ≥ 11 years. The prevalence of scoliosis among children with CP increased with decreasing motor functional level. The most important risk factors for progression of scoliosis were high initial Cobb angle, Cobb angle ≥ 30° at age 10 years, and GMFCS level V.


Calcium and calcium-activated currents in vagotomized rat primary vagal afferent neurons.
Adult inferior vagal ganglion neurons (nodose ganglion neurons, NGNs) were acutely isolated 4-6 days after section of their peripheral axons (vagotomy) and examined with the whole-cell patch-clamp technique. A subset (approximately 25 %) of vagotomized NGNs displayed depolarizing after-potentials (DAPs), not present in control NGNs. DAPs were inhibited by niflumic acid (125 microM) or cadmium (100 microM), and had a reversal potential near E(Cl), indicating that they were due to Ca(2+)-activated chloride current (I(Cl(Ca))). N-type, L-type, T-/R- and other types of voltage-dependent Ca(2+) channels provided about 43, 2, 16 and 40 % of the trigger Ca(2+) for DAP generation, respectively. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was estimated using fura-2 fluorescence. Resting [Ca(2+)](i) and peak [Ca(2+)](i) elevation induced by activating Ca(2+)-induced Ca(2+) release (CICR) stores with 10 mM caffeine were not significantly different among control NGNs, vagotomized NGNs with DAPs and vagotomized NGNs without DAPs, averaging 54 +/- 7.9 (n = 19; P = 0.49) and 2022 +/- 1059 nM (n = 19; P = 0.44), respectively. Blocking CICR with 10 microM ryanodine reduced DAP amplitude by approximately 37 %. Ca(2+) influx induced by action potential waveforms was increased by over 250 % in vagotomized NGNs with DAPs (19.0 +/- 2.1 pC) compared to control NGNs (5.0 +/- 0.8 pC) or vagotomized NGNs without DAPs (7.0 +/- 0.8 pC). L-type, N-type, T-/R-type and other types of Ca(2+) influx were increased proportionately in vagotomized NGNs with DAPs. In conclusion, a subset of vagotomized NGNs have increased Ca(2+) currents and express I(Cl(Ca)). These NGNs respond electrically to increases in [Ca(2+)](i) during regeneration.


Failure of spermatozoa from T/t mice to fertilize in vitro is overcome by zona drilling.
Failure of epididymal spermatozoa from T/t mutant mice, but not from t/t individuals, to fertilize oocytes in vitro was partially overcome by opening a small aperture in the zona pellucida with acidified Tyrode's solution to permit direct access of the spermatozoon to the vitellus. This study provides a model system to evaluate requirements for successful zona drilling in the treatment of human infertility and further insights into the effects of the t complex on sperm fertility.


Casein kinase 2 and microtubules control axon initial segment formation.
The axon initial segment (AIS) is a unique axonal subdomain responsible for the generation of the neuronal action potential and the maintenance of the axon-dendritic functional polarity. Despite its importance, the mechanisms controlling AIS development and maintenance remain largely unknown. Here we show that the AIS microtubule cytoskeleton is composed of a pool of more stable, detergent resistant, microtubules. This AIS specific characteristic is conferred by the presence of CK2, an important regulator of microtubule stability, in the AIS during its development and maturation. We show that CK2α and CK2α' subunits concentrate at the AIS from its initial development, at the same time as pIκBα and ankyrinG. CK2 pharmacological inhibition or suppression of CK2α expression with nucleofected interference RNAs modifies microtubule characteristics throughout the neuron, changes KIF5C distribution, and impairs its own concentration at the AIS, as well as that of ankyrinG, ankyrinG-GFP, pIκBα and voltage gated sodium channels. Moreover, CK2α concentration at the AIS depends on IκBα phosphorylation by IKK and ankyrinG. In conclusion, our results demonstrate a mutual dependence of CK2, ankyrinG and pIκBα for their concentration at the axon initial segment, which is related to the specific characteristics of microtubules at the AIS.


Confidentiality and the management of patients with epilepsy who fail to comply with doctor's advice not to drive: a survey of medical/legal opinions in Australia.
This study sought the opinions of a select group of professionals, trained in medicine and law concerning: professional privilege; management of patients who posed risks to society; and the legal charge to impose upon a patient with uncontrolled epilepsy who caused a fatality by driving contrary to medical advice. The second Academic Seminar of the Australian College of Legal Medicine was surveyed to define demographics and opinions. Of 23 respondents, 14 were trained in law and medicine, of whom eight had post graduate medical qualifications and seven had more than basic legal training; 20/23 supported professional privilege in medicine but 18/23 denied its absoluteness; 22/23 felt the doctor had a right to divulge information in the public interest. Only 14/23 (although still a majority opinion) felt this right was a duty and 6/23 refuted the same. When concerned regarding compliance not to drive, 7/23 would discuss it with family/friends in contravention of patient consent, 12/23 would report to the driving authorities where concern became fact, 13/23 would advise the patient that a report would be sent, 4/23 would report without the patient's knowledge and four would threaten but not send the report. In the case of a fatality consequent to non-compliance, 10/23 considered murder and 22/23 considered manslaughter charges to be appropriate. The majority supported professional privilege in the doctor/patient relationship but also supported the right or even a duty to report risks to society. Where a concern arose that a patient with epilepsy may drive contrary to advice, one-third of doctors would discuss with family/friends, without consent, one-half would report the patient to the driving authorities, while almost three-quarters would report the patient if concern was realised. Murder and manslaughter, serious charges, were deemed appropriate for patients who caused death by driving against medical advice.


Geographical discrimination of olive oils from Cv. 'Galega Vulgar'.
Olive oils from seven Portuguese regions were selected to study the effect of the geographical origin on the oils' composition. Quality parameters, fatty acids, tocopherols, hydroxytyrosol and tyrosol derivatives, and oxidative stability were evaluated. All olive oils could be classified as extra virgin, and the geographical origin significantly affected the oils chemical composition. Principal component analysis further confirmed the significant impact of the geographical origin on the composition and, indirectly, on stability of the oils, showing that the evaluated parameters could be used as markers for geographical origin identification. Alternatively, Fourier transform infrared spectroscopy was applied, allowing to establish a linear discriminant model that correctly identified the geographical origin of the olive oils with a mean sensitivity of 99 ± 3 % (internal validation), confirming the impact of the oil origin on its characteristics. This finding allowed foreseeing the future application of the spectroscopy approach as a green, fast and non-invasive authentication tool.


Bioremediation with freshwater bivalves: A sustainable approach to reducing the environmental impact of inland trout farms.
Integrated multi trophic aquaculture (IMTA) is well developed in seawater, while the only suitable organisms for bioremediation in freshwater are bivalves. The aim of this research has been to investigate a novel system, based on freshwater bivalves integrated with rainbow trout, for the bioremediation of inland aquaculture systems. The Unionid species selected for the experiments was Sinanodonta woodiana. Five mesocosm experiments were conducted to evaluate the efficiency of mussels in filtering the total bacteria and Aeromonas hydrophila, as well as their clearance efficiency on trout farm wastewater. The temperatures, dissolved oxygen, nitrates, and phosphates were monitored and were all within the physiological tolerance range of the species in all the experiments. The feasibility of bioremediation with S. woodiana in trout farming has thus been demonstrated, and among the tested rearing densities (3.75; 7.5; 15; 30 and 60 kg m-3) that of 7.5 kg m-3 was found to be optimal. The net reduction of the total bacterial concentration was as much as 72%, while that of A. hydrophila reached a level of 95-98%. No relevant effects of the mussels on particulate suspended material or sedimented material was observed, regardless of the temperature. The efficiency of freshwater bivalves in reducing the bacterial load, in particular toward A. hydrophila, indicates a bioremediation system with the possibility of interesting applications on inland fish farms, and as a biotechnological tool against the diffusion of antibiotic resistance in aquaculture.


The delayed addition of human mesenchymal stem cells to pre-formed endothelial cell networks results in functional vascularization of a collagen-glycosaminoglycan scaffold in vivo.
This paper demonstrates a method to engineer, in vitro, a nascent microvasculature within a collagen-glycosaminoglycan scaffold with a view to overcoming the major issue of graft failure due to avascular necrosis of tissue-engineered constructs. Human umbilical vein endothelial cells (ECs) were cultured alone and in various co-culture combinations with human mesenchymal stem cells (MSCs) to determine their vasculogenic abilities in vitro. Results demonstrated that the delayed addition of MSCs to pre-formed EC networks, whereby MSCs act as pericytes to the nascent vessels, resulted in the best developed vasculature. The results also demonstrate that the crosstalk between ECs and MSCs during microvessel formation occurs in a highly regulated, spatio-temporal fashion, whereby the initial seeding of ECs results in platelet derived growth factor (PDGF) release; the subsequent addition of MSCs 3 days later leads to a cessation in PDGF production, coinciding with increased vascular endothelial cell growth factor expression and enhanced vessel formation. Functional assessment of these pre-engineered constructs in a subcutaneous rat implant model demonstrated anastomosis between the in vitro engineered vessels and the host vasculature, with significantly increased vascularization occurring in the co-culture group. This study has thus provided new information on the process of in vitro vasculogenesis within a three-dimensional porous scaffold for tissue engineering and demonstrates the potential for using these vascularized scaffolds in the repair of critical sized bone defects.


Longitudinal analysis of regional brain changes in anti-NMDAR encephalitis: a case report.
Anti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations. A previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient's clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402-18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient's treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient's clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain. Our results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.


Identifying correlations between donor demographics and isohemagglutinin titers as a potential method to screen for low-titer group O whole blood.
With more hospitals using low-titer group O whole blood in trauma resuscitation, having an efficient screening method for low-titer donors is critical. Our blood center uses an automated screen for high-titer isohemagglutinins in our platelet donations while collecting detailed donor demographic information. Using this data, we can identify key demographics often associated with titer status, thereby helping develop a donor-triaging method for titering. Titer results were read with an automated microplate system as either high or low, based on agglutination, with a cutoff equivalent to 1:256 (both anti-A and anti-B). Donor demographic data analyzed included date of donation, blood group, age, gender, and ethnicity. 57,508 donations were collected from 2073 unique donors between 2014 and 2018. We found the following demographics to be correlated with titer status: gender, ABO blood group, age, and ethnicity. Variability in titer status was identified in 215 individuals. This represented around 10 % of the total unique donors and was split equally amongst gender. We also found that donors between the ages of 41-60 ha d the highest likelihood of having variability in titer status, peaking at 13 %, and this proportion declined past age 60. Titer status is associated with the following donor demographics: gender, ABO type, age, and ethnicity. We also discovered that variability in titer status is correlated with age. In blood centers that do not have automated and routine titer screening procedure, these findings could be used as a method to efficiently identify low-titer donors a-priori.


De Novo Trisomy 1q10q23.3 Mosaicism Causes Microcephaly, Severe Developmental Delay, and Facial Dysmorphic Features but No Cardiac Anomalies.
Proximal duplications of chromosome 1q are rare chromosomal abnormalities. Most patients with this condition present with neurological, urogenital, and congenital heart disease and short life expectancy. Mosaicism for trisomy 1q10q23.3 has only been reported once in the literature. Here we discuss a second case: a girl with a postnatal diagnosis of a de novo pure mosaic trisomy 1q1023.3 who has no urogenital or cardiac anomalies.


Outcome of left ventricular aneurysmectomy with patch repair in patients with severely depressed pump function.
To determine the efficacy of left ventricular (LV) aneurysm resection and endoventricular patch repair with septal exclusion in patients with severely depressed pump function, we retrospectively selected 62 patients (mean age 59 +/- 7 years) with preoperative LV ejection fraction < or = 20%, from a series of 322 patients with postinfarction LV aneurysm who underwent this type of surgery at our center during a 5-year period. Mean ejection fraction was 17 +/- 3%; all patients were in New York Heart Association (NYHA) class III/IV, and all had hemodynamic and electrophysiologic studies before and after surgery. We analyzed both operative and long-term survival, and hemodynamic, electrophysiologic, and angiographic variables, as well as the symptomatic state after surgery. Follow-up was available in all patients (mean 23 +/- 14 months). Subtotal endocardiectomy and cryotherapy were associated in patients presenting with spontaneous or inducible ventricular arrhythmias (VA). Hospital mortality rate was 19.3%. Ejection fraction improved from 17 +/- 3% to 37 +/- 10% (p < 0.001); ventricular arrhythmias decreased significantly after surgery. Factors influencing early mortality at multivariate analysis were the presence of critical lesions on the circumflex artery and the duration of cardiopulmonary bypass. At 1-year control, a significant reduction in NYHA class was observed and no patient was in NYHA class IV. The improvement in ejection fraction was maintained (39 +/- 11%), as well as the reduction in inducible and spontaneous ventricular arrhythmias. There were 5 late deaths at follow-up, accounting for a late mortality of 10% at 5 years.


Ecosystem services in conservation planning: Assessing compatible vs. incompatible conservation.
The compatible conservation of ecosystem services (ES) refers to the sustainable development of a region and the multiple dimensions of the region population's well-being. Applying the ES relationship to systematic conservation planning (SCP) can help determine the protection priorities associated with ES and support good zoning decisions. This study uses Nanchang, China as a case study to construct a multi-scenario ES protection scheme. This includes evaluating the spatial distribution characteristics of four core ES, and the ES relationships in the subregion in Nanchang. The ES relationship is then used to construct three ES conservation scenarios (synergetic, trade-off and incompatible), and the SCP tool is used for zoning. The results show the following. First, the incompatible scenario prioritizes the conservation of supporting services and provisioning services, which support ecological protection and cultivated land security. Second, given a land management and control threshold, the management zones can be compatible with a large proportion of secondary services in the synergetic scenario (22%). Fewer secondary services are compatible under the trade-off scenario (8%). As the compatible secondary service targets increase, each management zone area experiences a nonlinear change. The spatial change is more stable in the synergetic scenario compared to the trade-off scenario, and the space of management zone becomes discrete under the trade-off scenario. Third, the compatibility process has a feedback effect on the ES relationship. Compared with the trade-off scenario, compatible synergetic services are more stable with respect to changes in the ES relationship. Constructing ecological buffer zones takes up cultivated land, decreasing the synergy between carbon sequestration services and food production services. However, ecological buffer zones should play a role in certain areas. The compatibility of increased food production services and habitat services in priority conservation and controlled development zones enhance ES trade-offs. An increase in cultural services is compatible with carbon sequestration services in the ecological buffer zone. This changes the relationship between ES, from having a weak trade-off to having a weak synergy. Creating a compatible ES is a spatial trade-off process; these synergies and trade-offs should be considered in spatial planning. An appropriate proportion of ES should be allocated to each zone, to increase the coordinated management of the urban-rural ecology.


Potential effect of physiotherapeutic treatment on mortality rate in patients with severe sepsis and septic shock: a retrospective cohort analysis.
The aim of the study was to examine the onset and frequency of physiotherapeutic interventions (PTI) and their potential effects on the intensive care unit (ICU) mortality rate in patients with severe sepsis or septic shock. Retrospective data analysis. Univariate and multivariate Cox proportional-hazards regression analyses were performed. About 6.2% of all patients (n = 999, length of ICU stay 12 days, averaged SOFA score 14) developed sepsis within three years. Of these, 77% received at least once PTI. The relative number of PTI (RNPTI index, individually calculated by the number of PTI/length of stay) in patients with sepsis was 42%. The first physiotherapeutic treatment was five days after ICU admission. Cox regression multivariate analysis adjusted by disease severity scores, sedation state and other clinical variables found RNPTI index as significant risk factor for the ICU mortality rate (hazard ratio, 0.982; 95% confidence interval, 0.974-0.990; P < .001). Physiotherapists routinely assess and treat patients with sepsis. The frequency of PTI was associated with an improved outcome. Prospective studies are necessary to confirm the potential favorable impact.


Diffusion and perfusion MR imaging of the prostate.
Conventional anatomic MR imaging has evolved to a superior modality in the evaluation of prostate carcinoma and is now a widely established technique in the detection and staging of this disease, aiding in clinical decision making on treatment and therapy evaluation. Recent improvements in functional MR techniques, such as diffusion-weighted MR imaging and dynamic contrast-enhanced MR imaging, have greatly increased the impact of MR imaging in prostate cancer. The combination of T2-weighted imaging, diffusion-weighted MR imaging, and dynamic contrast-enhanced MR imaging may overcome the limitations of conventional T2-weighted MR imaging of the prostate and may be able accurately to detect, localize, stage, and grade prostate carcinoma and guide biopsies.


Single Marker Family-Based Association Analysis Not Conditional on Parental Information.
Family-based association analysis unconditional on parental genotypes models the effects of observed genotypes. This approach has been shown to have greater power than conditional methods. In this chapter, we review popular association analysis methods accounting for familial correlations: the marginal model using generalized estimating equations (GEE), the mixed model with a polygenic random component, and genome-wide association analyses. The marginal approach does not explicitly model familial correlations but uses the information to improve the efficiency of parameter estimates. This model, using GEE, is useful when the correlation structure is not of interest; the correlations are treated as nuisance parameters. In the mixed model, familial correlations are modeled as random effects, e.g., the polygenic inheritance model accounts for correlations originating from shared genomic components within a family. These unconditional methods provide a flexible modeling framework for general pedigree data to accommodate traits with various distributions and many types of covariate effects. Genome-wide association studies usually test more than 10,000 SNPs and thus traditional statistical methods accounting for the familial correlations often suffer from a computational burden. Multiple approaches that have been recently proposed to avoid this computational issue are reviewed. The single-marker analysis procedures are demonstrated using the R package gee and the ASSOC program in the S.A.G.E. package, including how to prepare input data, conduct the analysis, and interpret the output. ASSOC allows models to include random components of additional familial correlations that may be not sufficiently explained by a polygenic effect and addresses nonnormality of response variables by transformation methods. With its ease of use, ASSOC provides a useful tool for association analysis of large pedigree data.


Secondary prevention after acute myocardial infarction and coronary revascularisation: focus on Angiotensin converting enzyme inhibitors.
Cardiovascular disease (CVD) is responsible for an estimated one third of all deaths worldwide. One group of patients who are at a particularly high risk of cardiovascular events and death are those with stable coronary artery disease (CAD), especially if they have had a previous myocardial infarction (MI) or revascularisation. Lifestyle changes (smoking, alcohol intake, diet, exercise) and cardiac rehabilitation play an important part in reducing risk of recurrent events. In patients with a history of MI and/or those who underwent myocardial revascularisation these have to be supplemented with medication. Several pharmacological agents are known to improve prognosis in these patients, i.e. beta-blockers, antiplatelet agents, statins, and angiotensin converting enzyme inhibitors (ACEi). The present article focuses mainly on the role of ACEi in the prevention of cardiovascular events in patients with a history of MI or myocardial revascularization.


Receptors for substance P. III. Classification by competitive antagonists.
A series of ten octa- and five undecapeptide antagonists of SP have been tested in four isolated smooth muscle preparations in order to characterise the receptors mediating the SP-induced contractions of the guinea pig ileum (G.P.I.), the guinea pig trachea (G.P.T.) and the rabbit mesenteric vein (R.M.V.) and the relaxation of the dog carotid artery (D.C.A.). It has been shown that: (a) Indirect effects by substance P and related peptides, mediated by acetylcholine or prostaglandins reduce the affinity of [pro4,trp7,9,10]SP (4-11) (an SP-antagonist) only in the G.P.I. (b) Octapeptide antagonists are specific for SP, have no agonistic activities and exert a competitive antagonism against SP, its homologues and fragments. (c) Undecapeptide antagonists are weaker than the octapeptides in the G.P.I. and G.P.T. and slightly stronger in the D.C.A. and R.M.V. However these compounds still have variable degrees of agonistic activity in some tissues. Affinity of octapeptide antagonists bearing the basic structure [pro4,trp7,9]SP-(4-11) is increased by the additional replacement of Leu10 with trp, Met11 with Leu, Nle or Phe, but it is slightly reduced by substituting Phe8 with Val. Antagonists containing aliphatic residues at the C-terminal end, for instance [pro4,trp7,9,Nle11]SP-(4-11) are more potent than others in the R.M.V., while those with aromatic residues, for instance [pro4,trp7,9,10]SP-(4-11) are weak on the R.M.V. but fairly active on the G.P.T. These antagonists do not show any selectivity on the G.P.I. and the D.C.A. Comparison of antagonists affinities for receptor characterisation suggest the existence of three different functional sites for SP-related peptides. The site of the G.P.I. and D.C.A., which accepts both the antagonists containing aromatic or aliphatic groups at the C-terminal end; the site of the G.P.T. which prefers the aromatic and that of the R.M.V. which shows high affinity for aliphatic residues. The receptor classification emerging from data obtained with antagonists is compared with the classifications of the literature and with those based on the order of potencies of SP homologues and fragments.


Radiological diagnosis of incomplete partition type I versus type II: significance for cochlear implantation.
To investigate an extended cohort of patients with incomplete partition (IP) and examine the adequacy of the existing classifications based on radiological criteria and on their implications for cochlear implantation. Patients with IP admitted to a tertiary referral centre during the period 2000-2010 were retrospectively examined. The subjects were initially classified into IP-I, IP-II and atypical cases. For cochlear implant recipients relevant aspects were analysed. Eighty-three ears (49 patients) with IP were found, 19 with IP-I, 54 with IP-II and 10 atypical. Thirty-three patients received a cochlear implant (11 with IP-I, 19 with IP-II and three atypical) achieving heterogeneous though mostly promising results. Cerebrospinal fluid gushing was the commonest surgical complication, particularly in cases of IP-I. In general, patients with IP-II performed better than those with IP-I. Cochlear implantation promises adequate hearing rehabilitation for most patients with IP. As we move from IP-I to IP-II better results and lower risk for gushing shall be expected. Based on radiological findings we suggest a modified classification into IP-I, atypical IP-I (with large vestibular aqueduct (LVA) and better partition), IP-II (Mondini deformity) and atypical IP-IIa (without LVA) and b (without LVA but with semicircular canal dysplasia). • Radiological (CT and MR) features are of crucial importance for cochlear implantation • Imaging can identify two types of incomplete cochlear partition and atypical cases • Detailed pre-operative radiological assessment can help predict complications and outcome • A more comprehensive radiological classification of these anomalies is proposed.


The regulatory effect of hyaluronan on human mesenchymal stem cells' fate modulates their interaction with cancer cells in vitro.
Metastatic spread of cancer cells into a pre-metastatic niche is highly dependent on a supporting microenvironment. Human bone marrow-derived mesenchymal stem cells (bmMSCs) contribute to the tumor microenvironment and promote cancer metastasis by inducing epithelial-to-mesenchymal transition and immune evasion. The underlying mechanisms, however, are incompletely understood. The glycosaminoglycan hyaluronan (HA) is a central component of the extracellular matrix and has been shown to harbor pro-metastatic properties. In this study we investigated the highly disseminating breast cancer and glioblastoma multiforme cell lines MDA-MB-321 and U87-MG which strongly differ in their metastatic potential to evaluate the impact of HA on tumor promoting features of bmMSC and their interaction with tumor cells. We show that adipogenic differentiation of bmMSC is regulated by the HA-matrix. This study reveals that MDA-MB-231 cells inhibit this process by the induction of HA-synthesis in bmMSCs and thus preserve the pro-tumorigenic properties of bmMSC. Furthermore, we show that adhesion of MDA-MB-231 cells to bmMSC is facilitated by the tumor cell-induced HA-rich matrix and is mediated by the HA-receptor LAYN. We postulate that invasive breast cancer cells modulate the HA-matrix of bmMSC to adapt the pre-metastatic niche. Thus, the HA-matrix provides a potential novel therapeutic target to prevent cancer metastasis.


Is There a Role for Genetics in the Prevention of Sudden Cardiac Death?
The identification of patients at risk for sudden cardiac death (SCD) is fundamental for both acquired cardiovascular diseases (such as coronary artery diseases, CAD) and inherited arrhythmia syndromes (such as the long-QT syndrome, LQTS). Genetics may play a role in both situations, although the potential to exploit this information to reduce the burden of SCD varies among these two groups. Concerning acquired cardiovascular diseases, which affect most of the general population, preliminary data suggest an association between genetics and the risk of dying suddenly. The maximal utility, instead, is reached in inherited arrhythmia syndromes, where the discovery of monogenic diseases such as LQTS tracked the way for the first genotype-phenotype correlations. The aim of this review is to provide a general overview focusing on the current genetic knowledge and on the present and future applicability for prevention in these two populations at risk for SCD.


Re: The safety of oral calcium formate.
A Short Communication was published in the October 2002 issue of the New Zealand Veterinary Journal entitled An investigation of the safety of oral calcium formate in dairy cows using clinical, biochemical and histopathological parameters (McIntyre and Weston 2002). It appeared to be comparing results directly with those of a prior communication (Scott and Van Wijk 2000). The following should be considered when comparing the two papers. Haptoglobins were propounded by McIntyre and Weston as definitive indicators of acute inflammation, yet current literature does not give consistent viewpoints as to their value. The authors cited instances where the haptoglobin concentration was measured in cases of infective disease. However, Skinner et al (1991) believed that haptoglobin concentrations increase as a result of the infection rather than the trauma. To further complicate matters Alsemgeest et al (1994) found that haptoglobin concentrations were elevated in cattle with chronic rather than acute conditions whereas Horadagoda et al (1999) believed the concentrations of acute-phase proteins were higher in acute inflammation. However, they found serum amyloid A was more reliable as an indicator of acute, rather than chronic, inflammation than was haptoglobin. Therefore, histopathology would appear to give much more conclusive evidence of mucosal inflammation than the determination of haptoglobin...


Continuous warfarin versus periprocedural dabigatran to reduce stroke and systemic embolism in patients undergoing catheter ablation for atrial fibrillation or left atrial flutter.
Left atrial catheter ablation for patients with atrial fibrillation (AF) requires periprocedural anticoagulation to minimize thromboembolic complications. High rates of major bleeding complications using dabigatran etexilate for periprocedural anticoagulation have been reported, raising concerns regarding its safety during left atrial catheter ablation. We sought to evaluate the safety and efficacy of a dabigatran use strategy versus warfarin, at a single high-volume AF ablation center. We performed a retrospective analysis on consecutive patients undergoing left atrial ablation at Vanderbilt Medical Center from January 2011 through August 2012 with a minimum follow-up of 3 months. Patient cohorts were divided into two groups, those utilizing dabigatran etexilate pre- and post-ablation and those undergoing ablation on dose-adjusted warfarin, with or without low-molecular-weight heparin bridging. Dabigatran was held 24-30 h pre-procedure and restarted 4-6 h after hemostasis was achieved. We evaluated all thromboembolic and bleeding complications at 3 months post-ablation. A total of 254 patients underwent left atrial catheter ablation for atrial fibrillation or left atrial flutter. Periprocedural anticoagulation utilized dabigatran in 122 patients and warfarin in 135 patients. Three late thromboembolic complications occurred in the dabigatran group (2.5 %), compared with one (0.7 %) in the warfarin group (p = 0.28). The dabigatran group had similar minor bleeding (2.5 vs. 7.4 %, p = 0.07), major bleeding (1.6 vs. 0.7 %, p = 0.51), and composite of bleeding and thromboembolic complications (6.6 vs. 8.9 %, p = 0.49) when compared to warfarin. There were no acute thromboembolic complications in either group (<24 h post-ablation). In patients undergoing left atrial catheter ablation for AF or left atrial flutter, use of periprocedural dabigatran etexilate provides a safe and effective anticoagulation strategy compared to warfarin. A prospective randomized study is warranted.


Arsenite treatment induces oxidative stress, upregulates antioxidant system, and causes phytochelatin synthesis in rice seedlings.
The effects of arsenite treatment on generation of reactive oxygen species, induction of oxidative stress, response of antioxidative system, and synthesis of phytochelatins were investigated in two indica rice (Oryza sativa L.) cvs. Malviya-36 and Pant-12 grown in sand cultures for a period of 5-20 days. Arsenite (As(2)O(3); 25 and 50 μM) treatment resulted in increased formation of superoxide anion (O (2) (.-) ), elevated levels of H(2)O(2) and thiobarbituric acid reactive substances, showing enhanced lipid peroxidation. An enhanced level of ascorbate (AA) and glutathione (GSH) was observed irrespective of the variation in the level of dehydroascorbate (DHA) and oxidized glutathione (GSSG) which in turn influenced redox ratios AA/DHA and GSH/GSSG. With progressive arsenite treatment, synthesis of total acid soluble thiols and phytochelatins (PC) increased in the seedlings. Among antioxidative enzymes, the activities of superoxide dismutase (EC 184.108.40.206), catalase (EC 126.96.36.199), total ascorbate peroxidase (APX, EC 220.127.116.11), chloroplastic ascorbate peroxidase, guaiacol peroxidase (EC 126.96.36.199), monodehydroascorbate reductase (EC 22.214.171.124), and glutathione reductase (EC 184.108.40.206) increased in arsenite treated seedlings, while dehyroascorbate reductase (EC 126.96.36.199) activity declined initially during 5-10 days and increased thereafter. Results suggest that arsenite treatment causes oxidative stress in rice seedlings, increases the levels of many enzymatic and non-enzymatic antioxidants, and induces synthesis of thiols and PCs, which may serve as important components in mitigating arsenite-induced oxidative damage.


Characterization of naturally occurring auxotrophic mammalian cells.
In a previous study, several cultured cell lines were detected which are naturally occurring auxotrophs. In this investigation, the enzyme deficienceis involved are described. It is demonstrated that the Chinese hamster cell lines CHO(K1), YH21, RJK-36, and CHW-1102 are deficient in cystathionase and argininosuccinate synthetase. In addition, CHO (K1) and CHW-1102 were found to lack argininosuccinate lyase. CHW-1102 cells were also found to be unable to proliferate in medium containing branched-chain alpha-keto acids in place of the corresponding L-amino acids since CHW-1102 cells lack branched-chain aminotransferase.


A phase II study of high dose epirubicin in unresectable non small cell lung cancer.
Epirubicin (EPI), a doxorubicin analogue, is reported to have equal antitumour activity with lower cardiac and systemic toxicity. Recently, the maximum tolerated dose of this drug has been revised upwards with reported increased response rates in several malignancies. We initiated a phase II study of high-dose EPI as initial treatment for patients with advanced non-small cell lung cancer (NSCLC) (stage III and IV). Between May 1988 and November 1989, 25 patients were entered. The starting dose of EPI was 135 mg m-2, with dose attenuations and escalations of 15 mg m-2 based on mid-cycle evaluation of toxicity. Treatment was repeated every 3 weeks. Nine partial responses (36%, 95% CI: 18-57.5%) and 11 patients with disease stabilisation (44%) were observed. Median (range) time to progression was 19 (3-70) weeks. Median (range) survival is 32 (9-116+) weeks. There were no treatment related deaths. Major side effects were leukocytopenia WHO grade III/IV (23% of courses) and mucositis WHO grade II/III (15% of courses). In two patients left ventricular ejection fraction decreased greater than 15% compared to baseline values after a cumulative Epirubicin dose of 435 mg m-2, and therefore went off study. In none of the patients clinical signs of congestive heart failure were observed. We conclude from our data that high-dose EPI, contrary to previous negative studies using lower doses of EPI, ranks amongst the most active regimens against advanced NSCLC. Toxicity of high-dose EPI is moderate. Further evaluation of this compound in combination regimens is recommended.


AP-1 transrepressing retinoic acid does not deplete coactivators or AP-1 monomers but may target specific Jun or Fos containing dimers.
Retinoic acid (RA) inhibits tumor promotion in many models in vivo and in vitro, among them mouse epidermal JB6 cells. RA treatment suppresses 12-O-tetradecanoylphorbol-13-acetate (TPA) induced AP-1 activity, an activity that is required for transformation of JB6 P+ cells. The molecular mechanism of AP-1 transrepression by retinoids is unclear, especially as related to inhibition of transformation. Overexpression of AP-1 components did not rescue TPA induced AP-1 activation nor did a GST pull down experiment implicate direct binding, thus rendering unlikely both a Jun/Fos-RA-RAR direct interaction and a Jun/Fos sequestration mechanism. Overexpression of p300, SRC-1 or pCAF did not abrogate AP-1 suppression by RA, thus arguing against coactivator competition. Overexpression of the corepressor silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) suppressed AP-1 activity. However, SMRT but not RA inhibited cJun transactivation, suggesting SMRT does not mediate RA transrepression. RA treatment also did not block TPA induced ERK phosphorylation, Jun/Fos family protein expression except for cFos, or DNA binding of the AP-1 complex. The transcriptional activities of full-length JunB and full-length Fra-1, but not the transactivation domain fusions, were increased by TPA treatment and suppressed by RA. Since these full-length fusions have bzip domains, the results suggest that JunB and/or Fra-1-containing dimers may constitute one target of RA for transrepression of AP-1.


Aspartylglucosaminuria in the United States.
Aspartylglucosaminuria (AGU) was diagnosed in two unrelated males with progressive mental retardation, coarse facies and skeletal abnormalities. Until now, this disorder has been described in predominantly Finnish populations with only one previous case reported in the U.S. We conclude that AGU may be more common in non-Finnish populations than the number of reported cases would indicate and should be included in the differential diagnosis in patients with suspected lysosomal storage disorders regardless of their geographical or ethnic backgrounds.


Dislocation and strain mapping in metamorphic parabolic-graded InGaAs buffers on GaAs.
We investigate different architectures for parabolic-graded InGaAs metamorphic buffers grown on GaAs using transmission electron microscopy techniques. The different architectures include InGaP and AlInGaAs/InGaP superlattices with different GaAs substrate misorientations and the inclusion of a strain balancing layer. Our results correlate: (i) the density and distribution of dislocations in the metamorphic buffer and (ii) the strain in the next layer preceding the metamorphic buffer, which varies for each type of architecture. Our findings indicate that the dislocation density in the lower region of the metamorphic layer ranges between 108 and 1010 cm-2, with AlInGaAs/InGaP superlattice samples exhibiting higher values compared to samples with InGaP films. We have identified two waves of dislocations, with threading dislocations typically located lower in the metamorphic buffer (~ 200-300 nm) in comparison to misfit dislocations. The measured localised strain values are in good agreement with theoretical predications. Overall, our results provide a systematic insight into the strain relaxation across different architectures, highlighting the various approaches that can be used to tailor strain in the active region of a metamorphic laser. The online version contains supplementary material available at 10.1007/s10853-023-08597-y.


[Determination of hepatitis B markers in previously diagnosed hepatitis patients during a one-year period].
In this study, total 1699 sera collected from patients suspected viral hepatitis were investigated by means of Hepatitis B markers by ELISA method between June 1991-June 1992 in Microbiology laboratory of Cumhuriyet University, Faculty of Medicine, Sivas. HBsAg, Anti-HBs and Anti-HBc IgM were screened as Hepatitis B markers. As a result, 16.9% of 1699 patients' sera were positive for HBsAg, 28.9% of 1318 sera were positive for Anti-HBs and 5% of 1056 sera were positive for Anti-HBc IgM. The results were discussed in terms of prevalence of Hepatitis B infection and carrier state.


Is adaptive planning necessary for patients with large tumor position displacements observed on daily image guidance during lung SBRT?
For patients undergoing stereotactic body radiation therapy for lung cancer, their tumor positions may vary due to anatomical changes. This study is to investigate whether adaptive re-planning is necessary for patients with large tumor position displacements observed from daily kV-cone-beam computed tomography (kV-CBCT). We selected 16 fractions from 16 patients with recorded treatment couch shifts greater than 1.5 cm under kV-CBCT guidance. The treatment positions for these patients were manually restored in kV-CBCTs via bone-to-bone alignments (B2B) and tumor-to-tumor alignments (T2T) with corresponding planning CTs. The tumor volumes, including PTVs, ITVs, and GTVs, were transferred from the planning CTs to these kV-CBCTs. With the planned beam configurations and treatment isocenters, kV-CBCTs were imported into the treatment planning system for dose recalculations. To minimize uncertainties of the Hounsfield Unit (HU) in kV-CBCTs, uniformed HU values were assigned to the externals, ITVs, and lungs. The percentage volumes of GTVs, ITVs, and PTVs receiving the prescription dose (VRx) and the dose to the normal structures were analyzed. Seven out of the 16 patients were identified with >5mm tumor position displacements after subtracting the recorded couch shifts from the shifts of B2B alignment. For T2T alignments, 9 out of 16 (56.3%) patients had VRx of PTV <95% (the planning goal) with 91.4% as the lowest, while VRx of the GTV and ITV remained 100% for all 16 patients. For B2B alignments, 14 out of 16 (87.5%) patients have VRx of PTV <95%; 5 patients (31.3%) had VRx of ITV <95%; and 4 patients (25.0%) had VRx of GTV <99%. T2T alignment with 5 mm PTV margin was found superior to B2B alignment, resulting in adequate dose coverage to the ITVs, even for tumors with large positional changes. Adaptive re-planning may not be necessary under these scenarios.


Experience with in-service examinations of pediatric surgical trainees.
A formal examination is an effective device for assessing certain aspects of a resident's competence. Participation by outside examiners is advisable. Generalizations on the basis of 2 yr of experience may be premature, however, the oral examination, strengthened by outside examiners and complemented by a written clinical problem-solving test, has provided insight into the candidates' abilities and into their progress from the first to the second year. In addition, this process has identified strengths and weaknesses in the training program, which has led to modifications of the surgical curriculum. It is concluded that comprehensive oral and written examination of pediatric surgical trainees at the completion of their first year and again at the end of their second year yields information that is of importance to the trainee and to the faculty.


Heterogeneity of foam cell biogenesis across diseases.
Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of infectious and non-infectious origin. For decades, the paradigm underlying foam cell biology has been based on atherogenesis, a disease in which macrophages are cholesterol-enriched. Our previous work showed that foam cells in tuberculous lung lesions surprisingly accumulate triglycerides, suggesting multiple modalities of foam cell biogenesis. In the present study, we used matrix-assisted laser desorption/ionization mass spectrometry imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in murine lungs infected with the fungal pathogen Cryptococcus neoformans and in human papillary renal cell carcinoma resection tissues. We also analyzed neutral lipid content and the transcriptional program of lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data were consistent with in vitro findings showing that C. neoformans-infected macrophages accumulated triglycerides, while macrophages exposed to human renal cell carcinoma-conditioned medium accumulated both triglycerides and cholesterol. Moreover, macrophage transcriptome analyses provided evidence for condition-specific metabolic remodeling. The in vitro data also showed that although both Mycobacterium tuberculosis and C. neoformans infections induced triglyceride accumulation in macrophages, they did so by different molecular mechanisms, as evidenced by different sensitivity of lipid accumulation to the drug rapamycin and the characteristics of macrophage transcriptome remodeling. Collectively, these data demonstrate that the mechanisms of foam cell formation are specific to the disease microenvironment. Since foam cells have been regarded as targets of pharmacological intervention in several diseases, recognizing that their formation is disease-specific opens new research directions of biomedical significance.


Management of pediatric esophageal perforation.
Esophageal perforation is a serious complication necessitating immediate therapy. In a retrospective study we have evaluated the results in 13 children treated for esophageal perforation. Eleven of 13 perforations could be managed conservatively. In one child with extrapleural effusion, tube drainage was performed. The only death in this series occurred in a child who was brought for treatment after a 60-hour delay. Thoracotomy and multiple abscess drainage eventually proved unsuccessful. On the basis of our experience with children with esophageal perforation or with complications after esophageal atresia repair, we conclude that management of esophageal perforation in children differs substantially from therapy in adults and necessitates restrictive treatment guided by clinical symptoms.


Moving Past Burnout, Looking Toward Engagement.
Physician engagement is often discussed in the medical literature; yet health care research examining this construct has been disjointed and plagued by conceptual ambiguities. Examining validated organizational evidence, we offer 3 key antecedents of work engagement that show promise as resources for medical professionals and health care organizations: psychological safety, organizational justice, and job crafting. In addition, we outline the nomological network of related, yet distinct, concepts, to demonstrate the relationship between engagement, burnout, and job satisfaction. As health care organizations facilitate engagement, they provide an additional avenue to decrease physician burnout, while also positively impacting provider and organizational outcomes.


Elevated galectin-3 levels detected in women with hyperglycemia during early and mid-pregnancy antagonizes high glucose - induced trophoblast cells apoptosis via galectin-3/foxc1 pathway.
This study was to evaluate plasma galectin-3 levels from early pregnancy to delivery and explore the effects of galectin-3 on the function of trophoblast cells under high glucose exposure. The plasma galectin-3 levels were quantified by enzyme-linked immunosorbent assay (ELISA) in the China National Birth Cohort (CNBC) at Peking University First Hospital, and the underlying signaling pathway was identified by protein-protein interaction (PPI) analysis, gene set enrichment analysis (GSEA), quantitative PCR (qPCR), western blotting, small interfering RNA (siRNA) transfections, and flow cytometry. Significantly higher galectin-3 levels were found in patients with gestational diabetes mellitus (GDM group; n = 77) during the first and second trimesters than that in healthy pregnant women (HP group; n = 113) (P < 0.05). No significant differences in plasma galectin-3 levels were detected between GDM and HP groups in maternal third-trimester blood and cord blood. PPI analysis suggested potential interactions between galectin-3 and foxc1. The findings of GSEA showed that galectin-3 was involved in the cytochrome P450-related and complement-related pathways, and foxc1 was associated with type I diabetes mellitus. Additionally, high glucose (25 mM) significantly increased the expression levels of galectin-3 and foxc1 and induced apoptosis in HTR-8/SVneo cells. Further in vitro experiments showed that galectin-3/foxc1 pathway could protect HTR-8/SVneo cells against high glucose - induced apoptosis. Future studies were required to validate whether plasma galectin-3 might become a potential biomarker for hyperglycemia during pregnancy. Elevated galectin-3 levels might be a vital protective mechanism among those exposed to hyperglycemia during pregnancy.


A long-term neuropsychological evaluation in Fabry disease.
Fabry disease (FD) is a X-linked multi-systemic metabolic disorder with mainly renal, cardiac and neurological dysfunction. The neuropsychological impact is still unclear, with previous study results ranging from disturbance of speed of information processing and executive functions to a normal cognitive profile. The aim of our study was to gain further insight into the neuropsychological involvement of FD. Patients with genetically proven FD were enrolled at the Ghent University Hospital by their treating neurologist. We evaluated the cognitive status of each patient by a thorough neuropsychological test battery and these exact same neuropsychological assessments were repeated after a follow-up period of 2-4 years and at a second follow-up moment 1-4 years after the first follow-up. Thirteen patients with FD were included (8 female) with mean age of 41.5 years (SD ± 13.9) at baseline. All patients had normal neuropsychological test results on the subtests included in the cognitive battery at baseline, according to age-, gender- and education matched normative data. At the first follow-up moment (2-4 years after baseline), six patients were included (3 male), mean age 45.3 years. At the second follow-up (1-4 years after first follow-up), four patients (2 male) were included, with mean age 45 years. Both at the first and second follow-up moments, all patients obtained normal scores on the subtests. The cognitive functioning appeared to be in the normal range at baseline and did not decline over a follow-up period of 3-8 years, suggesting that cognition in FD patients may be well-preserved in time.


Ampicillin vs. Penicillin for in utero therapy.
The pharmacokinetics of penicillin G and ampicillin are reviewed as they pertain to their potential use in in vitro therapy.


Temporal Outcomes after Rituximab Therapy for Pemphigus Vulgaris.
Pemphigus vulgaris is an autoimmune blistering disease characterized by autoantibodies that target desmoglein adhesion proteins. Rituximab and corticosteroids are Food and Drug Administration‒approved therapies for pemphigus vulgaris. As newer treatments for pemphigus enter clinical trials, analysis of clinical and serologic outcomes after rituximab therapy as a function of time is essential to guide clinical trial design. In this study, we report detailed temporal and serologic outcomes of rituximab treatment of pemphigus vulgaris. The maximal prevalence of complete remission off oral systemic therapy after a single cycle of rituximab was 32.4% at 12 months or 43.1% by 36 months, including additional rituximab cycles. Using receiver operating characteristic curves to develop prediction models for complete remission after a single cycle of rituximab, >90.7% reduction in average desmoglein 3 ELISA titers from baseline to months 3‒9 was 94% sensitive, and an average absolute titer ≤130 RU/ml between months 3 and 9 was 96% specific, for achievement of complete remission off oral systemic therapy. All patients with negative titers at 6‒9 months ultimately achieved complete remission off oral systemic therapy. This dataset of clinical and serologic outcomes for patients with pemphigus vulgaris after rituximab therapy will facilitate clinical trial planning and also guide clinician and patient expectations after rituximab therapy.


Susceptibility to lipid peroxidation and accumulation of fluorescent products with age is greater in T-cells than B-cells.
The age-related loss of immune function, which is primarily due to loss of T-lymphocyte function, is also associated with accumulation in spleen lymphocytes of autofluorescent products indicative of peroxidation damage. In this study, we examined T-cell membranes for age-related changes which could be related to lipid peroxidation. Using fluorescence spectroscopy of CHCl3:CH3OH membrane extracts, we observed that old T-cells have a 2-fold greater accumulation of fluorescent products than old B-cells and that young T-cells, when exposed to free radicals in an in vitro system, accumulate significantly more fluorescent products over time than young B-cells. We used fluorescence polarization to show that young T-cell membranes are more fluid than young B-cell membranes. However, T-cell membrane fluidity decreases with age, whereas B-cell membrane fluidity does not change; in old mice, T-cell membranes are significantly less fluid than old B-cell membranes. Using two-dimensional electrophoresis, we showed that membrane extracts of old T-cells contain many more proteins than extracts of young T-cells. Our results indicate that age-related changes occur in T-cell membranes which could be due to their increased susceptibility to lipid peroxidation and these changes may contribute to the age-related decline in immune function.


Changes in neuron size in cynomolgus macaques infected with various immunodeficiency viruses and poliovirus.
Human immunodeficiency virus (HIV) infection leads to clinically significant neuronal pathology, but the underlying mechanism remains unclear. Infection of rhesus macaques with the simian immunodeficiency virus SIVmac251 has been shown to cause atrophy of hippocampal pyramidal cells. The aim of the current investigation was to determine whether SIVmac251 and other viruses with differing abilities to cause immune suppression or encephalitis could cause neuronal atrophy in cynomolgus macaques. Animals infected with SIVmac251 (n = 22), HIV-2 (n = 6). SIVmac239 (n = 7) and poliovirus (n = 10) were investigated, together with 16 controls. Hippocampal pyramidal cell diameter, averaged across the four CA subfields, was reduced by 16.6% in the SIVmac251 group (P < 0.0001) and by 13.3% in the HIV-2 group (P < 0.001), even though the latter virus does not generally cause immunosuppression. Conversely, SIVmac239, which does cause immunosuppression, caused an average neuronal hypertrophy of 6.8% (P = 0.033). Of possible relevance to the different behaviour of the two SIVs is that SIVmac239 is lymphocyte tropic and does not infect CNS microglia in vivo whereas SIVmac251 does. Animals inoculated with poliovirus into the lumbar spinal cord for polio vaccine neurovirulence testing acted as positive controls for CNS inflammation and they also showed an increase in neuronal diameter (4.1%, P = 0.025). The atrophy seen with SIVmac251 and HIV-2 involved all CA subfields but the hypertrophy following SIVmac239 or poliovirus infection was restricted to CA1 and CA2. These observations show a dissociation between the ability of immunodeficiency viruses to cause immune suppression and neuronal pathology and demonstrate that CNS inflammation per se may cause neuronal hypertrophy.


Deoxycytidine deaminase-resistant stereoisomer is the active form of (+/-)-2',3'-dideoxy-3'-thiacytidine in the inhibition of hepatitis B virus replication.
2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well as human immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant to deoxycytidine deaminase was found to be the more active antiviral stereoisomer than the (+)-form ((+)-SddC). The (+)-SddC is susceptible to deamination by deoxycytidine deaminase and is 25- and 12-fold more toxic than (-)-SddC in CEM cells in terms of anti-cell growth and anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture of their 5-fluoro analogs ((+/-)-FSddC). Unlike 2',3'-dideoxycytidine, which is a potent inhibitor of mitochondrial DNA synthesis and results in such delayed toxicity as peripheral neuropathy with long term usage, (-)-SddC does not affect mitochondrial DNA synthesis. The (-)form is phosphorylated to (-)-SddCMP and is subsequently converted to (-)-SddCDP and (-)-SddCTP. One additional major metabolite which has been tentatively assigned the name "(-)-SddCMP sialate" was also identified. No significant difference in terms of the profiles of the metabolites was found between 4 and 24 h. There is an appreciable amount of (-)-SddCTP detectable 24 h after removal of the drug. (-)-SddCTP was also found to be approximately 3-fold more potent than (+)-SddCTP in inhibiting human hepatitis B virus DNA polymerase. This is the first nucleoside analog with the unnatural sugar configuration demonstrated to have antiviral activity.


Depletion of T cells by type I interferon: differences between young and aged mice.
Type I IFN (IFN-I or IFN-alphabeta) plays an important role in the innate immune response against viral infection. Here we report that a potent inducer of IFN-alphabeta, polyinosinic-polycytidylic acid [poly(I:C)], led to the depletion of T cells in young, but not aged mice, and that this depletion was limited to central memory, but not effector memory, T cells. Although early activation of T cells in vivo by poly(I:C), as demonstrated by CD69, was not impaired with aging, the expression of active caspase-3 was higher in young compared with aged mice. This depletion of T cells and induction of active caspase-3 in young mice and of CD69 in both young and aged mice by poly(I:C) were blocked by anti-IFN-alphabeta Ab. Although poly(I:C) stimulated lower circulating levels of IFN-alphabeta in aged mice, administration of IFN-alphabeta after poly(I:C) did not induce depletion of T cells in aged mice. These results indicate that IFN-alphabeta plays a critical role in the depletion of T cells of young mice, and further suggest that the lower level of functional IFN-alphabeta and decreased induction of active caspase-3 in T cells of aged mice after poly(I:C) may be responsible for the increased resistance of T cells of aged mice to depletion.


NK cell count as predictor of clinical response in patients with rheumatoid arthritis treated with rituximab.
The relationship between antiCD20 therapy with rituximab and the lymphocytes phenotype in patients with rheumatoid arthritis was investigated, with an attempt to establish a relationship between commonly used clinical activity indices and variations in leukocyte count, in particular natural killer (NK) lymphocytes. Patients with seropositive (cyclic citrullinated peptides and rheumatoid factor positive) rheumatoid arthritis (according to the American College of Rheumatology 1987 criteria) refractory to conventional and antitumor necrosis factor-alpha agents who were subsequently treated with rituximab, a chimeric monoclonal antibody directed against CD20, were enrolled between January 2009 and September 2009. All subjects were treated with rituximab standard rheumatologic dose of 1.0 g on days 1 and 15 every 6 months for at least 2 years. A clinical evaluation was performed at baseline and subsequently every 3 months thereafter. At each assessment activated NK (CD56+/CD16+/CD54bright) cell count was collected and disease activity was assessed using Disease Activity Score in 28 Joints and the Simplified Disease Activity Index (SDAI). Thirty-four patients were enrolled (mean age ± standard deviation: 54.8 ± 12.8 years). Basal SDAI was 21.75 ± 5.4 and NK cell count mean value was 157.6 ± 90. After 24 months, SDAI was 14 ± 1.2 and NK cell count mean value was 301.7 ± 21 (P < 0.05). An inverted correlation between SDAI and NK count was observed at 3 months (r = -0.36, P < 0.05), 6 months (r = -0.48, P < 0.45), 9 months (r = -0.47, P < 0.05), 12 months (r = -0.41, P < 0.01), 15 months (r = -0.58, P < 0.05), 18 months (r = -0.53, P < 0.05), 21 months (r = -0.68, P < 0.05), and 24 months (r = -0.61, P < 0.05). A linear regression model between all variables collected and SDAI/Disease Activity Score in 28 Joints at 6 months and 12 months confirmed a significant relationship between SDAI/Disease Activity Score in 28 Joints and NK cell count. The data confirm the clinical efficacy of rituximab and suggests the use of NK cells as a predictor of clinical response in patients with rheumatoid arthritis.


Clinical outcome of left ventricular multipoint pacing versus conventional biventricular pacing in cardiac resynchronization therapy: a systematic review and meta-analysis.
Cardiac resynchronization therapy (CRT) is an effective treatment for selected patients with systolic heart failure. Unlike conventional biventricular pacing (BIP), the left ventricular multipoint pacing (MPP) can increase the number of left ventricular pacing sites via a quadripolar lead positioned in the coronary sinus. This synthetic study was conducted to integratively and quantitatively evaluate the clinical outcome of MPP in comparison with BIP. We systematically searched the databases of EMBASE, Ovid medline, and Cochrane Library through May 2018 for studies comparing the clinical outcome of MPP with BIP in the patients who accepted CRT. Hospitalization for reason of heart failure, left ventricular eject fraction (LVEF), CRT response, all-cause morbidity, and cardiovascular death rate was collected for meta-analysis. A total of 11 studies with 29,606 participants were included in this meta-analysis. Compared with BIP group, MPP decreased heart failure hospitalization (OR, 0.41; 95% CI, 0.33 to 0.50; P < 0.00001), improved LVEF (mean difference, 4.97; 95% CI, 3.11 to 6.83; P < 0.00001), increased CRT response (OR, 3.64; 95% CI, 1.68 to 7.87; P = 0.001), and decreased all-cause morbidity (OR, 0.41; 95% CI, 0.26-0.66; P = 0.0002) and cardiovascular death rate (OR, 0.21; 95% CI, 0.11-0.40; P < 0.00001). The published literature demonstrates that MPP was more effective than BIP in the heart failure patients who accepted cardiac resynchronization therapy.


Feather mites (Acarina) of the parakeet, Melopsittacus undulatus (Shaw) (Aves: Psittacidae).
The parakeet (or budgerigar) has been transported to many regions of the world. Two species of feather mites, Protolichus lunula (Robin) (Pterolichoidea: Pterolichidae) and Dubininia melopsittaci n. sp. (Analgoidea: Xolalgidae), are specific to this host; from distribution records, these ectoparasites probably have been distributed worldwide with their hosts.


Enhancement of membrane fouling mitigation and trace organic compounds removal by electric field in a microfiltration reactor treating secondary effluent of a municipal wastewater treatment plant.
Applying an electric field in the membrane filtration was an effective method to alleviate membrane fouling and enhance the trace organic compounds (TrOCs) removal. The secondary effluent of a municipal wastewater treatment plant was used as feed water to evaluate the performance of the electric field coupled microfiltration system. Applying a 1.25 V voltage reduced 22.9% membrane fouling by electrophoretic force, and the membrane fouling was alleviated by 70.8% at 3 V by electrochemical oxidation and electric field force. At 3 V, active chlorine and hydroperoxide generated on the electrodes and the acidic environment formed around the anode significantly inhibited the growth of microorganisms and their attachment on the membrane surface, and thus reduced the membrane fouling formed by microorganisms. Electrochemical oxidation also removed the protein in wastewater and changed the main organic components of membrane fouling from microorganisms, protein, and polysaccharide to humic substances and polysaccharide. Furthermore, the electrophoretic force and acidic environment reduced the electrostatic repulsion of humic substances and made them tend to aggregate and form hydrophilic porous fouling structures, which obviously lowered filtration resistance and showed significant membrane fouling mitigation. Also, the electric field effectively enhanced the removal of target TrOCs through electrochemical oxidation and electric field force improving the elimination of TrOCs from 8.5% ~ 26.1% at 0 V to 35.9% ~ 84.8% at 3 V.


Use of the signal-averaged electrocardiogram for predicting inducible ventricular tachycardia in patients with unexplained syncope: relation to clinical variables in a multivariate analysis.
The purpose of this study was to determine the predictors of electrically induced ventricular tachycardia in a large sample of patients with unexplained syncope and to examine the value of the signal-averaged electrocardiogram (ECG) in those patient subsets with varying pretest probability of ventricular tachycardia. In patients with unexplained syncope, electrophysiologic study can provide important diagnostic information, such as inducibility of ventricular tachycardia. The signal-averaged ECG can predict inducible ventricular tachycardia, but its utility has not been prospectively studied in a large group of patients with unexplained syncope. At six hospitals, 189 consecutive patients with unexplained syncope underwent signal-averaged ECG and electrophysiologic studies. Ventricular tachycardia was induced in 28 patients (15%). Univariate predictors of ventricular tachycardia included history of previous myocardial infarction, reduced left ventricular ejection fraction and abnormal signal-averaged ECG results. The signal-averaged ECG was the most sensitive test but had poor specificity. By multivariate analysis, the signal-averaged ECG and history of previous myocardial infarction were independently predictive. The risk of ventricular tachycardia increased 17-fold in patients with a previous myocardial infarction who also had an abnormal signal-averaged ECG. In patients with no history of previous myocardial infarction, no additional testing was useful in identifying those at risk for inducible ventricular tachycardia. The signal-averaged ECG was the most sensitive noninvasive test available to predict sustained ventricular tachycardia at electrophysiologic study but was false positive in many patients. A history of previous myocardial infarction followed by the signal-averaged ECG was the most efficient screening process for predicting electrically induced ventricular tachycardia.


Further study of the increased mortality following transurethral prostatectomy: a chart-based analysis.
Previous studies using large administrative databases found an elevated relative risk of reoperation and death after transurethral resection of the prostate compared to open prostatectomy. To investigate whether differences in case-mix unmeasured by administrative data explained this finding, we reviewed the charts of 485 patients who had undergone prostatectomy (236 open and 249 transurethral) at the Health Science Centre, Winnipeg, Manitoba, Canada between 1974 and 1980. Data from patient histories, physical examinations and laboratory evaluations were abstracted and used to control for case-mix in models comparing the rates of reoperation and mortality after transurethral versus open prostatectomy. Several models were specified. In all models the relative risk of dying after transurethral prostatectomy remained elevated (1.36 to 1.89), as did the risk for reoperation (3.62). A prospective trial is needed to establish the relative safety and effectiveness of transurethral and open prostatectomy.


Contagious risk taking: social information and context influence wild jackdaws' responses to novelty and risk.
Although wild animals increasingly encounter human-produced food and objects, it is unknown how they learn to discriminate beneficial from dangerous novelty. Since social learning allows animals to capitalize on the risk-taking of others, and avoid endangering themselves, social learning should be used around novel and unpredictable stimuli. However, it is unclear whether animals use social cues equally around all types of novelty and at all times of year. We assessed whether wild, individually marked jackdaws-a highly neophobic, yet adaptable species-are equally influenced by social cues to consume novel, palatable foods and to approach a startling object. We conducted these tests across two seasons, and found that in both seasons observers were more likely to consume novel foods after seeing a demonstrator do so. In contrast, observers only followed the demonstrator in foraging next to the object during breeding season. Throughout the year more birds were wary of consuming novel foods than wary of approaching the object, potentially leading to jackdaws' greater reliance on social information about food. Jackdaws' dynamic social cue usage demonstrates the importance of context in predicting how social information is used around novelty, and potentially indicates the conditions that facilitate animals' adjustment to anthropogenic disturbance.


DNA cleavage by 7-methylbenzopentathiepin: a simple analog of the antitumor antibiotic varacin.
The compound 7-methylbenzopentathiepin, a simple analog of the benzopentathiepin antitumor antibiotic varacin, was shown to be a potent thiol-dependent DNA-cleaving agent. Biological experiments previously suggested that DNA cleavage might play a role in the cytotoxicity of varacin; however, this is the first direct evidence that benzopentathiepins can cause DNA strand breaks under physiologically relevant conditions.


Design, Synthesis, and Application of a Small Molecular NIR-II Fluorophore with Maximal Emission beyond 1200 nm.
Small molecular fluorophores in the second near-infrared window (NIR-II) have aroused much interest because of their excellent performance. Herein, a new small molecular NIR-II fluorophore, FM1210, with maximal emission beyond 1200 nm is reported. Compared to the corresponding control fluorophore CF1065, FM1210 exhibits an increase of 145 nm in the emission maximum, which is ascribed to the simultaneous introduction of both a Se atom and amino groups into the benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole) skeleton. This large increase in the maximal emission enables FM1210 to be capable of in vivo imaging with lower autofluorescence, higher signal-to-background ratio, and better resolution. Moreover, nanosized FM1210 encapsulated in liposomes possesses passive targeting ability and good water solubility, and is suitable for imaging a tumor and even its vasculature with high signal-to-background ratio.


Cerebral Autosomal Dominant Arteriopathy (CADASIL) with cardiac involvement (ANOCA) and subcortical leukencephalopathy.
We report a rare case of a CADASIL-syndrome with cardiac involvement presenting as ANOCA (angina in the absence of obstructive coronary artery disease). Our case highlights the added value of non-invasive fractional flow reserve (FFR)CT over coronary CT angiography (CTA), and recommends CTA as useful indication in CADASIL patients for screening of occult coronary artery disease (CAD).


Transesophageal echocardiography guided transseptal puncture and nadir temperatures in cryoballoon pulmonary vein isolation.
Cryoballoon (CB) guided pulmonary vein isolation (PVI) is an established procedure in the treatment of atrial fibrillation (AF). Transseptal access is an indispensable step during PVI and may be associated with severe complications. For specific interventions, specific puncture sites of the fossa ovalis are advantageous. Here, we analyzed the potential impact of a transesophageal echocardiography (TOE) guided transseptal puncture on nadir temperatures in CB PVI. We retrospectively analyzed 209 patients undergoing CB PVI in our hospital. The use of TOE had been at the operator's discretion. No TOE-related complications such as perforation of the pharynx or esophagus or loss of teeth were noted. Concerning the applied freezes, we found significantly lower nadir temperatures in all PVs in the TOE group than in the non-TOE group. Procedure time and fluoroscopy time and complications were similar in both groups. TOE-guided TSP in CB PVI is safe and feasible. Our study found significantly lower nadir temperatures of CB freezes after TOE-guided TSP which potentially underscores the value of a more infero-anterior puncture site.


Central respiratory command and microglia: An early-life partnership.
Microglia, brain-resident macrophages, are key players in brain development, regulating synapse density, shaping neural circuits, contributing to plasticity, and maintaining nervous tissue homeostasis. These functions are ensured from early prenatal development until maturity, in normal and pathological states of the central nervous system. Microglia dysfunction can be involved in several neurodevelopmental disorders, some of which are associated with respiratory deficits. Breathing is a rhythmic motor behavior generated and controlled by hindbrain neuronal networks. The operation of the central respiratory command relies on the proper development of these rhythmogenic networks, formation of their appropriate interactions, and their lifelong constant adaptation to physiological needs. This review, focusing exclusively on the perinatal period, outlines recent advances obtained in rodents in determining the roles of microglia in the establishment and functioning of the respiratory networks and their involvement in certain pathologies.


Processing and analysis techniques for brain-stem auditory evoked potentials with localization of brain-stem lesions.
A computer assisted method of exact automatic measurement of BAEPs, mainly for the purpose of localization of brain-stem lesions, is described. The method presents analogue curves with superimposed confidence regions for the amplitudes and peak latencies of separate waves. The numerical output presents peak latencies, amplitudes, interpeak time intervals and central conduction times, all with normative values (60 healthy subjects), and +/- 2 and +/- 3 S.D. intervals and automatic labelling of pathological parameters (outside the chosen statistical limits). With the exception of the identification of separate waves in the often greatly distorted pathological BAEP the whole processing and display of the results are fully automatic.


The first facile optical density-dependent approach for the analysis of doxorubicin, an oncogenic agent accompanied with the co-prescribed drug; paclitaxel.
Doxorubicin (DRB) is an anthracycline oncogenic drug extracted from cultures of Streptomyces peucetius var. caesius. It is frequently recommended as an anti-neoplastic agent for the treatment of diverse malignancies. It exerts its antineoplastic effect either via inhibiting the enzyme topoisomerase II and/or via intercalation to DNA or reactive oxygen species generation. In the present article, the direct, simple, one-pot, somewhat eco-safe, and non-extractive spectrophotometric system was executed to track doxorubicin, a chemotherapeutic remedy, in the presence of paclitaxel, a naturally occurring Taxan antineoplastic radical, through the greenness rated method. DRB's optical density was studied in various mediums and solvents to develop the current approach. An acidic ethanolic solution was found to increase the optical density of the sample significantly. At 480 nm., the most remarkable optical density was obtained. Various experimental factors, including intrinsic media, solvent, pH, and stability time, were investigated and controlled. The current approach achieved linearity within the 0.6-40.0 µg mL-1 range, accompanied by a limit of both detection and quantification (LOD and LOQ) of 0.18 and 0.55 µg mL-1, correspondingly. The approach was validated under the ICH guidelines (Quality Guidelines). The system's greenness and enhancement degree were estimated.


Electrochemically treated glassy carbon electrode for amperometric detection in high-performance liquid chromatography.
The application of an electrochemically pre-treated glassy carbon electrode for the amperometric detection of electroactive components, such as tyrosine and oxipurinol, in biological samples was studied in order to demonstrate the usefulness of a pre-anodized electrode in high-performance liquid chromatography. The electrochemical pre-treatment was carried out in 0.2 M phosphate buffer (potassium dihydrogenphosphate-potassium hydroxide, pH 6.5) at 1900 mV vs. Ag/AgCl for 2 min. The pre-anodized electrode response for the oxidation of lactic acid and pyruvic acid was also studied. The electrochemical treatment enhanced and stabilized the electrode response to the oxidation of tyrosine and both acids.


Recurrent autonomous esophageal peristalsis in patients with chest discomfort.
Routine esophageal manometry revealed a novel pattern of esophageal motility, recurrent autonomous peristalsis, in five patients evaluated for chest discomfort and heartburn. In the absence of swallowing, esophageal peristalsis occurred at frequencies of 4-8 peristaltic sequences per minute for periods of 2-8 min. The recurrent peristaltic sequences developed spontaneously during manometry and were associated with the onset of vague chest discomfort in four patients; one patient reported no symptoms during recurrent peristalsis. Duration and propagation velocity of the recurrent peristaltic contractions differed significantly from primary peristalsis in four patients. Recurrent autonomous esophageal peristalsis is an unusual motor pattern that may be associated with vague chest discomfort. The circuit(s) mediating recurrent autonomous peristalsis are unknown.


Fatal acute alcohol intoxication in an ALDH2 heterozygote: a case report.
On an evening in November, a 25-year-old man was found dead in his bedroom. There were many empty snap-out sheets for flunitrazepam tablets in the trash at his bedside. He had been beaten by a gang of young people earlier in the morning of the same day. At the medico-legal autopsy, although there were many bruises and/or abrasions on the whole body, only slight subdural hemorrhage was observed, and none of them was thought to be the cause of death. Flunitrazepam and its metabolites were not detected in his body fluid by gas chromatography-mass spectrometry (GC-MS). Marked lung edema and a severe congestion of organs were observed. His blood alcohol concentration from the femoral vein was 2.00 mg/ml. Fatal cases of acute alcohol intoxication usually have shown higher alcohol concentration (2.25-6.23 mg/ml). Although the genotype of aldehyde dehydrogenase 2 (ALDH2) has not previously been mentioned as a contributing factor in determining the cause of death, in this case the genotype of ALDH2 was ALDH2*1/2 and thus is important. Those who possess the ALDH2*2 gene show high concentrations of acetaldehyde (AcH) at even comparatively lower alcohol levels. Consequently, the cause of death was considered to be acute alcohol intoxication including AcH poisoning.


The National Landscape of Acute Mastoiditis: Analysis of the Nationwide Readmissions Database.
To determine risk factors for readmission, prolonged length of stay, and discharge to a rehabilitation facility in patients with acute mastoiditis. Trends in treatment and complication rates were also examined. Retrospective cohort study. Nationwide Readmissions Database (2013, 2014). Pediatric and adult patients in the Nationwide Readmissions Database with a primary diagnosis of acute mastoiditis. Medical treatment, surgical intervention. Rates of and risk factors for readmission, prolonged length of stay, and discharge to a rehabilitation facility. Procedure and complication rates were also examined. Four thousand two hundred ninety-five pediatric and adult admissions for acute mastoiditis were analyzed. The overall rates of readmission, prolonged length of stay, and discharge to a rehabilitation facility were 17.0, 10.4, and 10.2%, respectively. Children 4 to 17 years of age had the highest rates of intracranial complications, and children ≤3 years were most likely to undergo operative intervention. Any procedure was performed in 31.2% of cases, and undergoing myringotomy or mastoidectomy was associated with lower rates of readmission but higher rates of prolonged length of stay. Those with intracranial complications and subperiosteal abscesses had the highest surgical intervention rates. Readmission, prolonged length of stay, and discharge to a rehabilitation facility are common in patients with acute mastoiditis with various sociodemographic and disease-related risk factors. While once a primarily surgical disease, a minority of patients in our cohort underwent procedures. Undergoing a surgical procedure was protective against readmission but a risk factor for prolonged length of stay.


11q deletions in human colorectal carcinomas: cytogenetics and restriction fragment length polymorphism analysis.
Deletions and/or allelic losses of a portion of the long arm of chromosome 11 were discovered by cytogenetic and restriction fragment length polymorphism analyses in 23 of 39 (59%) informative cases of colorectal carcinoma. By comparing the patterns of loss of heterozygosity and chromosome rearrangements in different patients, we could map a common target region to 11q22-23. This region may contain a tumor suppressor gene, the inactivation of which may be involved in the development of tumors of the large intestine. The subgroup of malignancies with 11q alterations seemed to be enriched by tumors that were located in the rectum, that were Dukes' stage A, and that were well differentiated and mucin producing.


Successful treatment of primary vaginal diffuse large B-cell lymphoma using chemotherapy.
Non-Hodgkins lymphomas (NHL) rarely affect the vagina. As a result, a standard treatment has not been defined. A 34-year-old female virgin patient with a primary vaginal NHL stage IEA, diffuse large cell B lineage, showed an excellent response to cytotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) without surgery or radiotherapy. She had experienced no recurrence after 40 months. In young patients who wish to preserve their fertility, chemotherapy alone may be the treatment of choice for primary diffuse large B-cell NHL of the lower female genital tract.


Ecology and genomics of Bacillus subtilis.
Bacillus subtilis is a remarkably diverse bacterial species that is capable of growth within many environments. Recent microarray-based comparative genomic analyses have revealed that members of this species also exhibit considerable genomic diversity. The identification of strain-specific genes might explain how B. subtilis has become so broadly adapted. The goal of identifying ecologically adaptive genes could soon be realized with the imminent release of several new B. subtilis genome sequences. As we embark upon this exciting new era of B. subtilis comparative genomics we review what is currently known about the ecology and evolution of this species.


Female factor IX deficiency due to maternally inherited X-inactivation.
X-chromosome inactivation is normally a random event that is regulated by the X chromosome itself. Rarely, females are affected by X-linked disorders from extremely skewed X-chromosome inactivation. Here, we report a family with hemophilia B with female expression through inherited X skewing that appears to be independent of either X chromosome. This finding suggests the possibility of a dominant autosomal contribution to inherited skewed X inactivation.


Wound-inducible potato inhibitor II genes: enhancement of expression by sucrose.
Expression of a chimeric potato Inhibitor II-CAT gene in transgenic tobacco plants was enhanced 50-fold when leaf tissue was floated on solutions containing 1% sucrose. The expression of the chimeric gene was also enhanced when leaf sections were floated on solutions of glucose, fructose, and maltose, but not when floated on solutions of mannitol. The increased expression due to sucrose was found to be correlated with an increase in CAT mRNA. Thus, the carbohydrates or their metabolic products may control Inhibitor II gene expression by regulating transcription. Levels of potato Inhibitor II proteins in leaf sections from young potato plants floated on 3% sucrose solutions increased 3-fold compared to leaf sections floated on water, supporting the possibility that sucrose may have a role in regulating or enhancing the expression of wound-inducible proteinase inhibitor genes in potato tissues. It is suggested that the Inhibitor II gene and perhaps other genes regulated by sucrose may contain a specific 'sucrose enhancer' that strongly increases transcription of genes already active at low levels.


Targeting the middle region of CP4-EPSPS protein for its traceability in highly processed soy-related products.
Transgenic components in genetically modified organisms consist not only of the transgenic genes, but also the transgenic protein. However, compared with transgenic DNA, less attention has been paid to the detection of expressed protein, especially those degraded from genetically modified soybean after food processing. In this study, the full length 5-enolpyruvyl-shikimate-3-phosphate synthase (CP4-EPSPS, 47.6 kD) protein was probed with the SC-16 (S19-R33) and the DC-16 (D219-K233) polyclonal antibodies in immunoblots. Both antibodies were able to detect the full length CP4-EPSPS and its residues in soy powder made from Roundup-Ready soybeans after heating and microwaving treatments which also reduced the molecular weight of the protein to 45.8 and 38.7 kD, respectively. Taken together the immunoblot results suggest that the middle region of the CP4-EPSPS protein possessed better stability than its N-terminal during thermal processing. This deduction was further validated by autoclave treatment, where a 37.4 kD residue of the protein was recognized by DC-16. A similar result was obtained in processed smoked sausage containing Roundup Ready soybean protein isolate (as an extender). The additional use of a further polyclonal antibody CK-17 (C372-K388), showed that compared with only the one signal for CP4-EPSPS detected by the SC-16 and CK-17 antibodies, the DC-16 middle region antibody detected four signals for CP4-EPSPS from five market sourced soy protein concentrates. Taken together, the study suggested that the middle region of CP4-EPSPS was more useful than the N- and C-terminal for tracing transgenic CP4-EPSPS protein and its remnants in highly processed soy-related products.


Urinary tract involvement in a child with epidermolysis bullosa simplex.
Epidermolysis bullosa is a rare disorder which may present various systemic involvement. We present a 15-month-old boy with epidermolysis bullosa simplex who was admitted with symptoms of hematuria and dysuria and discuss the pathology from a urological standpoint.


Donor-site necrosis following fibula free-flap transplantation: a report of three cases.
The free fibula flap is the microsurgeon's workhorse for the reconstruction of osseous or osteocutaneous defects. Donor-site morbidity of this flap is reported to occur infrequently, and is generally considered minor and transient. We present the case histories of three patients with necrosis at the fibula flap donor site to stress the risks and explain the possible mechanisms of such severe complications. The small risk of debilitating donor-site necrosis should be considered and discussed preoperatively with the patient.


Carbamazepine induces upward frequency shifts of spontaneous otoacoustic emissions.
In three subjects, we measured spontaneous otoacoustic emissions (SOAEs) when they were using carbamazepine (CBZ), and compared this to the SOAE measurement when they were not using CBZ. We observed 14 SOAEs showing a consistent upward shift of center frequency, related to CBZ intake. On average, the magnitude of the frequency shift increased with increasing frequency. The magnitude of the shift was 30-104 Hz, at frequencies ranging from 1.3 to 2.3 kHz, corresponding to a shift between 2.3 and 4.5%. Compared to other causes and manipulations known to change SOAE frequency, these shifts are relatively large. The underlying mechanism is most likely an increased stiffness of the cochlear partition. This would also explain the downward pitch shift due to CBZ, which has been reported by subjects with absolute pitch.