Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas.
We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first glioblastoma showed loss of the MSH6 wild-type allele, and the second glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary glioblastomas.


[Pulmonary ultrasound in the intensive care unit].
Pulmonary ultrasonography (PUSG) is a new diagnostic tool for pleuropulmonary disease in the critically ill patient. Images obtained in this study result from the interaction between the ultrasound shaft with the pleura, the pulmonary parenchyma and the air/liquid interface. These images are classified as horizontal and vertical. Their correct identification and interpretation requires a learning curve. Currently, PUSG is an excellent alternative to evaluate pulmonary condition of hospitalized patients in the intensive care unit (ICU). Sensitivity and specificity are high for pneumothorax, alveolar-interstitial syndrome and pleural effusion diagnosis. PUSG practiced in the ICU is one of the most promising diagnostic procedures in intensive care medicine, and the practice and indications of this tool will surely extend in the coming years. The objective of this study is to make known the general principles of PUSG and their use in the critically ill patient, based on cases of hospitalized patients in the ICU of the Medica Sur Clinical Foundation that were studied with PUSG.


[Postnatal variations in the electrophysiological characteristics of the mouse heart].
Electrocardiograms were recorded in 13 mice, from birth up to 57 days of age; during this period the heart rate, at rest, showed a marked increase (from 310 to 797 beats/min), occurring in two waves. Recordings of the intracellular electrical activity in the atria disclosed a different temperature dependence of the resting membrane potential, action potential duration and Vmax in the neonatal mouse as compared with the adult one. The results are consistent with the suggestion that a decrease of the 'slow inward' conductance/K+ outward conductance ratio still occurs during a postnatal period.


The effects of fish oil omega-3 fatty acid supplementation on mental health parameters and metabolic status of patients with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.
This study was conducted to evaluate the effects of fish oil omega-3 fatty acid supplementation on mental health parameters and metabolic status of women with polycystic ovary syndrome (PCOS). This randomized double-blind, placebo-controlled trial was conducted on 60 women with PCOS, aged 18-40 years old. Participants were randomly assigned into two groups to receive either 2 × 1000 mg/day fish oil omega-3 fatty acid (n = 30) or placebo (n = 30) after lunch for 12 weeks. Metabolic profiles were quantified at baseline and after the 12-week intervention. Compared with the placebo, omega-3 fatty acid intake led to a significant improvement in Beck Depression Inventory [β (difference in the mean outcomes measures between treatment groups after intervention) -1.05; 95% CI: -1.84, -0.26; p = .01], general health questionnaire (β -1.68; 95% CI: -3.12, -0.24; p = .02) and depression anxiety and stress scale (β -2.03; 95% CI: -3.60, -0.46; p = .01). Omega-3 fatty acid supplementation significantly decreased serum insulin levels (β -2.09 µIU/mL; 95% CI: -3.77, -0.41; p = .01), homeostasis model of assessment-insulin resistance (β -0.74; 95% CI: -1.13, -0.34; p < .001), total testosterone (β -0.23 ng/mL; 95% CI: -0.39, -0.06; p = .03) and hirsutism (β -0.75; 95% CI: -1.17, -0.33; p = .001), and significantly increased the quantitative insulin sensitivity check index (β 0.01; 95% CI: 0.003, 0.02; p = .008) compared with the placebo. Additionally, omega-3 fatty acid intake resulted in a significant decrease in high sensitivity C-reactive protein (β -1.46 mg/L; 95% CI: -2.16, -0.75; p < .001) and malondialdehyde (β -0.28 µmol/L; 95% CI: -0.52, -0.05; p = .03); also significant rises in plasma total glutathione (β 59.09 µmol/L; 95% CI: 7.07, 111.11; p = .02) was observed compared with the placebo. Omega-3 fatty acid supplementation did not change other metabolic parameters. Overall, omega-3 fatty acid supplementation for 12 weeks to patients with PCOS had beneficial effects on mental health parameters, insulin metabolism, total testosterone, hirsutism and few inflammatory markers and oxidative stress.


A Simulation Case Study of Knee Joint Compressive Stress during the Stance Phase in Severe Knee Osteoarthritis Using Finite Element Method.
Background and Objectives: Medial knee osteoarthritis is known to increase the mechanical load on the medial compartment of the knee joint during walking; however, it is not visually understood how much the mechanical load increases nor where in the medial compartment of the knee joint that load is focused. Therefore, we conducted a simulation study to determine the location and amount of the mechanical load in the medial compartment of the knee joint during the stance phase. Materials and Methods: Subject was a patient with right medial knee osteoarthritis. Computed tomography imaging and gait analysis were performed on subject. The CT image of the right knee was calculated using finite element analysis software. Since this software can set the flexion angle arbitrarily while maintaining the nonuniform material properties of the bone region, the model is constructed by matching the knee joint extension image obtained by CT to the loading response phase of gait analysis. The data of muscle exertion tension and vertical ground reaction force were inserted into the knee joint model created from the computed tomography-based finite element method, and the knee joint compressive stress was calculated. Results: With regard to compressive stress, the tibia showed high stress at 4.10 to 5.36 N/mm2. The femur showed high stress at 4.00 to 6.48 N/mm2. The joint compressive stress on the medial compartment of the knee joint was found to concentrate on the edge of the medial tibial condyle in the medial knee osteoarthritis subject. Conclusions: The measurement method of knee joint compressive stress by computed tomography-based finite element method can visually be a reliable method of measuring joint compressive stress in the medial knee osteoarthritis. This reflects the clinical findings because concentration of stress on the medial knee joint was observed at the medial osteophyte.


MALDI-ToF MS analysis of glycosyltransferase activities on gold surface arrays.
Glycan-processing enzymes such as glycosyltransferases and glycosidases are responsible for the makeup of the glycome. The definition of their substrate specificities is, therefore, a central task in glycomics. In addition, these enzymes are themselves useful synthetic tools for the generation of complex carbohydrate structures as an alternative to tedious chemical synthesis. There has been great interest in using microarrays for studying these glycoenzymes because it allows the specificity of the enzyme to be probed against a panel of immobilized potential substrates, and also expands the repertoire of sugar arrays available for further carbohydrate-protein interaction studies. In particular, self-assembled monolayers (SAMs) of alkanethiols on gold surfaces have proven to be a valuable platform for such studies due to their robustness and their biocompatible, well-defined structure. Furthermore, a direct observation of the change in mass of immobilized substrates due to enzymatic processing is possible through label-free MALDI-ToF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) technique. In this chapter, we describe the preparation of SAMs-coated gold surface arrays presenting carbohydrate or (glyco)peptide substrates, either pre-formed or directly synthesized on-chip, and MALDI-ToF MS analysis of glycosyltransferase activities on these immobilized substrates.


Chondroblastoma of the calcaneus: radiographic features with emphasis on location.
Fourteen cases of chondroblastoma of the calcaneus have been examined and the radiographic features described. Thirteen occured in males. In all but one case the location was either at the talocalcaneal articulation or adjacent to the posterior calcaneal cortex. A sclerotic margin was present in all instances. Occasionally calcifications and septations were seen.


High-resolution eye-tracking via digital imaging of Purkinje reflections.
Reliably measuring eye movements and determining where the observer looks are fundamental needs in vision science. A classical approach to achieve high-resolution oculomotor measurements is the so-called dual Purkinje image (DPI) method, a technique that relies on the relative motion of the reflections generated by two distinct surfaces in the eye, the cornea and the back of the lens. This technique has been traditionally implemented in fragile and difficult to operate analog devices, which have remained exclusive use of specialized oculomotor laboratories. Here we describe progress on the development of a digital DPI, a system that builds on recent advances in digital imaging to enable fast, highly precise eye-tracking without the complications of previous analog devices. This system integrates an optical setup with no moving components with a digital imaging module and dedicated software on a fast processing unit. Data from both artificial and human eyes demonstrate subarcminute resolution at 1 kHz. Furthermore, when coupled with previously developed gaze-contingent calibration methods, this system enables localization of the line of sight within a few arcminutes.


Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species.
The prairie vole (Microtus ochrogaster) is a socially monogamous rodent species that forms pair bonds after mating, a behavior in which central dopamine (DA) has been implicated. Here, we used male prairie voles to examine the effects of drug exposure on pair bonding and related neural circuitry. In our first experiment, amphetamine (AMPH) motivated behavior was examined using a conditioned place preference (CPP) paradigm and was shown to be mediated by activation of D1-like DA receptors. Next, we examined the effects of repeated AMPH exposure on pair bonding. Intact and saline pretreated control males displayed mating-induced partner preferences, whereas males pretreated with AMPH at the doses effective to induce CPP failed to show mating-induced partner preferences. Such AMPH treatment also enhanced D1, but not D2, DA receptor expression in the nucleus accumbens (NAcc). Furthermore, pharmacological blockade of D1-like DA receptors in the NAcc rescued mating-induced partner preferences in AMPH-treated males. Together, our data indicate that repeated AMPH exposure may narrow the behavioral repertoire of male prairie voles via a DA receptor-specific mechanism in the NAcc, resulting in the impairment of pair bond formation.


Sex and the older man--GP perceptions and management.
Despite the links between aging and sexual dysfunction, the majority of adults continue to be sexually active well into their later years. Conditions such as erectile dysfunction however, present one of many obstacles to maintaining a healthy sex life. Given the sensitive nature of sexual difficulties, many men are reluctant to seek medical advice. It is therefore essential that general practitioners are equipped to discuss and provide unbiased advice and treatment for men of all ages. This article reviews current knowledge regarding GP approaches to sexuality and the older man. Findings suggest that broader cultural beliefs about age appropriate sexuality are evident in general practice. Asking about sexual health remains a low priority for many GPs, particularly when it comes to older patients. Further education is needed to raise professional awareness about the importance of healthy sexuality in aging.


Infantile, Childhood, and Adolescent Epilepsies.
Infantile, childhood, and adolescent epilepsies comprise a diverse group of entities. Careful characterization of epilepsy into a specific electroclinical syndrome or etiology assists greatly in understanding both the natural history of the seizure disorder (pharmacoresistant versus pharmacoresponsive and self-limited versus lifelong) and the best therapeutic options for the child. Tremendous growth has been seen in the understanding of both genetic factors predisposing to epilepsy and neuroimaging techniques. Additionally, a number of studies have focused on the efficacy of certain therapies in specific syndromes or etiologies. This article reviews both common epilepsy syndromes (including benign focal epilepsy of childhood, absence epilepsy, and juvenile myoclonic epilepsy) and the rarer syndromes with associated management implications (eg, Dravet syndrome, progressive myoclonic epilepsy, and mitochondrial disorders) and addresses genetic and metabolic investigations.


[Osteopenia and osteoporosis in diabetic women over 40 years of age].
The aim of this study was to find the prevalence of osteopenia and osteoporosis in postmenopausal diabetic females and its association with the diabetic compensation and angiopathic complications. Bone mineral density was measured in 156 diabetic females, 44 of them had type 1 diabetes mellitus (mean age 53 +/- 8.9 years) and 112 type 2 (mean age 60 +/- 9.2 years). In the lumbar spine and proximal femur the prevalence of osteoporosis varied between 9-11% and 18-20% respectively. The respective prevalence of osteopenia amounted 30-36% and 34-48%. No statistically significant differences were found between type 1 and type 2 diabetes. Any association with diabetic compensation and the diabetic microangiopathic complications was not found. Only in females with osteoporosis the prevalence of cardiovascular heart disease was higher than in those with normal bone mineral density. The prevalence of osteoporosis and osteopenia in postmenopausal diabetic women is similar to those in the common population of the respective age.


Non-polar compounds of Persian Gulf sea cucumber Holothuria parva selectively induce toxicity on skin mitochondria isolated from animal model of melanoma.
Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melanoma. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling. In the present study, selective toxicity and apoptotic effect of three extracts of H. parva were assessed on skin mitochondria isolated from mouse animal models of melanoma. The mitochondria was isolated from melanoma cells via differential centrifuges and treated with various concentrations (250, 500 and 1000 µg/ml) of metanolic, diethyl ether and n-hexane extracts of H. parva. All the applied concentrations (250, 500 and 1000 µg/ml) of three extracts of H. parva increased the reactive oxygen species (ROS) generation only in the skin mitochondria isolated from melanoma cells group (in comparison to the control group). Additionally, all three extracts (250, 500 and 1000 µg/ml) induced swelling within the mitochondria, the collapse of the mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria. Flow-cytometry analysis demonstrated that n-hexane and diethyl ether extracts of H. parva selectively and progressively induced apoptosis only on melanoma but not healthy control skin cells group. Given these results, the potentially bioactive compounds found in H. parva render it a strong candidate for further research in molecular identification and confirmatory in vivo studies. Clinical trials are also warranted in the general process of novel drug discovery for the treatment of melanoma cancer.


Simultaneous determination of phenolic xenoestrogens by solid-phase extraction and high-performance liquid chromatography with fluorescence detection.
A highly sensitive and selective method for simultaneous determination of some hydroxyl group-containing endocrine disruptors, including bisphenol A (BPA), bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF) and 4-nonylphenol (4-NP), was developed. The method consists of precolumn derivatization of the analytes, solid-phase extraction (SPE) and subsequent chromatographic analysis by high-performance liquid chromatography (HPLC) with fluorescence detection. 4,4'-Cyclohexylidenebisphenol (BPZ) was used as an internal standard. Derivatization was carried out using 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoyl chloride (DIB-Cl) as a label. Parameters of the derivatization reaction (temperature, time, concentration of reagent, stability, etc.) and of the solid-phase extraction (recovery, solvent, etc.) were studied in detail. Detection limits of compounds studied in standard solutions ranged from 0.08-1.3 ppb (ng/ml). The proposed method was successfully applied to plastic samples; BPA was found in both polycarbonate and polyvinyl chloride plastics, while 4-NP was found in plastics made of polyvinyl chloride and another polymer.


Forced ammonia stripping from livestock wastewater: the influence of some physico-chemical parameters of the wastewater.
In highly alkaline aqueous solutions (pH >10), the main form of dissolved ammoniacal nitrogen is the unionized free ammonia. Free ammonia, being a gaseous molecule, is easily stripped out from the solution. Increasing wastewater pH is frequently used to force ammonia removal. Herein, the effect of the variation of some physico-chemical characteristics of liquid cattle wastewater on ammonia stripping was investigated. The results show that at pH 11.5, ammonia volatilization and consequently its removal through stripping, was not affected by the variation of total solids (1-10%), alkalinity (2,500-20,000 mg/L as CaCO3) and electrical conductivity (20-50 mS/cm), or by the alkali type (NaOH, KOH and Ca(OH)2) employed to increase pH. The only parameter which affected ammonia stripping rate was the variation of the concentration of bedding material (straw 0.5-5%). The results suggest that the process of forcing ammonia stripping rate at high pH is unaffected and is not limited by the variation of any of the investigated parameters, except bedding material. The parameter kOLa (1/min) of the mass transfer model of ammonia stripping regarding the control experiments (raw wastewater without increasing pH) was ca. 0.0002, while by increasing pH it increased more than 20-fold (0.004 to 0.0045).


Gliogenesis in the central nervous system.
Multipotential neuroepithelial stem cells are thought to give rise to all the differentiated cells of the central nervous system (CNS). The developmental potential of these multipotent stem cells becomes more restricted as they differentiate into progressively more committed cells and ultimately into mature neurons and glia. In studying gliogenesis, the optic nerve and spinal cord have become invaluable models and the progressive stages of differentiation are being clarified. Multiple classes of glial precursors termed glial restricted precursors (GRP), oligospheres, oligodendrocyte-type2 astrocyte (O-2A) and astrocyte precursor cells (APC) have been identified. Similar classes of precursor cells can be isolated from human neural stem cell cultures and from embryonic stem (ES) cell cultures providing a non-fetal source of such cells. In this review, we discuss gliogenesis, glial stem cells, putative relationships of these cells to each other, factors implicated in gliogenesis, and therapeutic applications of glial precursors.


Downregulation of mitogen-activated protein kinase 1 of Leishmania donovani field isolates is associated with antimony resistance.
Emergence of resistance to pentavalent antimonials has become a severe obstacle in the treatment of visceral leishmaniasis (VL) on the Indian subcontinent. The mechanisms operating in laboratory-generated strains are somewhat known, but the determinants of clinical antimony resistance are not well understood. By utilizing a DNA microarray expression profiling approach, we identified a gene encoding mitogen-activated protein kinase 1 (MAPK1) for the kinetoplast protozoan Leishmania donovani (LdMAPK1) that was consistently downregulated in antimony-resistant field isolates. The expression level of the gene was validated by real-time PCR. Furthermore, decreased expression of LdMAPK1 was also confirmed at the protein level in resistant isolates. Primary structure analysis of LdMAPK1 revealed the presence of all of the characteristic features of MAPK1. When expressed in Escherichia coli, the recombinant enzyme showed kinase activity with myelin basic protein as the substrate and was inhibited by staurosporine. Interestingly, overexpression of this gene in a drug-sensitive laboratory strain and a resistant field isolate resulted in increased the sensitivity of the transfectants to potassium antimony tartrate, suggesting that it has a role in antimony resistance. Our results demonstrate that downregulation of LdMAPK1 may be in part correlated with antimony drug resistance in Indian VL isolates.


Protective effect of Gelofusine against cRGD-siRNA-induced nephrotoxicity in mice.
Based on successful targeting to the αvβ3 integrin of cyclic arginine-glycine-aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin-eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage.


Fatigue, Stress Appraisal, and Emotional Functioning Among Youth With Sickle Cell Disease: A Daily Diary Study.
The aim of this study was to assess how fatigue is related to mood among youth with sickle cell disease (SCD) by evaluating if the cognitive appraisal of stress moderates the impact of fatigue on emotional functioning consistent with the Risk-and-Resistance Model of Chronic Illness. Daily diaries assessing fatigue (Numerical Rating Scale), pain intensity (Numerical Rating Scale), mood (Positive and Negative Affect Schedule for Children), and cognitive appraisal of stress (Stress Appraisal Measure for Adolescents) were collected from 25 youth with SCD (ages 11-18 years) for 8 consecutive weeks resulting in 644 daily diaries for analyses. When measured concurrently, higher fatigue was associated with higher negative mood controlling for pain and prior-night sleep quality. Fatigue predicted next-day negative mood through its interaction with primary and secondary appraisal of stress, consistent with stress appraisal as a protective factor. A similar pattern was observed for pain, which, like fatigue, is a common SCD-related stressor. Fatigue and negative mood are inter-related when concurrently assessed, but their temporal association in SCD suggests that mood changes are not an inevitable sequalae of increased fatigue; fatigue influenced subsequent levels of negative mood, but only in the presence of less adaptive cognitions about stress; specifically, a higher perceived threat from stress and a lower belief in the ability to manage stress. The results suggest specific cognitive targets for reducing the negative impact of fatigue on mood in SCD.


Species differences of inhibitory effects on P-glycoprotein-mediated drug transport.
Previously, we clarified the species differences in P-glycoprotein (P-gp)-mediated drug transport activity using human MDR1, monkey MDR1, canine MDR1, rat MDR1a, rat MDR1b, mouse mdr1a, and mouse mdr1b transfected LLC-PK(1) cell lines. However, the species differences in the inhibitory effects on P-gp-mediated drug transport have not been clarified yet. The purpose of the present study was to evaluate the species differences in the inhibitory effects of typical P-gp inhibitors, quinidine and verapamil, on P-gp-mediated drug transport using MDR1 transfected cell lines. The transcellular transport of [(3)H]daunorubicin, [(3)H]digoxin, and [mebmt-beta-(3)H]cyclosporin A across monolayers of the MDR1 transfected cells were measured in the presence or absence of P-gp inhibitors. On daunorubicin transport, the relative IC(50) value (quinidine IC(50)/verapamil IC(50)) of human P-gp was 5.25 and those from other species ranged from 0.89 to 10.70. The transport of digoxin and cyclosporin A also showed different relative IC(50) values among human, monkey, canine, rat, and mouse P-gps. The present study revealed that species differences in the inhibitory effects on P-gp-mediated drug transport should not be disregarded among human, monkey, canine, rat, and mouse. This study will provide useful information for predicting drug interactions mediated by P-gp.


Trypanosoma cruzi: data supporting clonality in Mexican stocks.
To further study genetic heterogeneity of Mexican stocks of Trypanosoma cruzi, genomic Southern analyses from 54 Mexican isolates and 5 South American reference stocks were carried out. The membranes were hybridized with a homologous cDNA clone from the ribosomal protein S4 that identifies allelic bands from a single gene type locus. These allelic bands were sequentially numbered depending on their relative size. Mexican T. cruzi stocks were quite homogeneous: 31 cases (57%) showed a homozygous genotype 3/3, and 21 isolates (38%) exhibited the heterozygote genotype 2/3. Just 2 Mexican stocks (3%) showed a different genotype 2/5, but the potential parental homozygous 2/2 was never observed. Being that T. cruzi is a diploid organism, the apparent absence of the presumptive parental homozygous genotype 2/2 argues against sexual reproduction within the population, at least as a common event. Therefore, these data support a clonal population structure of T. cruzi in Mexico.


The Use of Intracardiac Echocardiography in Transjugular Intrahepatic Portosystemic Shunt Procedure.
Transjugular intrahepatic portosystemic shunt (TIPS) is a complex intervention with a steep learning curve that requires centers of expertise to improve technical success and reduce complications. Portal venous access is the most challenging step of the procedure and requires planning and image guidance strategies to prevent vascular or bile duct injury and further complications. Intracardiac echocardiography (ICE) has been reported to be a safe and accurate tool that provides images of the portal vein anatomy in real time. The use of ICE has become the standard of care in several centers. It is now frequently used to target the portal vein in complex TIPS procedures. This review article describes some technical aspects and indications of ICE-guided TIPS.


Stereoselective synthesis of organosulfur compounds incorporating N-aromatic heterocyclic motifs and quaternary carbon centers via a sulfa-Michael triggered tandem reaction.
A novel sulfa-Michael addition (SMA)-triggered tandem reaction was developed by combining a SMA reaction with a simultaneous rearomatization process utilizing a less reactive carbonyl group as an intramolecular electrophile partner, which provided a unique synthetic route to access various organosulfur compounds incorporating an N-aromatic heterocyclic motif and quaternary carbon centers.


A novel octanuclear nickel(II)-molybdenum(VI) heterometallic cluster based on the salicylhydroxamate ligand.
Salicylhydroxamic acid (H3shi) is known for its strong coordination ability and multiple coordination modes, and can easily coordinate to metal cations to form compounds with five- or six-membered rings, as well as mono-, di- and multinuclear compounds with interesting structures having potential applications in organic chemistry, coordination chemistry, and the materials and biological sciences. A novel octanuclear nickel(II)-molybdenum(VI) heterometallic cluster based on the salicylhydroxamate ligand, namely di-μ3-acetato-di-μ2-acetato-di-μ3-hydroxido-di-μ3-oxido-tetraoxidooctakis(pyridine-κN)bis(μ5-salicylhydroxamato)hexanickel(II)dimolybdenum(VI) monohydrate, [Mo2Ni6(C7H4NO3)2(C2H3O2)4O5(OH)2(C5H5N)8]·H2O, (I), was synthesized by the reaction of sodium molybdate, nickel acetate and salicylhydroxamic acid in a dimethylformamide/pyridine/methanol solution at room temperature. The salicylhydroxamate(3-) (shi(3-)), acetate and oxide ligands adopt complicated coordination modes and link six Ni(II) and two Mo(VI) cations into the octanuclear heterometallic cluster. All of the metal cations exhibit octahedral coordination geometries and are connected to each other through the sharing of corners, edges or planes. The heterometallic clusters are further connected to form two-dimensional supramolecular layers through weak C-H...O hydrogen bonds. Studies of the magnetic properties of the title compound reveal antiferromagnetic interactions between the Ni(II) cations.


BACing up the interferon-gamma locus.
In this issue of Immunity, Hatton et al. (2006) identify evolutionarily conserved noncoding sequences (CNSs) upstream of the interferon-gamma gene, then show by using a BAC transgene reporter that CNS-22 is a key regulator of interferon-gamma expression.


[Hemolytic anemia associated with breast neoplasm].
We describe a patient with a microangiopathic hemolytic anemia, associated with thrombocytopenia, in consequence of breast cancer in an advanced phase. Microangiopathic hemolytic anemia is a rare and serious compliance of malignant neoplasms, in particular of breast and gastric carcinomas. Microangiopathic hemolytic anemia has always a serious prognosis: survivance in non-treated patients is of a few weeks. Our patient, treated by chemotherapy, has gained a partial remission of MHA, with a reduction of blood transfusions.


[Improve the understanding of hepatic disease related pulmonary vascular disease].
Hepatic disease-related pulmonary vascular disease refers to the changes in the structure or function of pulmonary circulation caused by liver parenchymal or hepatic vascular diseases, mainly including hepatopulmonary syndrome characterized by hypoxemia, portopulmonary hypertension characterized by pulmonary hypertension, and hepatic vascular shunt characterized by increased cardiac output and pulmonary hypertension. Early diagnosis and treatment of liver disease and early evaluation of liver transplantation may significantly improve the prognosis for patients with hepatic disease-related pulmonary vascular disease. Moreover, it is necessary to improve clinicians' understanding of this disease and strengthen multidisciplinary cooperation, improve the level of diagnosis and treatment.


EBRA migration patterns of the Plasmacup with ceramic or polyethylene inserts: a randomised study.
In this prospective randomised study, the influence of different bearing materials on migration and wear was measured and their effect on the function of the artificial joint and the patient outcome was investigated. Mid-term results were recorded so that recommendations can be made on the use of certain bearings, which minimise wear and thus the danger of subsequent aseptic loosening. Sixty-six patients met the inclusion criteria and were willing to take part in the study. These patients were randomised to 2 groups. All of them had total hip arthroplasty with implantation of a cementless Bicontact stem and Plasmacup using a cementless press-fit technique. Thirty-five of these patients were given a ceramic-ceramic bearing and 31 patients a ceramic-polyethylene bearing (gamma sterilised/nitrogen environment). At the most recent follow-up, they underwent detailed clinical and radiological examination and evaluation by means of the Harris Hip Score, Hannover function questionnaire and single-film X-ray analysis (EBRA). The overall follow-up rate was 65.2 % (43 of 66) and the mean follow-up period was 8.1 (7.1 - 9.2) years. The median Harris Hip Score at the time of follow-up was 90.1 (58.7 - 99.9) points. The average Hannover function score was 87.14 % (63.9 - 100). In 4 of 66 cases (6.1 %) there was a tendency for the Plasmacup to subsidence in the first postoperative months that was slight but detectable by EBRA; however, this stopped subsequently. This primary subsidence was independent of the chosen bearing material. No significant difference in the clinical and radiological parameters was found between the two groups. The very good results with regard to the rate of loosening confirm the press-fit cup fixation concept. The study shows a similar medium-term result for the ceramic-ceramic and ceramic-polyethylene bearing so that use of both bearings can continue to be recommended. Only long-term studies with sufficiently large numbers of patients will be able to show whether significant differences can be detected between the two slide bearings with regard to wear and migration behaviour and so that a recommendation can be given to the surgeon.


rbcL gene in global molecular data repository.
The ribulose-bisphosphate carboxylase (rbcL) gene sequence data in the molecular data repository has been increasing significantly, over the years with contributions from different parts of the world. The abundance of the gene has enhanced its applications in several ways. Bulk records were obtained from National Center for Biotechnology Information (NCBI) GenBank database using the entrez efetch utility as implemented in the Biopython package version 1.77. Records corresponding to the following keywords "rbcL AND plants [filter] AND biomol_genomic [PROP] AND is _nuccore [filter]" were created. Generated records were cleaned and then further analysed using the code file in the supplementary materials. Country information was obtained by searching reference information for matches to countries present in the pycountry package. Where no match was found, null was returned. This data article contains information about the plant family and species whose rbcL gene sequence has been deposited on the NCBI and regions of the world that has contributed to the rbcL repository growth. This data can be used to analyse the intra and inter family relatedness of plant and compare with existing relationships the molecular characterization of plants, evolutionary relationship studies, inferring biogeography origin of plant.


Giant polypoid tumor expressing on the pyloric ring.
A 66-year-old Japanese man was referred to our hospital because of suspected duodenal cancer. Upper gastric endoscopy revealed a giant polypoid-type tumor that extended from the duodenum bulb to the pyloric ring. A computed tomography scan revealed a slightly enhanced lobular tumor protruding into the duodenum bulb. Positron emission tomography showed an accumulation of (18)F-fluorodeoxyglucose in the area extending from the antrum of the stomach to the duodenum bulb. Since an endoscopic ultrasound test suggested that the tumor might invade the muscular tunic, indications of endoscopic mucosal resection were not favored, and the tumor was curatively removed via distal gastrectomy. The histopathologic diagnosis was papillary adenocarcinoma, and the invasion depth was the mucosal layer without vascular invasion, which was different from the preoperative diagnosis. Our case suggests the difficulties in precise diagnosis of the invasion depth of the giant polypoid cancer.


Patients' evaluation of shape, size and colour of solid dosage forms.
The aim of the study was to investigate the swallow ability and the patient preferences of tablets and capsules with different sizes, shapes, surfaces and colours. Patients were asked to swallow tablets with different surface and size, while tablets with different shape and colour were visually assessed. They were asked to indicate their preferences. Gelatine capsules were found easier to swallow than tablets and coated tablets were found easier than uncoated normal tablets. The preferred colour was white both for tables and capsules, and the most disliked colours were purple tablets and brown capsules. The preferred shape was strongly arched circular for small tablets, oval for medium sized and big tablets. The difficulty to swallow tablets increased with increasing size. According to the results of this study, the ideal tablet is small and white, strongly arched circular and coated. If the amount of drug requires a bigger tablet, the preferred fomat is oblong or oval with a coating. In general capsules were preferred over tablets.


Evaluation of Versatile CdS Nanomaterials Based Liquid Crystals Switchable Device.
Novel synthesis and properties of versatile CdS nanostructures (e.g., Nano-brush, nano-cube, nanosphere) dispersed liquid crystals application in chemical friendly medium exploring this article. Most recent studies, CdS nano-wire brush with the stacking fault structures were hydrothermally synthesized through a dissolution-recrystallization approach in concentrated ammonia solvent in one step solution, for the first time. Those structures-property relations with respect to ferroelectric hydrogen-bonded liquid-crystalline complex (HBLC; AC + 5BAO) controlled and efficient formation of surface relief nanostructures. A successful attempt has been made to form hydrogen bonding between CdS nanostructures and supramolecular LC with p–n-alkyloxy benzoic acids (n-OBA). The formation of an inter-H-bond is evinced through FTIR study, as well as Gaussian simulation also ensures complete formation of intermolecular hydrogen bond optimized geometry. In contrast, a new sensitive response of smectic G ordering observed in this series is investigated by constructing a phase diagram obtained from two binary mixtures of CdS nanostructures influenced by homogeneous liquid crystals. Temperature-dependent dielectric relaxation, tilt angle, electro-optical switching measurements allow for monitoring very unique and useful behavior in that the polarization of the emission from the semiconductor nanostructures can be controlled by an external bias. It reveals electrically tunable interaction of the composites may allow for engineering of practical electro-optic switchable device.


Bacteremia Caused by Kalamiella piersonii Found in an Infant During the Course of Gastrointestinal Food Allergy.
Kalamiella piersonii is rare pathogen, and its pathogenicity to humans has been unknown. We describe an infant with bacteremia caused by Kalamiella piersonii. The patient was a 2-month-old girl presented with diarrhea, poor oral intake, and vomiting. The patient was tentatively diagnosed with acute enterocolitis. After admission, the patient developed a fever and blood culture yielded Gram-negative cocci, first determined to be Pantoea septica by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. However, genetic analysis of 16S rRNA allowed its identification as Kalamiella piersonii (GenBank accession number is OQ547240). Other housekeeping genes such as gyrB, rpoB, and atpD also identified the isolated strain as Kalamiella piersonii. The patient was successfully treated with cefotaxime without sequelae. Later, the patient was diagnosed as non-IgE-mediated gastrointestinal food allergy. Our experience indicated that Kalamiella piersonii is a potential human pathogen that can cause invasive infections even in infants and children. Identification of Kalamiella piersonii is difficult with routine conventional tests, and detailed studies including genetic analyses are necessary to clarify the pathogenicity of Kalamiella piersonii in humans.


Evaluation of the efficacy of immunocastration vaccine composed of gonadotrophin-releasing hormone conjugated with Salmonella typhimurium flagellin in rats.
Immunocastration is an alternative method to replace surgical castration that is commonly performed in domestic and pet animals. In this study, a new immunocastration vaccine was developed, and its efficacy was evaluated in male rats. Six tandem copies of gonadotrophin-releasing hormone (GnRH) peptide were genetically fused to Salmonella typhimurium flagellin fljB (STF2) that is a ligand of toll-like receptor 5 (TLR5). The recombinant STF2-GnRH protein expressed in Escherichia coli was used as the immunocastration vaccine. Sixteen male rats were equally assigned to four groups. Excluding the control rats, three groups were immunized with 100, 200 and 400 μg of the STF2-GnRH vaccine, respectively. All of the immunized rats developed significantly higher titres of antibodies to GnRH than the control rats. The size and weight of both testes and epididymides from the immunized rats were significantly smaller than those of the control rats. Testicular tissues in the immunized rats demonstrated atrophy of seminiferous tubules and decreased numbers of both spermatogonia and spermatocytes. These data indicate that the newly developed STF2-GnRH vaccine has a potent immunogenicity to GnRH and efficiently suppresses the development of testes in rats.


Resilient biotic response to long-term climate change in the Adriatic Sea.
Preserving adaptive capacities of coastal ecosystems, which are currently facing the ongoing climate warming and a multitude of other anthropogenic impacts, requires an understanding of long-term biotic dynamics in the context of major environmental shifts prior to human disturbances. We quantified responses of nearshore mollusk assemblages to long-term climate and sea-level changes using 223 samples (~71,300 specimens) retrieved from latest Quaternary sediment cores of the Adriatic coastal systems. These cores provide a rare chance to study coastal systems that existed during glacial lowstands. The fossil mollusk record indicates that nearshore assemblages of the penultimate interglacial (Late Pleistocene) shifted in their faunal composition during the subsequent ice age, and then reassembled again with the return of interglacial climate in the Holocene. These shifts point to a climate-driven habitat filtering modulated by dispersal processes. The resilient, rather than persistent or stochastic, response of the mollusk assemblages to long-term environmental changes over at least 125 thousand years highlights the historically unprecedented nature of the ongoing anthropogenic stressors (e.g., pollution, eutrophication, bottom trawling, and invasive species) that are currently shifting coastal regions into novel system states far outside the range of natural variability archived in the fossil record.


Antinociceptive Effects of an Anti-CGRP Antibody in Rat Models of Colon-Bladder Cross-Organ Sensitization.
Irritable bowel syndrome (IBS) and bladder pain syndrome/interstitial cystitis (BPS/IC) are comorbid visceral pain disorders seen commonly in women with unknown etiology and limited treatment options and can involve visceral organ cross-sensitization. Calcitonin gene-related peptide (CGRP) is a mediator of nociceptive processing and may serve as a target for therapy. In three rodent models, we employed a monoclonal anti-CGRP F(ab')2 to investigate the hypothesis that visceral organ cross-sensitization is mediated by abnormal CGRP signaling. Visceral organ cross-sensitization was induced in adult female rats via transurethral infusion of protamine sulfate (PS) into the urinary bladder or infusion into the colon of trinitrobenzene sulfonic acid (TNBS). Colonic sensitivity was assessed via the visceromotor response to colorectal distension (CRD). Bladder sensitivity was assessed as the frequency of abdominal withdrawal reflexes to von Frey filaments applied to the suprapubic region. PS- or TNBS-induced changes in colonic and bladder permeability were investigated in vitro via quantification of transepithelial electrical resistance (TEER). Peripheral administration of an anti-CGRP F(ab')2 inhibited PS-induced visceral pain behaviors and colon hyperpermeability. Similarly, TNBS-induced pain behaviors and colon and bladder hyperpermeability were attenuated by anti-CGRP F(ab')2 treatment. PS into the bladder or TNBS into the colon significantly increased the visceromotor response to CRD and abdominal withdrawal reflexes to suprapubic stimulation and decreased bladder and colon TEER. These findings suggest an important role of peripheral CGRP in visceral nociception and organ cross-sensitization and support the evaluation of CGRP as a therapeutic target for visceral pain in patients with IBS and/or BPS/IC. SIGNIFICANCE STATEMENT: A monoclonal antibody against calcitonin gene-related peptide (CGRP) was found to reduce concomitant colonic and bladder hypersensitivity and hyperpermeability. The results of this study suggest that CGRP-targeting antibodies, in addition to migraine prevention, may provide a novel treatment strategy for multiorgan abdominopelvic pain following injury or inflammation.


Arabidopsis α Aurora kinases function in formative cell division plane orientation.
To establish three-dimensional structures/organs, plant cells continuously have to adapt the orientation of their division plane in a highly regulated manner. However, mechanisms underlying switches in division plane orientation remain elusive. Here, we characterize a viable double knockdown mutant in Arabidopsis thaliana group α Aurora (AUR) kinases, AUR1 and AUR2, (aur1-2 aur2-2), with a primary defect in lateral root formation and outgrowth. Mutant analysis revealed that aur1-2 aur2-2 lateral root primordia are built from randomly oriented cell divisions instead of distinct cell layers. This phenotype could be traced back to cytokinesis defects and misoriented cell plates during the initial anticlinal pericycle cell divisions that give rise to lateral root primordia. Complementation assays showed that the Arabidopsis α group Aurora kinases are functionally divergent from the single β group member AUR3 and that AUR1 functions in division plane orientation prior to cytokinesis. In addition to defective lateral root patterning, aur1-2 aur2-2 plants also show defects in orienting formative divisions during embryogenesis, divisions surrounding the main root stem cell niche, and divisions surrounding stomata formation. Taken together, our results put forward a central role for α Aurora kinases in regulating formative division plane orientation throughout development.


Biomedical evidence engineering for data-driven discovery.
With the rapid development of precision medicine, a large amount of health data (such as electronic health records, gene sequencing, medical images, etc.) has been produced. It encourages more and more interest in data-driven insight discovery from these data. A reasonable way to verify the derived insights is by checking evidence from biomedical literature. However, manual verification is inefficient and not scalable. Therefore, an intelligent technique is necessary to solve this problem. This article introduces a framework for biomedical evidence engineering, addressing this problem more effectively. The framework consists of a biomedical literature retrieval module and an evidence extraction module. The retrieval module ensembles several methods and achieves state-of-the-art performance in biomedical literature retrieval. A BERT-based evidence extraction model is proposed to extract evidence from literature in response to queries. Moreover, we create a dataset with 1 million examples of biomedical evidence, 10 000 of which are manually annotated. Datasets are available at https://github.com/SendongZhao.


Deep brain stimulation in Huntington's disease: assessment of potential targets.
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder that has very few effective therapeutic interventions. Since the disease has a defined neural circuitry abnormality, neuromodulation could be an option. Case reports, original research, and animal model studies were selected from the databases of Medline and PubMed. All related studies published up to July 2014 were included in this review. The following search terms were used: "Deep brain stimulation," "DBS," "thalamotomy," "pallidal stimulation," and "Huntington's Disease," "HD," "chorea," or "hyperkinetic movement disorders." This review examines potential nodes in the HD circuitry that could be modulated using deep brain stimulation (DBS) therapy. With rapid evolution of imaging and ability to reach difficult targets in the brain with refined DBS technology, some phenotypes of HD could potentially be treated with DBS in the near future. Further clinical studies are warranted to validate the efficacy of neuromodulation and to determine the most optimal target for HD.


[Applications of the inferior vena cava filter for the prevention of the risk for pulmonary emboli].
The most serious and fatal complication of deep venous thrombosis (DVT) is still accepted as pulmonary embolism (PE). One of the methods used for PE prophylaxis is inferior vena cava filter(VCF). Between 1999 and 2000, VCF is used in 12 patients (8 male, 4 female) who were hospitalized in Trauma and Surgical Emergency Service of Istanbul Medical Faculty. 10 of the VCF used were permanent and 2 of them were temporary filters. 8 permanent filter were applied to patients with life-long paraplegia or quadriplegia due to spinal cord injury. Two patients to whom permanent filters were applied had malignancy. Patient who had the diagnosis of late stage cervical carcinoma, had DVT. In this patient, because of the high bleeding risk, we applied permanent filter. In the other patient, who had the diagnosis bladder carcinoma, had DVT despite the usage of low molecular weight heparin. In two patients who needed short term PE prophylaxis, had temporary VCF. In one of these patients, primary diagnosis was subarachnoidal hemorrhage due to head trauma. In the 8th day of hospitalization, DVT occurred. Because of high risk of intracranial bleeding, VCF was performed. The second patient had the diagnosis of subdural hematoma and subarachnoidal hemorrhage due to head trauma and multiple lower extremity fractures. VCF were applied in Istanbul Medical Faculty, Department of Radiology. For cannulation line of permanent VCF (LGM Venatech-B. Braun) right femoral vein was used. For temporary filters (Proliser Cordis-Johnson and Johnson Company), right internal jugular vein was the preferred way. Two multitrauma patients who had permanent filters died due to sepsis and multiorgan failure. In the follow up of other patients during the average period of 7.6 months, any problem due VCF application or by related complication and PE did not occur. Although larger patient groups with follow up period are necessary to evaluate better, we think that in PE prophylaxis, VCF is safe and effective modality.


Deep time and the search for anthropoid origins.
Recent fossil discoveries, phylogenetic analyses, revised reconstructions of continental drift, and accumulating molecular evidence have all yielded new information relating to anthropoid origins within the broader context of primate evolution. There is an emerging consensus among molecular studies that four superorders of eutherian mammals can be recognized: Afrotheria, Euarchontoglires (to which primates belong), Laurasiatheria, and Xenarthra. Overall, molecular phylogenies for mammals agree with some statistical analyses of the primate fossil record in indicating an early origin for primates around 85 Ma ago, and the divergence of haplorhines and strepsirrhines at ca. 77 Ma. Such an ancient date for the origin of haplorhines is some 17 Ma prior to the first known possible primate, and some 22 Ma before the earliest fossil evidence of undoubted euprimates. Because anthropoid fossils date back at least to the late Eocene and perhaps to the middle Eocene, and given indications of an early origin for primates, it is unlikely that ancestral anthropoids arose within any other currently known clade of fossil primates (adapiforms, omomyiforms, strepsirrhines, or tarsiiforms). Implications of new molecular, morphological, and biogeographic lines of evidence are explored with respect to the likely time and place of the origin of anthropoids. Four competing, testable hypotheses are reviewed in detail: 1) the Paratethyan hypothesis, 2) the continental Asian hypothesis, 3) the Indo-Madagascar hypothesis, and 4) the African hypothesis. A case is made that current evidence best supports a relatively ancient Gondwanan origin for primates, as well as a Gondwanan (African or Indo-Madagascan) origin for anthropoids at least as old as that of any other currently documented major primate clade. Available fossil evidence at present seems to be most compatible with the African hypothesis, but it is noteworthy that primates are included not in Afrotheria but in Euarchontoglires.


Diné Navajo Resilience to the COVID-19 pandemic.
To date, there are no studies of COVID-19 cases and deaths in the Navajo Nation, US. The primary objective of this manuscript is to understand whether counties with a higher proportion of Navajo (Diné) population also had higher cases and deaths of COVID-19 and whether these dropped with vaccination. We undertook a cross-sectional analysis of county level data from March 16, 2020-May 11, 2021. Data were obtained from public repositories and the US Census for the Navajo Nation, including northeastern Arizona, southeastern Utah, and northwestern New Mexico. The primary outcome measure is the number of individuals with confirmed cases or deaths of COVID-19. A secondary outcome was COVID-19 vaccinations. The 11 counties in Navajo Nation have a wide variation in the percent Navajo population, the resources available (ICU beds and occupancy), and COVID-19 outcomes. Overall, there was a substantial increase in the number of cases from March 16 -July 16, 2020 (the height of the pandemic) with a doubling time of 10.12 days on Navajo Nation. The percent Navajo population was a strong predictor of COVID-19 cases and deaths per million population. COVID-19 vaccinations were inversely associated with COVID-19 cases and deaths in these counties. The COVID-19 pandemic on the Navajo Nation is a story of resilience. Navajo Nation was one of the hardest hit areas of the United States, with peak cases and deaths due to COVID-19. With an aggressive vaccination effort, these cases and deaths were strikingly curtailed, showing the resilience of the Navajo (Diné) people.


Anticoagulant and antiplatelet activity of aqueous extracts of Citrus sinensis and Lippia alba : interactions and potential for the development of antithrombotics.
Citrus sinensis and Lippia alba are herbal medicines widely used in the form of tea (infusion, decoction), which ethanolic extracts have already shown great anticoagulant activity in vitro . For this reason, they seem to be excellent candidates for the development of new antithrombotics and also have the potential to interact with them. The aim of this study was to evaluate the activity of aqueous extracts in blood coagulation and platelet aggregation, in addition to analysing the micromolecular composition of these species. Thrombin generation test (TGT) by the Calibrated Automated Thrombogram method and Platelet Aggregation Test by turbidimetry were performed to evaluate the biological activities, while the chemical composition was qualitatively evaluated using high-performance liquid chromatography. Aqueous extracts were elaborated according to the folk use. All extracts were effective in reducing thrombin formation in TGT. Infusion of L. alba and infusion and decoction of C. sinensis at a concentration of 0.6 mg/ml significantly reduced platelet aggregation induced by ADP, and only the decoction of L. alba at the same concentration was able to significantly reduce collagen-induced platelet aggregation. The presence of phenylpropanoids and flavonoids in C. sinensis and L. alba extracts was verified. Furthermore, hesperidin was identified in C. sinensis through coinjection. C. sinensis and L. alba are rich in phenolics and demonstrated an in-vitro effect on important processes of haemostasis (blood coagulation, platelet agreggation), corroborating the potential of C. sinensis and L. alba for the development of antithrombotics and interact with them.


Palladium-Catalyzed Directed Atroposelective C-H Allylation via β-H Elimination: 1,1-Disubstituted Alkenes as Allyl Surrogates.
Transition-metal-catalyzed dehydrogenative C-H allylation with 1,1-disubstituted alkenes via β-H elimination remains challenging, because of the low reactivity and difficulty of controlling selectivity. Herein, the development of a Pd(II)-catalyzed directed atroposelective C-H allylation with methacrylates is described. Exclusive allylic selectivity was achieved. A vast array of axially chiral biaryl-2-amines are efficiently synthesized with excellent enantioselectivities (up to >99% enantiomeric excess).


Contact dermatitis to hair dye: an update.
Exposure to hair dyes has long been known as a significant risk factor for development of allergic contact dermatitis among the exposed population as these lead to severe eczema of face and upper trunk in the consumer and hand eczema in hair-dressers. Currently, para-phenylenediamine (PPD) is the main ingredient used in permanent hair color products in the market and is the most important allergen. Prevalence of PPD sensitization is high in patients with contact dermatitis across all continents, with hair dye use being the commonest cause. In order to decrease the burden of disease, use of alternative natural dyeing agents among consumers and use of barrier neoprene gloves among hairdressers should be encouraged apart from stringent legislation to reduce the amount of PPD reaching the consumer.


Development of Bronze Phase Titanium Dioxide Nanorods for Use as Fast-Charging Anode Materials in Lithium-Ion Batteries.
Bronze phase titanium dioxide (TiO2(B)) nanorods were successfully prepared via a hydrothermal method together with an ion exchange process and calcination by using anatase titanium dioxide precursors in the alkali hydrothermal system. TiO2 precursors promoted the elongation of nanorod morphology. The different hydrothermal temperatures and reaction times demonstrated that the synthesis parameters had a significant influence on phase formation and physical morphologies during the fabrication process. The effects of the synthesis conditions on the tailoring of the crystal morphology were discussed. The growth direction of the TiO2(B) nanorods was investigated by X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The as-synthesized TiO2(B) nanorods obtained after calcination were used as anode materials and tested the efficiency of Li-ion batteries. This research will study the effects of particle morphologies and crystallinity of TiO2(B) derived from a modified hydrothermal method on the capacity and charging rate of the Li-ion battery. The TiO2(B) nanorods, which were synthesized by using a hydrothermal temperature of 220 °C for 12 h, presented excellent electrochemical performance with the highest Li storage capacity (348.8 mAh/g for 100 cycles at a current density of 100 mA/g) and excellent high-rate cycling capability (a specific capacity of 207.3 mAh/g for 1000 cycles at a rate of 5000 mA/g).


Rapid-onset hyponatremia and delirium following duloxetine treatment for postherpetic neuralgia: Case report and literature review.
Hyponatremia following duloxetine treatment has been reported in patients with major depressive disorder, fibromyalgia, diabetic neuropathy, or sciatic pain. The manifestations of duloxetine-induced hyponatremia are varying in different individuals. The overall prognosis for this type of hyponatremia is favorable if properly managed. Herein, we reported rapid-onset hyponatremia and delirium in an older patient after 2 doses of duloxetine, which was used to control his postherpetic neuralgia. Laboratory examinations revealed a rapid decline in serum sodium level and indicated the possibility of syndrome of inappropriate antidiuretic hormone (SIADH). Discontinuation of duloxetine, restriction of water intake, and intravenous supplement of normal saline were adopted to manage the hyponatremia. Serum concentration of sodium gradually normalized following aforementioned strategies. Special attention to the electrolyte abnormality is recommended in old patients undergoing duloxetine treatment.


Primum Non Nocere and the 5 Rights.
Overutilization of hyperbaric oxygen therapy (HBOT) is commonplace and primarily associated with outpatient wound care. While the number of hospitals providing HBOT is at an all-time high, the number of those willing to treat patients in immediate need is at an all-time low. Huge areas of the country, including major population areas, are now completely devoid of 24/7 HBOT availability and inpatient access. Purchasers of healthcare, including the Centers for Medicare and Medicaid Services, have become increasingly concerned to the point that several strategies have been introduced to constructively deal with this issue. This commentary serves as a counterpoint to concerns that one such approach, prior authorization of elective indications, adversely delays medically necessary care. The historical evolution of HBOT practice will be described to underscore how this problem has become so widespread and, to date, largely unchecked. It will also address the paradoxical national crisis of access for emergencies.


DNA Methylation Expression Profile of Blood Heat Syndrome and Blood Stasis Syndrome in TCM Psoriasis.
Traditional Chinese medicine (TCM) emphasizes treatment based on syndrome differentiation. This study aimed to clarify the characteristics of DNA methylation expression profiles in peripheral blood mononuclear cells (PBMCs) in patients with psoriasis and analyze the differences in these profiles among different TCM syndromes of psoriasis in order to provide a material basis for the diversity of these syndromes. Blood samples were collected from 32 participants, including 14 patients with psoriatic blood heat syndrome (BHS), 12 patients with psoriatic blood stasis syndrome (BSS), and 6 healthy controls. PBMCs were extracted and subjected to DNA quality inspection. An Illumina Human Methylation 850k chip was used to sequence each group of samples. According to gene annotation classification together with CpG island annotation classification, the differentially methylated regions between sample groups were screened, while Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were applied to perform functional analyses of DMGs. Finally, the DMGs closely correlating with psoriatic severity were screened using Spearman's correlation analysis. Compared with normal controls, patients with psoriasis showed an overall trend of hypermethylation. In psoriasis, the differential methylation probes were mainly distributed on gene body region on the genome, while those in CpG regions were mainly distributed in CpG islands. Compared with healthy controls, the overall trends in methylation were similar in psoriatic BHS and BSS patients compared to healthy controls. However, bioinformatic analysis revealed different functions of DMGs. We also found that the methylation levels of TRIM14 and PRDM16 were closely correlated with PASI scores and could serve as potential biomarkers to assess the severity of psoriasis. Our study, for the first time, indicated the possible involvement of DNA methylation in regulating the characteristics of TCM syndromes of psoriasis, providing a new direction for research into TCM psoriatic syndromes.


Proton transport properties in an ionic liquid having a hydroxyl group.
An ionic liquid having a hydroxyl group, choline bis(trifluoromethylsulfonyl)amide ([N(111(2OH))][N(Tf)(2)]), was synthesized to investigate the effect of hydroxyl groups on the proton transport. 1,1,1-Trifluoro-N-(trifluoromethylsulfonyl)methanesulfoneamide (HN(Tf)(2)) as a proton source was mixed with the choline derivative at various molar ratios. Their thermal properties, viscosities, and ionic conductivities were investigated. [N(111(2OH))][N(Tf)(2)] showed a melting point at 27 °C, and its thermal stability was higher than 400 °C. The viscosity of [N(111(2OH))][N(Tf)(2)]/HN(Tf)(2) mixtures increased as the acid molar fraction increased. The ionic conductivity of [N(111(2OH))][N(Tf)(2)] was 2.1 × 10(-3) S cm(-1) at 25 °C; the ionic conductivity monotonously decreased as the acid molar fraction increased. There was a clear correlation between the ionic conductivity and the viscosity for the mixtures of the choline derivative and the acid. PFG-NMR measurements were carried out to investigate the diffusion behavior of protons. Although the acid and the hydroxyl group were indistinguishable by (1)H NMR, the self-diffusion coefficient of the (1)H of the hydroxyl group and the acid was larger than those of other (1)H nuclei. This difference suggests that a fast intermolecular proton transfer exists between the hydroxyl group and the acid.


Parental investment in Tibetan populations does not reflect stated cultural norms.
In this paper, we examined both stated norms of sex preference and actual sex-biases in parental investment in a Tibetan pastoralist society. We collected detailed demographic data on infant mortality, infant feeding, the length of interbirth intervals, and a decision when giving gifts, to examine sex-biased parental investment. Our results indicate a mismatch between self-reported son preference and measures of actual parental investment that favor daughters. We interpret this female-biased parental investment as a possible response to daughters generating more economic resources. However, the stated sex preferences of both sexes reflect cultural norms that appear to have remained unchanged over a long period, which may reflect the importance of male roles in the past. Our behavioral measures of parental investment are those most likely to be in the control of women (such as breastfeeding and interbirth interval), so this mismatch between stated and actual investment may be especially true of women.


Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia.
Protective interactions with bystander cells in micro-environmental niches, such as lymph nodes (LNs), contribute to survival and therapy resistance of chronic lymphocytic leukemia (CLL) cells. This is caused by a shift in expression of B-cell lymphoma 2 (BCL-2) family members. Pro-survival proteins B-cell lymphoma-extra large (BCL-XL), BCL-2-related protein A1 (BFL-1) and myeloid leukemia cell differentiation protein 1 (MCL-1) are upregulated by LN-residing T cells through CD40L interaction, presumably via nuclear factor (NF)-κB signaling. Macrophages (Mφs) also reside in the LN, and are assumed to provide important supportive functions for CLL cells. However, if and how Mφs are able to induce survival is incompletely known. We first established that Mφs induced survival because of an exclusive upregulation of MCL-1. Next, we investigated the mechanism underlying MCL-1 induction by Mφs in comparison with CD40L. Genome-wide expression profiling of in vitro Mφ- and CD40L-stimulated CLL cells indicated activation of the phosphoinositide 3-kinase (PI3K)-V-Akt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which was confirmed in ex vivo CLL LN material. Inhibition of PI3K-AKT-mTOR signaling abrogated MCL-1 upregulation and survival by Mφs, as well as CD40 stimulation. MCL-1 can be regulated at multiple levels, and we established that AKT leads to increased MCL-1 translation, but does not affect MCL-1 transcription or protein stabilization. Furthermore, among Mφ-secreted factors that could activate AKT, we found that induction of MCL-1 and survival critically depended on C-C motif chemokine receptor-1 (CCR1). In conclusion, this study indicates that two distinct micro-environmental factors, CD40L and Mφs, signal via CCR1 to induce AKT activation resulting in translational stabilization of MCL-1, and hence can contribute to CLL cell survival.


Bullous pemphigoid antigen: isolation from normal human skin.
A protein moiety from epidermal PBS-soluble products was isolated by gel filtration (Bio-Gel A-1.5m) and ion exchange chromatography (DEAE-cellulose). This protein (A-1-Epid) was not retarded by DEAE-cellulose in Tris-HCl buffer, 15mM, pH 8.1. By IEP against an antiserum to epidermal antigens, it showed a single cathodal arc. On disc electrophoresis, at low pH (4.3) a single band was apparent. On SDS gels this protein demonstrated two bands, one with a molecular weight of 20,000, and the second with a molecular weight of 9,200. This purified antigen was able to block the staining of the basement membrane zone produced by bullous pemphigoid antibodies on monkey esophagus and normal human skin with the use of indirect immunofluorescence. This study also demonstrates that bullous pemphigoid antigen (A-1-Epid) and a second epidermal protein (A-2-Epid) are present in the PBS-soluble products of human esophageal mucosa, saliva, and urine. These antigens appear to be unrelated with the blood group substances or secretor status of the donors.


Reactivation of severe, acute pulmonary tuberculosis during treatment with pegylated interferon-alpha and ribavirin for chronic HCV hepatitis.
The unexpected observation of severe pulmonary tuberculosis after a 7-month combined pegylated interferon-ribavirin for chronic hepatitis C, prompted us to search an eventual immunodeficiency (lymphopenia and/or depletion of CD4+ T-lymphocytes. The retrieval of a chest radiograph incidentally performed 11 y before and showing a probable primary tuberculosis, paralleled a negligible clinical history. The enlargement of interferon indications needs careful evaluation for prior (usually missed) tuberculosis, to prevent or avoid its possible reactivation. Latent tuberculosis is increasingly reported because of extended life expectancy, immigration, and recent availability of cure for multiple chronic disorders, which are often borne by primary-secondary immunodeficiency.


In Vivo Bioimaging and Photodynamic Therapy Based on Two-Photon Fluorescent Conjugated Polymers Containing Dibenzothiophene-S,S-dioxide Derivatives.
As a critical component for photodynamic therapy toward cancer treatment, photosensitizers require high photoinduced reactive oxygen species generation efficiency, good biocompatibility, and high phototoxicity. Herein, a series of donor-acceptor conjugated polymers containing dibenzothiophene-S,S-dioxide derivatives are designed and synthesized, which can be used as effective photosensitizers. The resulting copolymer PTA5 shows strong green light emission with high photoluminescence quantum yields owing to the intercrossed excited state of local existed and charge transfer states. The PTA5 nanoparticles can be fabricated by encapsulation with a biocompatible polymer matrix. Upon excitation at 800 nm, these nanoparticles present a relatively large two-photon absorption cross section of 3.29 × 106 GM. These nanoparticles also exhibit good photostability in water and thus can be utilized for bioimaging. The tissue-penetrating depths of up to 170 μm for hepatic vessels and 380 μm for blood vessels of mouse ear were achieved using PTA5 nanoparticles. Furthermore, PTA5 nanoparticles show impressive reactive oxygen species generation capability under the irradiation of a white light source. This can be attributed to the effective intersystem crossing between high-level excited state. Upon irradiation with white light (400-700 nm) at 50 mW cm-2 for 5 min every other day, the tumor growth can be effectively suppressed in the presence of PTA5 nanoparticles. These findings demonstrate that PTA5 nanoparticles can be used as a photosensitizer for photodynamic therapy.


[The clinical laboratory training after the graduate in local training hospital setting].
As clinical training has become a compulsory element of the training of physicians, all doctors are now required to undergo training in basic abilities of diagnosis and treatment. Clinical training has become possible in local medical organizations as well as university hospitals and large hospitals. There are full-time clinical pathologists in the laboratory staff of large hospitals, but they have little time for clinical trainees in the present educational system in the field of clinical laboratory. In mid-size and small hospitals, there is no clinical pathologist at the central diagnostic and treatment division, and clinical laboratory technicians are expected to play roles of trainers. It is important for the training administrator to prepare an environment in which clinical trainees can learn the selection of examinations, execution of examinations, interpretation of results, and actual handling of patients and, particularly in the execution of examinations, to cooperate with the director of the examination division and see that trainees can learn the necessary skills that they must acquire. The training administrator must also formulate a program to help clinical trainees to develop the abilities necessary for them to function as a member of team care. Such a program must not only be effective for the training of physicians but also contribute to the development of laboratory technicians and to improvements in the quality of medical care that is provided.


Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity.
A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.


Potential sources of sugar for the phlebotomine sandfly Lutzomyia youngi (Diptera: Psychodidae) in a Colombian coffee plantation.
Sugar-deprived Lutzomyia youngi were exposed to each of the five most numerous plant species in a Colombian coffee plantation for 24 h and then tested for the presence of fructose by the cold anthrone assay. Many flies exposed to coffee (Coffea arabica) (up to 55% in an individual test) and guamo (Inga edulis) (up to 28.0%) gave positive results. Although some flies also took sugar from red-flowered balsam (Impatiens balsamina) and bamboo (Bambusa angustifolia), none of the insects exposed to plantain (Musa paradisiaca) gave a positive result unless the plants were infested with aphids (Pentalonia sp.). Although sandflies were successfully marked in the laboratory by exposing them to coffee and guamo plants whose roots had been treated with RbCl at 5000 p.p.m., RbCl was not detected by atomic emission spectrometry in wild specimens caught in the vicinity of RbCl-labelled coffee and guamo.


The Human Monocyte-A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation.
Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response.


Retinoids in nephrology: promises and pitfalls.
Retinoids, a family of vitamin A metabolites or analogs, play an important role in regulating cell proliferation, differentiation, and apoptosis. The biological importance of retinoids in the kidney and the potential of retinoids in the treatment of renal diseases are reviewed. Vitamin A deficiency and mutations of retinoid nuclear receptors cause abnormalities in fetal kidneys, which might predispose to adult diseases such as hypertension. Further, the therapeutic value of retinoids in animal models of kidney diseases, such as lupus nephritis, puromycin aminonucleoside nephrosis, anti-glomerular basement membrane nephritis, mesangioproliferative nephritis, and acute renal allograft rejection has been unveiled recently. Retinoids target mesangial cells, podocytes, tubular epithelial cells, interstitial fibroblasts, as well as lymphocytes and macrophages. The anti-inflammation, anti-coagulation effects, and the proliferation- and immunity-modulating actions of retinoids, have been widely appreciated. Our recent in vitro data revealed a direct antifibrotic effect and a cytoprotective effect of retinoids in various renal cell types. In animal studies, the adverse effects of retinoids are generally minimal; however, the clinical use of retinoids in other diseases points to some major side effects. In addition, in vitro, retinoids can induce lipid accumulation in smooth muscle cells and macrophages and increase expression of some proinflammatory molecules, indicating that their clinical toxicity profile in the setting of renal diseases needs to be better understood. Retinoids not only are important in renal development, but also show promise as a new generation of renal medication and deserve to be tested in clinical trials to clarify their full potential.


Variants and differential diagnosis of Guillain-Barré syndrome.
Guillain-Barré syndrome is characterized by acute progressive weakness, areflexia and maximal motor disability that occur within 4 weeks of onset. Its clinical and pathological spectra range extends from classical acute inflammatory demyelinating polyneuropathy to axonal variants with (acute motor sensory axonal neuropathy) or without (acute motor axonal neuropathy) sensory involvement. Moreover, several clinical variants (Fisher syndrome, ataxic Guillain-Barré syndrome and pharyngeal-cervical-brachial weakness) have been proposed. The association of clinical characteristics of Guillain-Barré syndrome with specific infections and the presence of antiganglioside antibodies also has been reported. Guillain-Barré syndrome now is recognized as a heterogeneous disorder with various clinical manifestations and recent neurophysiological and pathological findings have led to its reclassification. This review summarizes current concepts about the clinical spectrum of Guillain-Barré syndrome and its variants and about differential diagnosis.


Th-1/Th-2 cytokine pattern in human amoebic colitis.
Amoebiasis, caused by Entamoeba histolytica, is still considered a major health problem in developing countries. Since the immune response during human amoebiasis has not been clearly defined, we chose to evaluate cytokine production in patients suffering from amoebic colitis. A case-control association study was carried out on 62 subjects, including 31 patients with amoebic colitis and 31 healthy controls (age, sex and geographic region-matched). Serum levels of IL-12, IFN-gamma, IL-13 and IL-5 were measured by solid-phase sandwich enzyme linked immunosorbant assay. Serum levels of IFN-gamma, IL-12, IL-13 and IL-5 were higher in the patients with amoebic colitis than in healthy controls, but were only statistically increased for IL-5 (p = 0.04) and IL-13 (p = 0.014). Stratification of patients according to gender revealed that IL-13 was significantly elevated in men as compared to levels measured in women (p = 0.04). These findings suggest that E. histolytica induce a mixed Th-1/Th-2 response with a polarization toward Th-2 during the early stage of amoebiasis, which may aide in developing a clinical illness.


Autoradiographic analysis of RNA synthesis in the oocyte-nurse cell complex of the polychaete Ophryotrocha labronica.
Females of the polychaete Ophryotrocha labronica have been pulse labelled with [5-3H] uridine, and the incorporation of label into the RNA of the oocyte-nurse cell complex was followed by light and electron microscope autoradiography. Up to its regression the polyploid nurse cell displays an intense synthesis of rRNA and mRNA, which sustains an extensive production of electron-dense protein granules in it. Concomitantly rRNA and mRNA are synthesized also in the oocyte. Short-term treatment (7h) of polychaete females with alpha-amanitin provokes serious disturbances of oogenesis and subsequent embryonic development, irrespective of when it is applied during oogenesis. In contrast actinomycin gives such effects only when it is applied at the onset of oogenesis. A previous investigation has demonstrated that nurse cell granules are gradually exported through an intercellular canal to the oocyte, where a fraction of them is incorporated into the typical yolk granules. The present labelling experiments indicate that nurse cell RNA is associated with the exported yolk precursor material. From inhibition experiments with alpha-amanitin and from in situ hybridizations with a poly(U)probe it appears that mRNA is particularly involved. At the final collapse of the nurse cell practically all its contents are transferred to the oocyte. From that time the ooplasm is found to contain nuage-like RNA aggregates, which in contrast to other [5-3H]uridine-labelled ooplasmic structures (yolk granules, and minor granules and aggregates) have a non-uniform distribution. The possible origin and function of these aggregates is discussed. The investigation indicates that the nurse cell has a significant export of RNA essentially similar to that from insect nurse cells.


Exogenous insulin use and hypertension in adult patients with type 2 diabetes mellitus.
Endogenous hyperinsulinemia, along with insulin resistance, is associated with hypertension. This study investigated the link between exogenous insulin use and hypertension in patients with type 2 diabetes mellitus. Using national health insurance records in Taiwan, data from 87,850 adult patients with type 2 diabetes mellitus were collected cross-sectionally with retrospective recall for onset of events. Data were analyzed to evaluate the strength of association, consistency, dose-response relationship, and temporality between exogenous insulin use and hypertension. There were 5927 insulin users, who were characterized by being 1 year older in age, female preponderance, longer duration of diabetes, slightly lower body mass index, and less smoking but higher prevalence of hypertension with higher blood pressure. After adjustment for age, sex, body mass index, duration of diabetes, smoking, and parental hypertension, the odds ratios (95% confidence interval [CI]) for hypertension for patients using insulin for less than 5 years, 5 to 9 years, and 10 years or more were 1.14 (95% CI, 1.06-1.23), 1.35 (95% CI, 1.18-1.54), and 1.46 (95% CI, 1.24-1.74), respectively, compared with nonusers. In insulin users who did not have hypertension at the start of insulin use, the respective odds ratios for those using insulin for 5 to 9 years and 10 years or more were 1.5 (95% CI, 1.25-1.80) and 2.15 (95% CI, 1.72-2.70), respectively, compared with those using insulin for less than 5 years. In patients with type 2 diabetes mellitus, insulin users are at higher risk for development of hypertension. These observational data suggest the need for further study of the relationship between exogenous insulin use and hypertension.


Permeability of biological and synthetic molecules through dentine.
The diffusion through dentine by a number of biological and synthetic molecules, including resins and dyes, is reported. In vitro measurements were derived by experiments with a modified 'split-chamber device'. Diffusion was found to be indirectly proportional to dentine thickness for all molecules. Permeability of water-soluble molecules and ethanol-soluble molecules was proportional to the molecular weights, except for fluorescein, hydrogen peroxide (H2O2) and urethane dimethacrylate. The resin components tested are not soluble enough in an aqueous medium to diffuse through 0.5 mm dentine at sufficient concentrations to cause cytotoxicity to pulpal cells.


Novel Alzheimer risk factor IQ motif containing protein K is abundantly expressed in the brain and is markedly increased in patients with Alzheimer's disease.
Alzheimer's disease (AD) is complex and highly heterogeneous. Less than 10% of AD cases are early-onset (EOAD) caused by autosomal dominantly inherited mutations in amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), each of which can increase Aβ generation and, thus, amyloid plaques. The remaining 90% of cases of AD are late-onset (LOAD) or sporadic. Intense research efforts have led to identification of many genes that increase the risk of AD. An IQ motif containing protein K (IQCK) was recently identified by several investigators as an Alzheimer's disease risk gene. However, how IQCK increases AD risk is completely unknown. Since IQCK is a novel gene, there is limited information on its physiological characterization. To understand its role in AD, it is first important to determine its subcellular localization, whether and where it is expressed in the brain, and what type of brain cells express the IQCK protein. Therefore, in this study, we show by immunocytochemical (ICC) staining that IQCK is expressed in both the nucleus and the cytoplasm of SH-SY5Y neuroblastoma cells as well as HeLa cells but not in either HMC3 microglial or CHO cells. By immunohistochemistry (IHC), we also show that IQCK is expressed in both mouse and human neurons, including neuronal processes in vivo in the mouse brain. IHC data also show that the IQCK protein is widely expressed throughout the mouse brain, although regional differences were noted. IQCK expression was highest in the brainstem (BS), followed by the cerebellum (CB) and the cortex (CX), and it was lowest in the hippocampus (HP). This finding was consistent with data from an immunoblot analysis of brain tissue homogenates. Interestingly, we found IQCK expression in neurons, astrocytes, and oligodendrocytes using cell-specific antibodies, but IQCK was not detected in microglial cells, consistent with negative in vitro results in HMC3 cells. Most importantly, we found that actin-normalized IQCK protein levels were increased by 2 folds in AD brains relative to normal control (NC) brains. Furthermore, the IQCK protein was found in amyloid plaques, suggesting that IQCK may play a pathogenic role in either Aβ generation or amyloid plaque deposition in AD.


[An unusual cause of obstructive jaundice: giant gastroduodenal artery aneurysm].
Visceral artery aneurysms are rare vascular lesions. Hepatic aneurysms are the second most common type of visceral aneurysm after those of the splenic artery. These aneurysms often have a nonspecific clinical presentation and are difficult to diagnose before rupture. Because the natural course of hepatic aneurysms leads to rupture, with a high rate of morbidity and mortality, their early diagnosis is essential for surgical correction. We report a case of obstructive jaundice caused by a 7-cm gastroduodenal artery aneurysm in which the diagnosis was suggested by abdominal computed tomography and magnetic resonance cholangiography and was confirmed by angiography. The patient was surgically treated. In the following 48 h he presented ischemic-based acute hepatic failure and underwent left hepatic lobe resection. The patient finally died from a pulmonary thromboembolism.


The Impact of Simvastatin on Lipidomic Markers of Cardiovascular Risk in Human Liver Cells Is Secondary to the Modulation of Intracellular Cholesterol.
Statins are the first-line lipid-lowering therapy for reducing cardiovascular disease (CVD) risk. A plasma lipid ratio of two phospholipids, PI(36:2) and PC(18:0_20:4), was previously identified to explain 58% of the relative CVD risk reduction associated with pravastatin, independent of a change in low-density lipoprotein-cholesterol. This ratio may be a potential biomarker for the treatment effect of statins; however, the underlying mechanisms linking this ratio to CVD risk remain unclear. In this study, we investigated the effect of altered cholesterol conditions on the lipidome of cultured human liver cells (Hep3B). Hep3B cells were treated with simvastatin (5 μM), cyclodextrin (20 mg/mL) or cholesterol-loaded cyclodextrin (20 mg/mL) for 48 hours and their lipidomes were examined. Induction of a low-cholesterol environment via simvastatin or cyclodextrin was associated with elevated levels of lipids containing arachidonic acid and decreases in phosphatidylinositol species and the PI(36:2)/PC(18:0_20:4) ratio. Conversely, increasing cholesterol levels via cholesterol-loaded cyclodextrin resulted in reciprocal regulation of these lipid parameters. Expression of genes involved in cholesterol and fatty acid synthesis supported the lipidomics data. These findings demonstrate that the PI(36:2)/PC(18:0_20:4) ratio responds to changes in intracellular cholesterol abundance per se, likely through a flux of the n-6 fatty acid pathway and altered phosphatidylinositol synthesis. These findings support this ratio as a potential marker for CVD risk reduction and may be useful in monitoring treatment response.


Synthesis of daumone derivatives and their antiangiogenic activities on chorioallantoic membrane.
Daumone, a dauer-inducing pheromone and a series of lipid derivatives were synthesized from daumone to investigate structure-activity trends. Lipid derivatives demonstrated potent in vivo antiangiogenic activity on the chorioallantoic membrane, which exceeded that of fumagillin and thalidomide as reference agents. Among the 11 synthetic compounds tested, new derivatives 3, 11 and 13 showed the most potent antiangiogenic activity, which was twice that of fumagillin and thalidomide, replacing these as the most potent known antiangiogenic agents.


Debate: Does it matter how you lower blood pressure?
Whether it matters how pressure is lowered has been debated since antihypertensive drugs proved to prevent cardiovascular events. However, in clinical trials, while the stroke benefit predicted by a given difference in blood pressure was achieved, the results for myocardial infarction were roughly half that expected. This suggested that adverse drug effects of diuretics and beta-blockers might have detracted from their hypotensive effects. Trials with newer antihypertensive classes have revealed superior effects on outcomes associated with converting enzyme inhibitor use, and that alpha-blockers are less cardioprotective than diuretics. These studies establish that simple blood pressure reduction is an inadequate guide to therapy. The challenge now will be to determine the optimal therapy for each hypertensive patient.


Study of polybrominated diphenyl ethers using both positive and negative atmospheric pressure photoionization and tandem mass spectrometry.
Atmospheric pressure photoionization (APPI) was assessed for the mass spectrometric analysis of polybromodiphenyl ethers (PBDEs) on the basis of a set of 17 standard compounds. Positive and negative ionization modes were both investigated. M(+.) ions were formed under positive ion conditions whereas the negative ion mode yielded [M-Br+O](-) ions. The behavior of these APPI-produced ions towards collisional activation was studied using an ion trap mass spectrometer. In positive ion mode, the loss of Br(2) was one of the major fragmentation pathways, and was favored for ortho-substituted PBDEs. Conversely, the loss of COBr(.) occurred only for non-ortho-substituted congeners. The collisional excitation of [M-Br+O](-) ions in the ion trap also led to the loss of Br(2), to the elimination of HBr, and to the formation of product ions by cleavage of the ether bond. The formation of para-quinone radical anions was observed for PBDEs ranging from penta- to hepta-congeners, whereas brominated aromatic carbanions were formed preferentially for the most brominated PBDEs studied in this work (hepta- or deca-BDEs). M(+.) ions did not undergo this fragmentation process.


Past, present, and future of orthopedic surgery in hemophilia: looking to a world without bleeding and arthropathy in the near future.
The purpose of this article is to review the literature on orthopedic surgery in people with hemophilia (PWH), to better understand its past and present and attempt to predict the future. A Cochrane Library and PubMed (MEDLINE) search of studies related to orthopedic surgery in PWH was analyzed. A downward trend in orthopedic surgery in PWH has been observed. Patients on continuous prophylaxis are less likely to require orthopedic surgery. In patients with hemophilia, the risk of major bleeding remains high after total joint arthroplasty, even with factor replacement. Cases of acute compartment syndrome, pseudotumors, and even limb amputations are still observed in PWH. Orthopedic surgery for PWH should always be performed in specialized centers with multidisciplinary expertise in the correct management of hemophilia. It is paramount to perform an accurate preoperative coagulation screening before surgery. The availability of prophylaxis through replacement and the recent non-replacement therapy in well-developed countries will diminish substantially or hopefully abolish completely the need for surgery in the treatment of PWH. Therefore, we are looking to a world without bleeding and arthropathy in the next future. Unfortunately, this is not true for under-developed countries.