[Malignant neoplasms of the ovary in Berlin, capital of East Germany, 1975-1979].
Some data characterizing the situation in ovarian cancer control in Berlin, capital of the GDR, during the period 1975-1979 were analyzed. The analysis demonstrates a slight decline of the age-standardized incidence rate to 19,9/100 000. Only 23% of all cases were detected in stage I. 65% of the patients had advanced tumors of stages III or IV. There was an increase of patients treated with radical surgery up to the age of 65 years. The 5-year-survival rate amounted to 21% and was strongly related to the age of patients and the tumor stage.


New Scalable Approach toward Shape Memory Polymer Composites via "Spring-Buckle" Microstructure Design.
Shape memory polymers (SMPs) have attracted tremendous research interest since their discovery. However, most advances in research of SMPs are based on molecular designs, i.e., "bottom-up" strategies. Due to the viscoelasticity of polymers, slow and incomplete shape variations are inevitable for most existing SMPs. Here, we propose a simple and scalable approach to design and fabricate SMP composites (SMPCs) based on a "spring-buckle" microstructure design. Specifically, a highly elastic "spring" is employed as a basic skeleton for the SMPCs, onto which self-adhesive and stimuli-responsive "buckles" are installed as reversible switch units. The resultant SMPCs with such "spring-buckle" microstructure enable quick programming at ambient temperature and ultrafast (2-3 s) and nearly complete (∼100%) shape recovery triggered by organic solvents, benefiting from a unique capillary effect. This structural approach provides a novel design philosophy for shape memory materials and opens up new opportunities for their applications in sensor, actuator, aerospace, and other applications.


Blood pressure support in the very low-birth-weight infant during the first week of life.
The immature cardiovascular system of very preterm infants predisposes them to low systemic blood flow during the first week of life, a state that may be damaging to multiple organ systems. There are many treatment strategies for the maintenance of cardiovascular equilibrium in these infants, each with its own advantages and risks. Caregivers are responsible for assessing the circulatory status of each patient and evaluating the effectiveness of interventions aimed at maintaining adequate systemic blood flow. Therefore, it is important to have an understanding of the mechanics of transitional circulation, the relationship between blood pressure and systemic blood flow, and the therapies used to treat infants with compromised organ perfusion.


Experimental quantification of the feline leukaemia virus in the cat flea (Ctenocephalides felis) and its faeces.
Cat fleas (Ctenocephalides felis) were fed via artificial membranes and infected with the feline leukaemia virus (FeLV) from cell cultures. After removing the fleas from the blood source, the quantity of virus in the flea and its faeces was measured over a defined period of time. The virus was detectable in the fleas for up to 30 h at room temperature and up to 115 h at 4 degrees C. In the faeces, the amount of virus decreased much more slowly--after 2 weeks half of the initial amount of virus could still be detected. Thus the faeces might be a source of further infections, e.g. for the flea larvae or the cat itself.


Lymphocytotoxic antibodies in systemic lupus erythematosus patients and their relatives: reactivity with the HLA antigenic molecular complex.
Lymphocytotoxic activity of sera from systemic lupus erythematosus (SLE) patients and their families was inhibited by 50% or more by preincubation of target cells with Fab2 fragments of xenoantisera against beta 2 microglobulin or the heavy chain of the HLA-A,B,C antigenic molecular complex. An antiHLA-DR xenoantiserum had less blocking effect on peripheral blood mononuclear cells but was effective at blocking reactivity of these sera against cultured B lymphoid cell lines. The repertoire of specificities in family members' sera differed from each other and their respective proband with respect to their reactions with cultured lymphoid cell lines. These data indicate that lymphocytotoxic antibodies (LCA) found in most patients with SLE and some of their relatives include a subpopulation with specificity for determinants present on major histocompatibility gene products. They also suggest that LCA in relatives represent a defect in immune regulation which allows expression of existing autoimmune potentials rather than immunization with a single "lupus" antigen.


Cationic surfactants-modified natural zeolites: improvement of the excipients functionality.
In this study an investigation of cationic surfactants-modified natural zeolites as drug formulation excipient was performed. The aim of this work was to carry out a study of the purified natural zeolitic tuff with high amount of clinoptilolite as a potential carrier for molecules of pharmaceutical interest. Two cationic surfactants (benzalkonium chloride and hexadecyltrimethylammonium bromide) were used for modification of the zeolitic surface in two levels (equal to and twice as external cation-exchange capacity of the zeolitic tuff). Prepared samples were characterized by Fourier transform infrared spectroscopy, thermogravimetric, high-performance liquid chromatography analysis, and powder flow determination. Different surfactant/zeolite composites were used for additional investigation of three model drugs: diclofenac diethylamine, diclofenac sodium, and ibuprofen by means of adsorption isotherm measurements in aqueous solutions. The modified zeolites with two levels of surfactant coverage within the short activation time were prepared. Determination of flow properties showed that modification of zeolitic surface reflected on powder flow characteristics. Investigation of the model drugs adsorption on the obtained composites revealed that a variation between adsorption levels was influenced by the surfactant type and the amount present at the surface of the composites. In vitro release profiles of the drugs from the zeolite-surfactant-drug composites revealed that sustained drug release could be attained over a period of 8 hours. The presented results for drug uptake by surfactant-zeolite composites and the afterward drug release demonstrated the potential use of investigated modified natural zeolite as excipients for advanced excipients in drug formulations.


Reporter mice express green fluorescent protein at initiation of meiosis in spermatocytes.
Transgenic mice were generated using a heat shock protein 2 (Hspa2) gene promoter to express green fluorescent protein (GFP) at the beginning of meiotic prophase I in spermatocytes. Expression was confirmed in four lines by in situ fluorescence, immunohistochemistry, western blotting, and PCR assays. The expression and distribution of the GFP and HSPA2 proteins co-localized in spermatocytes and spermatids in three lines, but GFP expression was variegated in one line (F46), being present in some clones of meiotic and post-meiotic germ cells and not in others. Fluorescence activated cell sorting (FACS) was used to isolate purified populations of spermatocytes and spermatids. Although bisulfite sequencing revealed differences in the DNA methylation patterns in the promoter regions of the transgene of the variegated expressing GFP line, a uniformly expressing GFP reporter line, and the Hspa2 gene, these differences did not correlate with variegated expression. The Hspa2-GFP reporter mice provide a novel tool for studies of meiosis by allowing detection of GFP in situ and in isolated spermatogenic cells. They will allow sorting of meiotic and post-meiotic germ cells for characterization of molecular features and correlation of expression of GFP with stage-specific spermatogenic cell proteins and developmental events.


Reciprocal modulation of helper Th1 and Th17 cells by the β2-adrenergic receptor agonist drug terbutaline.
Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (β2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a β2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4+ CXCR3- CCR6+ ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the β2AR.


Acute and chronic effects of extensive radiofrequency lesions in the canine caval veins: implications for ablation of atrial arrhythmias.
Although radiofrequency (RF) ablation within the caval veins has been increasingly used to treat a variety of atrial tachyarrhythmias, the consequences of RF ablation in the caval veins are unknown. We explored the acute and chronic angiographic and pathological effects of extensive RF ablation in the caval veins. Under fluoroscopy guidance, conventional (4 mm tip, 60 degrees C, 60 seconds) RF applications (n = 6-7) were delivered in each vena cava (from +/-2 cm into the vein to the veno-atrial junction) of 15 dogs (10 +/- 3 kg). Animals were killed 1 hour and 5 weeks after ablation for histological analysis. Angiography was performed before ablation (acute dogs only) and at sacrifice to assess the degree of vascular stenosis. In acute dogs (n = 5), luminal narrowing was noted in 10/10 (100%) targeted veins (mild in two; moderate in three and severe in five, including two total occlusions). In the six chronic animals that completed the protocol (four died during follow-up), stenosis was also observed in 12/12 (100%) ablated veins (mild in six; moderate in four and severe in two). Of these, one superior vena cava was suboccluded with development of extensive collateral circulation. Histologically, acute lesions displayed typical transmural coagulative necrosis, whereas chronic lesions revealed intimal proliferation, necrotic muscle replaced with collagen, endovascular contraction, and disruption and thickening of the internal elastic lamina. In this model, extensive RF ablation in the caval veins may result in significant vascular stenosis. These findings may have implications for catheter ablation of arrhythmias originating within the caval veins.


Development of carbon-graphene-based aptamer biosensor for EN2 protein detection.
In this study, we developed a screen-printed carbon-graphene-based electrochemical biosensor for EN2 protein detection. The engrailed-2 (EN2) protein, a biomarker for prostate cancer, is known to be a strong binder to a specific DNA sequence (5'-TAATTA-3') to regulate transcription. To take advantage of this intrinsic property, aptamer probes with TAATTA sequence was immobilized onto the screen-printed carbon-graphene electrode surface via EDC-NHS coupling approach. Cyclic voltammetry (CV) of the electrochemical measurement technique was employed for the quantitative detection of EN2 protein. The hindrance to the redox reaction of potassium ferricyanide on the biosensor surface due to the binding of the immobilized aptamer with its target EN2 protein quantified the protein concentration. Under optimum conditions, the aptamer biosensor can detect EN2 protein over a linear range from 35 to 185 nM with a detection limit of 38.5 nM.


Complications of peritoneovenous shunt for malignant ascites.
A peritoneovenous (PV) shunt was placed in eight patients with intractable malignant ascites. The shunt successfully controlled the ascites in six patients. The median survival time of the entire group was 2 months, with one patient alive at 22 months. Two of seven patients had secondary shunt failure: one from an unknown cause which could not be corrected by revision and another which was corrected by revision following removal of psammoma bodies in the valve. The complications of the shunt included transient edema (four patients), transient intravascular coagulation (four patients), and fever (two patients). Tumor embolization was suspected pathologically in two of eight patients although the ascitic fluid contained malignant cells in seven of eight patients. The PV shunt is a satisfactory palliative procedure for malignant ascites in the presence of adequate cardiac function and in the absence of urinary obstruction. The presence of bloody effusion or major intra-abdominal mass lesions contra-indicates a successful PV shunt. The acute adverse effets of the PV shunt (fever, fluid overload, and fulminant disseminated intravascular coagulation) may be prevented or minimized by preoperative fluid removal to obviate a major intravascular infusion of colloid and biologically active pyrogen and thromboplastin.


Nondisclosure of HIV infection to sex partners and alcohol's role: a Russian experience.
Nondisclosure of one's HIV infection to sexual partners obviates safer sex negotiations and thus jeopardizes HIV transmission prevention. The role of alcohol use in the disclosure decision process is largely unexplored. This study assessed the association between alcohol use and recent nondisclosure of HIV serostatus to sex partners by HIV-infected risky drinkers in St. Petersburg, Russia. Approximately half (317/605; 52.4 %) reported not having disclosed their HIV serostatus to all partners since awareness of infection. Using three separate GEE logistic regression models, we found no significant association between alcohol dependence, risky alcohol use (past 30 days), or alcohol use at time of sex (past 30 days) with recent (past 3 months) nondisclosure (AOR [95 % CI] 0.81 [0.55, 1.20], 1.31 [0.79, 2.17], 0.75 [0.54, 1.05], respectively). Alcohol use at time of sex was associated with decreased odds of recent nondisclosure among seroconcordant partners and among casual partners. Factors associated with nondisclosure were relationship with a casual partner, a serodiscordant partner, multiple sex partners, awareness of HIV diagnosis less than 1 year, and a lifetime history of sexually transmitted disease. Nondisclosure of HIV status to sex partners is common among HIV-infected Russians, however alcohol does not appear to be a predictor of recent disclosure.


Serum transforming growth factor-beta1 level reflects disease status in patients with esophageal carcinoma after radiotherapy.
To evaluate the relationship between changes in serum transforming growth factor beta1 (TGFbeta1) level and curative effect of radiotherapy (RT) in patients with esophageal carcinoma. Ninety patients with histologically confirmed esophageal carcinoma were enrolled. Serum samples for TGFbeta1 analysis were obtained before and at the end of RT. An enzyme-linked immunosorbent assay was used to measure serum TGFbeta1 level. Multivariate analysis was performed to investigate the relationship between disease status and changes in serum TGFbeta1 level. Serum TGFbeta1 level in patients with esophageal carcinoma before RT was significantly higher than that in healthy controls (P < 0.001). At the end of RT, serum TGFbeta1 level was decreased in 67.82% (59/87) of the patients. The overall survival rate at 1, 3 and 5 years was 48.28% (42/87), 19.54% (17/87) and 12.64% (11/87), respectively. Main causes of death were local failure and regional lymph node metastasis. In patients whose serum TGFbeta1 level decreased after RT, the survival rate at 1, 3 and 5 years was 61.02% (36/59), 28.81% (17/59) and 18.64% (11/59), respectively. The survival rate at 1 year was 17.86% (5/28) in patients whose serum TGFbeta1 level increased after RT, and all died within 18 mo (P < 0.01). Serum TGFbeta1 level may be a useful marker for monitoring disease status after RT in patients with esophageal carcinoma.


Large differences in erythrocyte stability between species reflect different antioxidative defense mechanisms.
We have developed a screening assay for erythrocyte stability, which is rapid, easy, inexpensive, robust, and suitable for handling a large number of samples in parallel. Erythrocytes are incubated overnight in 96-well microtiter plates in absence or presence of various oxidants, intact cells are pelleted by centrifugation, and lysis is determined by release of intracellular constituents into the supernatant as either activity of lactate dehydrogenase (LDH) or absorbance of hemoglobin at 406 nm. There is good correlation between the methods. A number of advantages by the present method are that only small amounts of blood is needed, washing is optional, erythrocytes may be stored for at least one day before assay, and large numbers of samples can be handled in parallel. Using this set-up, we have compared erythrocyte stability from several different animal species. We find that erythrocyte susceptibility towards lysis induced by H2O2 and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is highly species dependent. The different susceptibility between species is due to cellular components, since swapping of plasma between species has little or no effect. As a novel observation, we find that erythrocytes from chicken are the most sensitive of the species tested towards lysis by H2O2 and are almost four orders of magnitude more sensitive than erythrocytes from man. This is due to a much lower content of catalase in erythrocytes from chicken. A more narrow range is observed for susceptibility towards AAPH and the ranking between the species is different. Thus, chicken erythrocytes are more resistant towards AAPH than some mammals by up to two orders of magnitude. This differential stability towards different oxidative stressors is likely due to evolution/selection of different defense mechanisms.


Association of the Pro12Ala Polymorphism with the Metabolic Parameters in Women with Polycystic Ovary Syndrome.
To investigate the association of peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism with polycystic ovary syndrome (PCOS) and its effect on the metabolic parameters in PCOS women. The study used PCR to identify the presence of the PPARG Pro12Ala polymorphism in 100 PCOS women and 120 age-matched healthy women. All participants were subjected to anthropometry, biochemical and metabolic evaluation. Significant difference in the genotypes distributions of PPARG Pro12Ala polymorphism was observed among PCOS women and controls (p = 0.03). The frequency of the polymorphic allele Ala was significantly higher in PCOS cases than that in the controls (OR = 2.01, p = 0.01). The carries of the variant allele Ala in PCOS women showed significant higher values in body mass index (BMI), systolic and diastolic blood pressure, waist circumference, waist to hip ratio, sum of skin folds, fasting blood glucose, fasting blood insulin, HOMA-IR, fasting triglycerides, total cholesterol and low-density lipoprotein than non-carriers. The PPARG Pro12Ala polymorphism might contribute to the risk of PCOS and abnormal metabolic parameters and could be considered as a biomarker for early diagnosis and clinic prediction of metabolic complications.


Combination therapy Eve and Pac to induce apoptosis in cervical cancer cells by targeting PI3K/AKT/mTOR pathways.
This study aimed to investigate the anti-cervical cancer effects of everolimus (Eve) and paclitaxel (Pac) when used alone or in combination. Human cervical cancer cells HeLa and SiHa were divided into four group: Blank control group (control), everolimus group (Eve), paclitaxel group (Pac) and combined therapy group (Eve + Pac). The cell viability was detected by CCK-8 assay and the cell cloning ability was detected by clonegenic assay. Flow cytometry was used to detect cell apoptosis. Meanwhile, the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR) and their phosphorylated proteins were studied by western blot. The HeLa and SiHa cells proliferation and cloning ability were significantly inhibited in drug treatment groups compared with control group (p < .05), and the Eve + Pac combinatorial therapy showed the better results than single treatment with Eve or Pac. Combination of Eve and Pac has synergistic effect on the induction of apoptosis in cervical cancer cells. In addition, the protein ratios in HeLa and SiHa cell treated with the Eve + Pac combination were significantly lower than that of cervical cancer cells treated with either Eve or Pac cell alone. Our study suggested that Eve + Pac provide a novel therapeutic strategy for cervical cancer.


Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that plays a pivotal role in obesity and diabetes. PPARgamma has two isoforms, PPARgamma1 and PPARgamma2. We investigated the functional differences between PPARgamma1 and PPARgamma2 by selectively disrupting PPARgamma2 in mice. In contrast to the embryonic lethality of PPARgamma-deficient mice, PPARgamma2(-/-) mice survived. Although normal development was identified in other tissues we examined, PPARgamma2(-/-) mice exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue. In addition, insulin sensitivity was impaired in male PPARgamma2(-/-) mice, with dramatically decreased expression of insulin receptor substrate 1 and glucose transporter 4 in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. Consistent with in vivo data, PPARgamma2(-/-) mouse embryonic fibroblasts showed a dramatically reduced capacity for adipogenesis in vitro compared with wild-type mouse embryonic fibroblasts. Taken together, our data demonstrate that PPARgamma2 deficiency impairs the development of adipose tissue and insulin sensitivity. PPARgamma2(-/-) mice may provide a tool to study the role of PPARgamma2 in obesity and diabetes.


Inorganic photochemical protein scissors: photocleavage of lysozyme by Co(III) complexes.
Photocleavage of chicken hen egg lysozyme by three Co(III)ammine complexes, hexamminecobalt(III) chloride ([Co(NH3)6]+3), pentamminechloro cobalt(III)chloride ([Co(NH3)5Cl]+2), and tetramminecarbonato cobalt(III) nitrate ([Co(NH3)4CO3]+), is reported here. Photocleavage resulted in two fragments of molecular masses of approximately 10.5 kDa and approximately 3.5 kDa which add-up to that of the parent molar mass. Detailed studies on the influence of irradiation time, excitation wavelength, the type of ligand coordinated to Co(III), concentration of the metal complex, the addition of competing metal ions, and quenchers on the protein photocleavage are reported. The Co(III) complexes also photocleaved apotransferrin, bovine serum albumin, and yeast enolase. Near-equimolar concentrations of Ni(II), Co(II) or Gd(III) inhibited the photocleavage, and therefore, binding of Co(III) metal complexes to Ni(II)/Co(II)/Gd(III) binding sites on lysozyme is necessary for the observed photocleavage. Since these ions are known to bind to Asp52 on lysozyme, we suspect that the above Co(III) complexes bind at this site, and initiate the protein cleavage. The Co(III) complexes have appropriate photochemical reactivities to cleave the peptide backbone, and they may be useful in the design of novel photochemical approaches to cleave the protein backbone.


[Coronary artery motion estimation using X-ray cineangiogram].
This paper presents an approach for estimating the non-rigid motion of coronary arteries using digital angiographic images. Displacement vectors of vessel points are obtained by finding points correspondences in two successive frames. Smoothness of motion field and vessel deformation measurement are considered in matching, and unmatched regions are also dealt with in the fact that the vessel after deformation may have different size with its original station. The search strategy for optimal matching is carried out using dynamic programming (DP) so that computing cost is reduced. Results of this motion estimation method applied to synthetic and clinical images have shown that the method is accurate, with a root mean square error about one pixel for simulated data. For the case of actual X-ray coronary angiographic images, visual inspection of the detected pairs of points shows that the results are very encouraging.


Haemolymph pressure regulation in Porcellio laevis Latr. (Porcellionidae, Isopoda).
Hydrostatic pressure in the haemocoele in Porcellio laevis adults ranges between 3.69 to 12.92 mm Hg (50 to 175 mm H2O). Mechanism involved in haemolymph pressure regulation includes characteristic contractions of intersegmental body musculature. The effects of temperature, humidity, decapitation, destruction of thoracic ganglion, and the injection of insect Ringer and eserine into the haemocoele on intersegmental muscular contractions were studied. The significance of these findings is discussed.


[Severe community acquired pneumonia due to Staphylococcus aureus in children. About two cases].
The staphylococcal pneumonia is the prerogative of the infant but rare cases were observed in the childhood. We report the observation of two children aged respectively of six years and three years and a half having presented a particular form of severe staphylococcal pneumonia apart from any context of immunodepression. The identification of the particular strains producing toxins Like the Panton and Valentine leukocidin constitutes the first stage of the comprehension of this atypical form of pneumonia. Through these observations and with a review of literature we underline the specific clinical and biological aspects of this form.


RETINAL MICROCIRCULATION INVESTIGATION IN TYPE I AND II DIABETIC PATIENTS WITHOUT RETINOPATHY USING AN ADAPTIVE OPTICS RETINAL CAMERA.
State of art imaging techniques might be a useful tool to early detect the retinal vessels lesions in diabetes. This analytical observational study investigates the retinal microcirculation changes in type I and II diabetic patients without retinopathy using adaptive optics ophthalmoscopy (AOO) and optical coherence ophthalmoscopy angiography (OCTA). Fifty-five subjects were included in this study and were divided in three groups: type I diabetic group (n=16), type II diabetic group (n=19) and control group (n=20). An adaptive optics retinal camera was used to assess the parameters of the temporal superior retinal arterioles. Moreover, vessel density of the superficial capillary plexus across the parafoveal area was measured with OCT-A. All cases were investigated once, in a cross-sectional design. Diabetic patients from both groups had a higher wall-to-lumen-ratio compared to the controls (p=0.01 and 0.01, respectively). Interestingly, no significant differences were found between the two diabetic groups (p=0.69). Moreover, the vessel density was smaller in the type I diabetic group than in the control group (p=0.001). AOO might be a useful tool to detect early retinal vascular changes in diabetes before any clinical signs and together with OCTA it might bring important information on the prognostic and pathophysiology of the disease.


Insight Into the Mechanism of Exercise Preconditioning in Ischemic Stroke.
Exercise preconditioning has attracted extensive attention to induce endogenous neuroprotection and has become the hotspot in neurotherapy. The training exercise is given multiple times before cerebral ischemia, effectively inducing ischemic tolerance and alleviating secondary brain damage post-stroke. Compared with other preconditioning methods, the main advantages of exercise include easy clinical operation and being readily accepted by patients. However, the specific mechanism behind exercise preconditioning to ameliorate brain injury is complex. It involves multi-pathway and multi-target regulation, including regulation of inflammatory response, oxidative stress, apoptosis inhibition, and neurogenesis promotion. The current review summarizes the recent studies on the mechanism of neuroprotection induced by exercise, providing the theoretical basis of applying exercise therapy to prevent and treat ischemic stroke. In addition, we highlight the various limitations and future challenges of translational medicine from fundamental study to clinical application.


Synergistic effect of all-trans-retinoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro.
To investigate the effect of all-trans-retinoic acid (ATRA) on arsenic trioxide (As(2)O(3))-induced apoptosis of human hepatoma, breast cancer, and lung cancer cells in an attempt to find a better combination therapy for solid tumors. Human hepatoma cell lines HepG2, Hep3B, human breast cancer cell line MCF-7, and human lung adenocarcinoma cell line AGZY-83-a were treated with As(2)O(3) together with ATRA. Cell survival fraction was determined by MTT assay, cell viability and apoptosis were measured by annexin V-fluorescein isothiocyanate (FITC) and PI staining, and intracellular glutathione (GSH) and glutathione-S-transferase (GST) activities were determined using commercial kits. Cytotoxicity of ATRA was low. ATRA (0.1, 1, and 10 micromol/L) could synergistically potentiate As(2)O(3) to exert a dose-dependent inhibition of growth and to induce apoptosis in each of the cell lines. HepG2 and Hep3B with low intracellular GSH or GST activities were remarkably sensitive to As(2)O(3) or As(2)O(3)+ATRA, while AGZY-83-a with higher GSH or GST activities was less sensitive to As(2)O(3) or As(2)O(3)+ATRA. Treatment with 2 micromol/L As(2)O(3) for 72 h significantly decreased intracellular GSH and GST levels in each of the cell lines, and 1 micromol/L ATRA alone reduced minimal intracellular GSH and GST levels. ATRA potentiated the effect of As(2)O(3) on intracellular GSH levels, but intracellular GST levels were not significantly affected by the combination of As(2)O(3) and ATRA for 72 h as compared to As(2)O(3) alone. ATRA can strongly potentiate As(2)O(3)-induced growth-inhibition and apoptosis in each of the cell lines, and two drugs can produce a significant synergic effect. The sensitivity to As(2)O(3) or As(2)O(3)+ATRA is inversely proportional to intracellular GSH or GST levels in each of the cell lines. The GSH redox system may be the possible mechanism by which ATRA synergistically potentiates As(2)O(3) to exert a dose-dependent inhibition of growth and to induce apoptosis.


Informing Efforts to Develop Nitroreductase for Amine Production.
Nitroreductases (NRs) hold promise for converting nitroaromatics to aromatic amines. Nitroaromatic reduction rate increases with Hammett substituent constant for NRs from two different subgroups, confirming substrate identity as a key determinant of reactivity. Amine yields were low, but compounds yielding amines tend to have a large π system and electron withdrawing substituents. Therefore, we also assessed the prospects of varying the enzyme. Several different subgroups of NRs include members able to produce aromatic amines. Comparison of four NR subgroups shows that they provide contrasting substrate binding cavities with distinct constraints on substrate position relative to the flavin. The unique architecture of the NR dimer produces an enormous contact area which we propose provides the stabilization needed to offset the costs of insertion of the active sites between the monomers. Thus, we propose that the functional diversity included in the NR superfamily stems from the chemical versatility of the flavin cofactor in conjunction with a structure that permits tremendous active site variability. These complementary properties make NRs exceptionally promising enzymes for development for biocatalysis in prodrug activation and conversion of nitroaromatics to valuable aromatic amines. We provide a framework for identifying NRs and substrates with the greatest potential to advance.


ROS-Mediated Apoptosis and Autophagy in Ovarian Cancer Cells Treated with Peanut-Shaped Gold Nanoparticles.
Even with considerable improvement in treatment of epithelial ovarian cancer achieved in recent years, an increasing chemotherapy resistance and disease 5-year relapse is recorded for a majority part of patients that encourages the search for better therapeutic options. Gold nanoparticles (Au NPs) due to plethora of unique physiochemical features are thoroughly tested as drug delivery, radiosensitizers, as well as photothermal and photodynamic therapy agents. Importantly, due to highly controlled synthesis, it is possible to obtain nanomaterials with directed size and shape. In this work, we developed novel elongated-type gold nanoparticles in the shape of nanopeanuts (AuP NPs) and investigated their cytotoxic potential against ovarian cancer cells SKOV-3 using colorimetric and fluorimetric methods, Western blot, flow cytometry, and fluorescence microscopy. Peanut-shaped gold nanoparticles showed high anti-cancer activity in vitro against SKOV-3 cells at doses of 1-5 ng/mL upon 72 hours treatment. We demonstrate that AuP NPs decrease the viability and proliferation capability of ovarian cancer cells by triggering cell apoptosis and autophagy, as evidenced by flow cytometry and Western blot analyses. The overproduction of reactive oxygen species (ROS) was noted to be a critical mediator of AuP NPs-mediated cell death. These data indicate that gold nanopeanuts might be developed as nanotherapeutics against ovarian cancer.


[Treatment efficacy of dietary supplement Licofor for dry eye associated with meibomian gland dysfunction].
Objective: To evaluate the clinical efficacy of dietary supplement Licofor in the treatment of dry eye associated with meibomian gland dysfunction (MGD). Methods: This was a prospective, randomized controlled clinical trial. Sixty patients [25 males, 35 females, aged (42±13) years] who had dry eye associated with MGD were recruited in Xiangya Hospital of Central South University from December 2018 to October 2019. The patients were equally divided into two groups: 30 cases (60 eyes) in the experimental group and 30 cases (60 eyes) in the control group. All subjects were treated with eye hot compress, artificial tears and antibiotic ointment. After that, the experimental group and control group were received dietary supplementary Licofor or placebo daily for 12 weeks. The symptoms and signs of dry eye, morphology and function of meibomian gland, and inflammatory response were assessed at the beginning, 4th, 8th and 12th week of treatment. Results: After 12 weeks of treatment, statistically significant improvements in ocular surface disease index (OSDI) scores, tear break-up time (TBUT), corneal fluorescein staining (CFS), the morphology of eyelid margin, meibomian gland orifice, meibomian gland expressibility, meibum quality, and periglandular inflammatory cell density were determined in both groups (all P<0.05). In the Licofor group, the improvement of OSDI scores [16.7 (12.5, 20.8) vs 20.8 (18.8, 22.9), P<0.001], the morphology of eyelid margin, meibomian gland orifice and periglandular inflammatory cell density [443 (318, 513) vs 553 (415, 676)/mm2, P=0.002] were more significant (all P<0.05). Conclusion: The combined treatment of licofor and conventional treatment can significantly improve symptoms of dry eye, the morphology of eyelid margin, meibomian gland orifice, meibum quality, and eyelid inflammation response of dry eye associated with MGD.


High invasive pollen transfer, yet low deposition on native stigmas in a Carpobrotus-invaded community.
Invasive plants are potential agents of disruption in plant-pollinator interactions. They may affect pollinator visitation rates to native plants and modify the plant-pollinator interaction network. However, there is little information about the extent to which invasive pollen is incorporated into the pollination network and about the rates of invasive pollen deposition on the stigmas of native plants. The degree of pollinator sharing between the invasive plant Carpobrotus affine acinaciformis and the main co-flowering native plants was tested in a Mediterranean coastal shrubland. Pollen loads were identified from the bodies of the ten most common pollinator species and stigmatic pollen deposition in the five most common native plant species. It was found that pollinators visited Carpobrotus extensively. Seventy-three per cent of pollinator specimens collected on native plants carried Carpobrotus pollen. On average 23 % of the pollen on the bodies of pollinators visiting native plants was Carpobrotus. However, most of the pollen found on the body of pollinators belonged to the species on which they were collected. Similarly, most pollen on native plant stigmas was conspecific. Invasive pollen was present on native plant stigmas, but in low quantity. Carpobrotus is highly integrated in the pollen transport network. However, the plant-pollination network in the invaded community seems to be sufficiently robust to withstand the impacts of the presence of alien pollen on native plant pollination, as shown by the low levels of heterospecific pollen deposition on native stigmas. Several mechanisms are discussed for the low invasive pollen deposition on native stigmas.


Nuclear translocation of phospholipase C-delta1 is linked to the cell cycle and nuclear phosphatidylinositol 4,5-bisphosphate.
Nuclear phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate, fluctuate throughout the cell cycle and are linked to proliferation and differentiation. Here we report that phospholipase C-delta(1) accumulates in the nucleus at the G(1)/S boundary and in G(0) phases of the cell cycle. Furthermore, as wild-type protein accumulated in the nucleus, nuclear phosphatidylinositol 4,5-bisphosphate levels were elevated 3-5-fold, whereas total levels were decreased compared with asynchronous cultures. To test whether phosphatidylinositol 4,5-bisphosphate binding is important during this process, we introduced a R40D point mutation within the pleckstrin homology domain of phospholipase C-delta(1), which disables high affinity phosphatidylinositol 4,5-bisphosphate binding, and found that nuclear translocation was significantly reduced at G(1)/S and in G(0). These results demonstrate a cell cycle-dependent compartmentalization of phospholipase C-delta(1) and support the idea that relative levels of phosphoinositides modulate the portioning of phosphoinositide-binding proteins between the nucleus and other compartments.


Pre-Hospital Induced Hypothermia Improves Outcomes in a Pig Model of Traumatic Hemorrhagic Shock.
Extensive preclinical evidence suggests that induced hypothermia can protect tissues from ischemia-reperfusion injury, reduce organ damage, and improve survival in the advanced stages of shock. We assessed the effects of induced hypothermia on the hemodynamic parameters and coagulation capacity during hemorrhagic shock (HS) and fluid resuscitation, in a pig model of HS with multiple intestinal perforations. Pigs (n=16) were randomized into 2 groups: a hypothermia (HT) group (n=8, 34°C) and a normothermia (NT) group (n=8, 38°C). Hypothermia to 34°C was induced with a cold blanket at the pre-hospital stage. Traumatic HS shock was induced using multiple intestinal perforations. Pulse indicator continuous cardiac output (PiCCO) was used to monitor hemodynamic changes. Coagulation capacity was measured using thromboelastography (TEG) at baseline as well as during resuscitation periods. Survival was documented for 72 h post-trauma. Mortality in the hypothermic HS group was low, but there were no significant differences in mortality between the groups (mortality=2/8 HT vs. 5/8 NT, p=0.137). During hypothermia, the heart rate, extravascular lung water index (EVLWI), oxygen uptake index (VO2), and oxygen delivery index (DO2) in the HT group were significantly lower than those in the NT group. There were no significant differences between the 2 groups in the other hemodynamic indices or prothrombin time. Analyses of thromboelastometry at 34°C during hypothermia showed significant differences for reaction time (R) and alpha angle, but not for maximal amplitude (MA). Rewarming reversed the coagulation changes induced by hypothermia. Induced mild hypothermia (34°C) in the pre-hospital stage affects hemodynamic parameters and the coagulation system but does not worsen outcomes in a pig HS model. The hypothermia-induced coagulation changes were reversed during rewarming without evidence of harmful effects. Our results suggest that pre-hospital induced hypothermia can be performed carefully following major trauma.


There's no place like home: achieving safety, permanency, and well-being for lesbian and gay adolescents in out-of-home care settings.
A study was conducted with 45 self-identified gay, lesbian, bisexual, transgendered, and questioning (GLBTQ) youth and agency staff at the two known gay-affirming child welfare agencies in the United States: Green Chimneys GLBTQ Programs in New York City and Gay and Lesbian Social Services in Los Angeles, California. The study examined the question, "What are the challenges presented in ensuring permanency, safety, and well-being for gay and lesbian youth in a gay-affirming child welfare environment?" Guided by the framework outlined in the Child and Family Services Reviews National Standards, which support better outcomes for children and youth, the investigators sought to explore the challenges of ensuring permanency, safety, and well-being for this population, as these challenges were identified by the agency staff and youth who live and work in either of these two gay-affirming programs.


Temsirolimus Sensitive Stimulation of Platelet Activity, Apoptosis and Aggregation by Collagen Related Peptide.
The mammalian target of rapamycin (mTOR) inhibitor temsirolimus stimulates apoptosis of tumor cells and is thus therapeutically used for the treatment of diverse malignancies. On the other hand, temsirolimus has been shown to protect against apoptosis of hippocampal neurons. Similar to nucleated cells, blood platelets may enter suicidal death characterized by cell shrinkage and cell membrane scrambling. Platelet apoptosis is frequently preceded by Ca2+ entry, degranulation, integrin activation and stimulation of caspases. Those events could be triggered by collagen related peptide (CRP). The present study explored whether treatment of platelets with temsirolimus modifies platelet activation, caspase activity, platelet shrinkage, and phosphatidylserine abundance. Platelets isolated from wild-type mice were exposed for 30 minutes to temsirolimus (40 µg/ml) without or with additional CRP (2 µg/ ml or 5 µg/ml) treatment. Flow cytometry was employed to estimate cytosolic Ca2+-activity ([Ca2+]i) from Fluo-3 fuorescence, platelet degranulation from P-selectin abundance, integrin activation from αIIbβ3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding and relative platelet volume from forward scatter. In the absence of CRP, the administration of temsirolimus (40 µg/ml) significantly decreased [Ca2+]i, but did not significantly modify P-selectin abundance, activated αIIbβ3 integrin, annexin-V-binding, cell volume, caspase activity and aggregation. Exposure of platelets to CRP was followed by significant increase of [Ca2+]i, P-selectin abundance, αIIbβ3 integrin activity, annexin-V-binding, ROS, caspase activity and aggregation, effects significantly blunted in the presence of temsirolimus. CRP further decreased forward scatter, an effect again significantly blunted by temsirolimus. Temsirolimus is a powerful inhibitor of platelet activation and suicidal platelet death.


Gene therapy in ophthalmology: validation on cultured retinal cells and explants from postmortem human eyes.
Gene therapy studies in primates can provide important information regarding vector tropism, specific cellular expression, biodistribution, and safety prior to clinical trials. In this study, we report the assessment of transduction efficiency of recombinant adeno-associated virus (rAAV) vectors using human postmortem retina. Transductions were performed using two in vitro models prepared from human tissue: dissociated cell cultures and retinal explants. These models were used to assess cellular tropism and selectivity of rAAV vectors encoding for fluorescent proteins under the control of different promoters. These promoters were a ubiquitous cytomegalovirus promoter and a cell type-specific promoter targeting expression in ON bipolar cells. The results demonstrate that this in vitro approach can limit the use of living primates for the validation of gene therapy in vision and ophthalmology.


The compromised recognition of turnip crinkle virus1 subfamily of microrchidia ATPases regulates disease resistance in barley to biotrophic and necrotrophic pathogens.
MORC1 and MORC2, two of the seven members of the Arabidopsis (Arabidopsis thaliana) Compromised Recognition of Turnip Crinkle Virus1 subfamily of microrchidia Gyrase, Heat Shock Protein90, Histidine Kinase, MutL (GHKL) ATPases, were previously shown to be required in multiple layers of plant immunity. Here, we show that the barley (Hordeum vulgare) MORCs also are involved in disease resistance. Genome-wide analyses identified five MORCs that are 37% to 48% identical on the protein level to AtMORC1. Unexpectedly, and in clear contrast to Arabidopsis, RNA interference-mediated knockdown of MORC in barley resulted in enhanced basal resistance and effector-triggered, powdery mildew resistance locus A12-mediated resistance against the biotrophic powdery mildew fungus (Blumeria graminis f. sp. hordei), while MORC overexpression decreased resistance. Moreover, barley knockdown mutants also showed higher resistance to Fusarium graminearum. Barley MORCs, like their Arabidopsis homologs, contain the highly conserved GHKL ATPase and S5 domains, which identify them as members of the MORC superfamily. Like AtMORC1, barley MORC1 (HvMORC1) binds DNA and has Mn2+-dependent endonuclease activities, suggesting that the contrasting function of MORC1 homologs in barley versus Arabidopsis is not due to differences in their enzyme activities. In contrast to AtMORCs, which are involved in silencing of transposons that are largely restricted to pericentromeric regions, barley MORC mutants did not show a loss-of-transposon silencing regardless of their genomic location. Reciprocal overexpression of MORC1 homologs in barley and Arabidopsis showed that AtMORC1 and HvMORC1 could not restore each other's function. Together, these results suggest that MORC proteins function as modulators of immunity, which can act negatively (barley) or positively (Arabidopsis) dependent on the species.


A novel bio-sensor based on DNA strand displacement.
DNA strand displacement technology performs well in sensing and programming DNA segments. In this work, we construct DNA molecular systems based on DNA strand displacement performing computation of logic gates. Specifically, a class of so-called "DNA neurons" are achieved, in which a "smart" way inspired by biological neurons encoding information is developed to encode and deliver information using DNA molecules. The "DNA neuron" is bistable, that is, it can sense DNA molecules as input signals, and release "negative" or "positive" signals DNA molecules. We design intelligent DNA molecular systems that are constructed by cascading some particularly organized "DNA neurons", which could perform logic computation, including AND, OR, XOR logic gates, automatically. Both simulation results using visual DSD (DNA strand displacement) software and experimental results are obtained, which shows that the proposed systems can detect DNA signals with high sensitivity and accretion; moreover, the systems can process input signals automatically with complex nonlinear logic. The method proposed in this work may provide a new way to construct a sensitive molecular signal detection system with neurons spiking behavior in vitro, and can be used to develop intelligent molecular processing systems in vivo.


Adsorption, dissociation, penetration, and diffusion of N2 on and in bcc Fe: first-principles calculations.
We report first-principles calculations of adsorption, dissociation, penetration, and diffusion for the complete nitridation mechanism of nitrogen molecules on a pure Fe surface (bcc, ferrite phase). The mechanism of the definite reaction path was calculated by dividing the process into four steps. We investigated various reaction paths for each step including the energy barrier based on the climb image nudged elastic band (CI-NEB) method, and the complete reaction pathway was computed as the minimum energy path (MEP). The adsorption characteristics of nitrogen (N) and molecular nitrogen (N2) indicate that nitrogen atoms and molecules are energetically favorable at the hollow sites on pure Fe(100) and (110). The dissociation of the nitrogen molecule (N2) was theoretically supported by electronic structure calculations. The penetration of nitrogen from the surface to the sub-surface has a large energy barrier compared with the other steps. The activation energy calculated for nitrogen diffusion in pure bcc Fe was in good agreement with the experimental results. Finally, we confirmed the rate-determining step for the full nitridation reaction pathway. This study provides fundamental insight into the nitridation mechanism for nitrogen molecules in pure bcc Fe.


Swine Influenza Virus Induces RIPK1/DRP1-Mediated Interleukin-1 Beta Production.
Nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome plays a pivotal role in modulating lung inflammation in response to the influenza A virus infection. We previously showed that the swine influenza virus (SIV) infection induced NLRP3 inflammasome-mediated IL-1β production in primary porcine alveolar macrophages (PAMs), and we were interested in examining the upstream signaling events that are involved in this process. Here, we report that the SIV-infection led to dynamin-related protein 1 (DRP1) phosphorylation at serine 579 and mitochondrial fission in PAMs. IL-1β production was dependent on the reactive oxygen species (ROS) production, and DRP1 phosphorylation resulted in the upregulation of the NLRP3 inflammasome. Furthermore, the requirement of the kinase activity of receptor-interacting protein kinase 1 (RIPK1) for the IL-1β production and RIPK1-DRP1 association suggested that RIPK1 is an upstream kinase for DRP1 phosphorylation. Our results reveal a critical role of the RIPK1/DRP1 signaling axis, whose activation leads to mitochondrial fission and ROS release, in modulating porcine NLRP3 inflammasome-mediated IL-1β production in SIV-infected PAMs.


The clinical course of human immunodeficiency virus infection in genetically identical children.
Human immunodeficiency virus (HIV) infection in children is associated with diverse clinical manifestations and highly variable rates of progression. There is little information concerning the clinical course of HIV infection in genetically identical children. We review the cases of identical triplets who were infected with HIV at 1 day of age via a blood transfusion from a common unit of contaminated blood. The subsequent clinical manifestations of HIV infection in the triplets were remarkably uniform. Moreover, the patients' CD4 cell counts declined at similar rates. These patients enhance our understanding of the role of viral and host factors in determining the clinical progression of HIV infection.


Bacterial endosymbionts in the gills of the deep-sea wood-boring bivalves Xylophaga atlantica and Xylophaga washingtona.
Bacterial endosymbionts found in gill tissues in several bivalve families convert otherwise unavailable energy sources (sulfide, methane, or cellulose) to forms readily metabolized by their hosts. We investigated the existence of such a symbiosis in two species of Xylophaga (family Pholadidae). The genus Xylophaga includes opportunistic species that are the predominant colonizers of wood at depths greater than 150 m. It has been hypothesized that, like their shallow-water counterparts the shipworms (family Teredinidae), species of Xylophaga utilize wood for nutrition. Results from transmission and scanning electron microscopy of X. atlantica and X. washingtona clearly demonstrate the presence of endosymbionts that resemble the shipworm endosymbionts both morphologically and in their anatomical location within the gills. Xylophaga and the teredinids both have a caecum packed with wood chips but lack the dense populations of microorganisms associated with cellulose digestion in termites or ruminants. These observations suggest that Xylophaga has evolved a symbiotic solution to wood digestion similar to that seen in shipworms. Hence, the Xylophaga symbiosis suggests a mechanism for the conversion of terrestrially derived cellulosic carbon from wood into animal biomass in the deep sea.


Structural insight into DFMO resistant ornithine decarboxylase from Entamoeba histolytica: an inkling to adaptive evolution.
Polyamine biosynthetic pathway is a validated therapeutic target for large number of infectious diseases including cancer, giardiasis and African sleeping sickness, etc. α-Difluoromethylornithine (DFMO), a potent drug used for the treatment of African sleeping sickness is an irreversible inhibitor of ornithine decarboxylase (ODC), the first rate limiting enzyme of polyamine biosynthesis. The enzyme ODC of E. histolytica (EhODC) has been reported to exhibit resistance towards DFMO. The basis for insensitivity towards DFMO was investigated by structural analysis of EhODC and conformational modifications at the active site. Here, we report cloning, purification and crystal structure determination of C-terminal truncated Entamoeba histolytica ornithine decarboxylase (EhODCΔ15). Structure was determined by molecular replacement method and refined to 2.8 Å resolution. The orthorhombic crystal exhibits P2(1)2(1)2(1) symmetry with unit cell parameters a = 76.66, b = 119.28, c = 179.28 Å. Functional as well as evolutionary relations of EhODC with other ODC homologs were predicted on the basis of sequence analysis, phylogeny and structure. We determined the tetrameric crystal structure of EhODCΔ15, which exists as a dimer in solution. Insensitivity towards DFMO is due to substitution of key substrate binding residues in active site pocket. Additionally, a few more substitutions similar to antizyme inhibitor (AZI), a non-functional homologue of ODCs, were identified in the active site. Here, we establish the fact that EhODC sequence has conserved PLP binding residues; in contrast few substrate binding residues are mutated similar to AZI. Further sequence analysis and structural studies revealed that EhODC may represent as an evolutionary bridge between active decarboxylase and inactive AZI.


The pattern of catecholamine response to burst activity in leopard frogs, Rana pipiens.
It is well known that burst activity causes a rapid breakdown of muscle glycogen and extensive accumulation of lactate in frogs. During recovery, it has been shown that lactate is nearly totally recycled into muscle glycogen. Since catecholamines are likely to play some role in the regulation of postexercise repletion of muscle glycogen, the pattern of catecholamine response was assessed in frogs during intense physical activity and the ensuing recovery period. Chronically cannulated frogs were forced to swim until exhaustion, and serial blood samples were taken at regular time intervals for the measurements of catecholamines. The pattern of changes in plasma and muscle lactate and glucose and muscle glycogen during and after burst activity is similar to that reported in previous studies using noncannulated frogs, a result which indicates that the animals recover well from the surgical trauma associated with cannulation. The concentrations of plasma catecholamines in frogs at rest are comparable to those measured in other amphibians, and the levels of plasma epinephrine in resting frogs are much higher than those of norepinephrine. Burst activity causes a marked increase in plasma catecholamines, with higher levels reached by epinephrine. During recovery, the concentration of plasma catecholamines returns to normal within 30 min. Although this pattern of catecholamine response to intense physical activity may be favorable to the repletion of muscle glycogen postexercise, it remains to be clarified how critical the low levels and fast reduction in plasma catecholamines are for optimum glycogen resynthesis.


Sjogren's thrombocytopenia.
Primary Sjogren's is a multisystem autoimmune disease which predominantly affects the exocrine glands. pSS may occasionally present in an atypical way which may defy correct diagnosis for a considerable period of time. Clinically important immune-mediated cytopenia (or a combination of cytopenias) may be the first manifestation of an occult SS and have only been rarely described with Sjogren's. This case exemplifies the atypical presentation of pSS and hence should be considered in the differential diagnosis of patients with unexplained cytopenias.


Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression.
Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.


Molecular and clinical perspectives of polyomaviruses: emerging evidence of importance in non-kidney transplant populations.
JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) are deoxyribonucleic acid (DNA) viruses, members of the family Polyomaviridae. These viruses establish persistent infections, and reactivate from latency in their host under immunosuppression. During the last few years there has been recognition of the morbidity related to polyomaviruses, particularly BKV in kidney transplant recipients. More importantly, recent studies indicate the potential implication of JCV, BKV, and SV40 in renal dysfunction among nonrenal organ transplant patients. Polyomaviruses are tumor-inducing viruses and animal models have provided evidence of the oncogenicity of these pathogens. Although data are not conclusive, molecular studies suggest an association of BKV and SV40 with malignancies among solid organ transplant patients. As new and potent immunosuppressive agents are introduced into clinical practice, it is believed that the incidence of polyomavirus-related diseases in organ transplantation might increase. This review evaluates the biologic and epidemiologic features of these 3 viruses, the data regarding their infections in nonkidney organ transplant patients and describes future directions in the management and research of these opportunistic pathogens.


Beam diffraction effects in sound transmission of a fluid-embedded viscoelastic plate at normal incidence.
The characteristics of a sound beam transmitted through a fluid-embedded viscoelastic plate at normal incidence can deviate significantly from those of a plane-wave. Phenomena such as frequency shift, signal amplification or reduction, and changed beam properties, are observed for resonance peaks associated with specific leaky Lamb modes. When interpreting measurements using plane-wave theory, such deviations will influence the measurement of material parameters and plate thickness. The finite-element-based models used in this study describe the signal chain from the electrical voltage excitation at the piezoelectric transducer terminals to the sound pressure propagated through the plate and fluid to the position at which it is measured by a hydrophone. The measured phenomena are described at a quantitative level.


Genetic diversity of colistin resistance Nosocomial Acinetobacter baumannii strains from Iran.
Drug-resistant Acinetobacter baumannii is a global health problem since its ability to acquire new resistance mechanisms. Here, we aimed to determine the association of common types of A. baumannii and assess their drug resistance of A. baumannii and contribution of integrons (Ints) and oxacillinase genes in Zanjan, Iran. Among 68 isolated Acinetobacters from patients, 48 isolates were A. baumannii strains. Antibiotic susceptibility pattern and colistin resistance were determined by disk diffusion and broth microdilution, respectively. The presence of Int I, II, III, and oxacillinase genes examined using polymerase chain reaction. The clonal relationship of clinical isolates of A. baumannii determined by Pulsed Field Gel Electrophoresis method. The results showed the highest antibiotic susceptibility (58%) for colistin. 96% of isolates were considered as multidrug resistant, and 46% as extensively drug resistant, and 16% as pandrug resistant. Frequencies of Int I, II, III resistance genes were 60%, 28%, and 0%, respectively, and 12% of strains had no isoform of Ints. Frequencies of Carbapenem resistance genes were 74%, 24%, 100%, and 4% for blaOXA-23, blaOXA-24, blaOXA-51, and blaOXA-58, respectively. The above samples were group into 26 pulsotypes. The studied A. baumannii strains had several resistance genes, and the colistin resistance showed an extraordinary ascending tendency that could be a severe issue in nosocomial infections, and the presence of high genetic diversity indicated a variation in A. baumannii strains and possibly a variety of sources of contamination or infection.


Silicon carbide nanomaterial as a coating for solid-phase microextraction.
Silicon carbide has excellent properties, such as corrosion resistance, high strength, oxidation resistance, high temperature, and so on. Based on these properties, silicon carbide was coated on stainless-steel wire and used as a solid-phase microextraction coating, and polycyclic aromatic hydrocarbons were employed as model analytes. Using gas chromatography, some important factors that affect the extraction efficiency were optimized one by one, and an analytical method was established. The analytical method showed wide linear ranges (0.1-30, 0.03-30, and 0.01-30 μg/L) with satisfactory correlation coefficients (0.9922-0.9966) and low detection limits (0.003-0.03 μg/L). To investigate the practical application of the method, rainwater and cigarette ash aqueous solution were collected as real samples for extraction and detection. The results indicate that silicon carbide has excellent application in the field of solid-phase microextraction.


Mobile magic: try it, you'll like it.
Mobility affords conformity that results in less polyethylene stress and perhaps less load on the underlying bone. Wear has been documented to be less. There are excellent long-term data on large numbers of patients, and I would submit that if you try it, both you and your patients will love it.


A Case of Advanced Hepatocellular Carcinoma with Partial Response after Continuous Ramucirumab Treatment beyond Radiological Progression.
A 73-year-old male was initially treated with sorafenib for advanced stage HCC. However, the disease progressed 2 months after starting sorafenib. Progressive disease (PD) was confirmed by radiological examination, which revealed mediastinal and abdominal lymph node metastasis, pulmonary metastasis, and intrahepatic recurrence. The patient was enrolled in the REACH-2 (NCT02435433) trial and randomized to receive ramucirumab (8 mg/kg div. every 2 weeks). The patient had a Child-Pugh score of 6A and his AFP level was found to be 1,256.8 ng/mL at initiation. Radiological examination revealed PD, 5 months after starting ramucirumab. Ramucirumab treatment was continued after the confirmation of radiological PD, not but clinical progression, as allowed by the study protocol. His AFP level increased after continuous ramucirumab treatment, however, it suddenly decreased from 7,653 ng/mL to within normal limits 10 months after initiation of ramucirumab treatment. Radiological evaluation revealed a significant decrease in the size of the tumors, which constituted a partial response (PR). We reported a rare case of advanced HCC with PR to a continuous ramucirumab treatment after radiological PD.


Transient anti-CD40L co-stimulation blockade prevents immune responses against human bullous pemphigoid antigen 2: implications for gene therapy.
Skin grafts from mice expressing human bullous pemphigoid antigen 2 (hBPAG2) in epidermal basement membrane elicit hBPAG2-specific IgG and graft loss in wild-type (Wt) recipients. Graft loss was dependent on CD4+ T cells and correlated with the production and tissue deposition of hBPAG2-specific IgG. To explore the role of CD40/CD40 ligand (CD40L) interaction in this model, Wt mice grafted with transgenic (Tg) skin were treated with hamster anti-CD40L mAb MR1. In contrast to grafted Wt mice treated with equivalent doses of control IgG, 22 of 23 MR1-treated Wt mice did not develop hBPAG2-specific IgG or graft loss for >or=60 days. MR1-treated mice also accepted a second Tg skin graft without durable production of hBPAG2-specific IgG or graft loss. Moreover, splenocytes and enriched CD4+ T cells from MR1-treated graft recipients transferred un- or hyporesponsiveness to hBPAG2 to other mice and demonstrated a dominant tolerant effect over cotransferred naive splenocytes following adoptive transfer to Rag2-/- mice. Successful inhibition of hBPAG2-specific IgG production and Tg graft loss following CD40:CD40L co-stimulatory blockade in this model provides opportunities to study mechanisms of peripheral tolerance and generate antigen-specific regulatory CD4+ cells-issues of relevance to patients with pemphigoid as well as individuals undergoing gene replacement therapy for epidermolyis bullosa.


Reaching beyond arm length in normal aging: adaptation of hand trajectory and dynamic equilibrium.
The authors investigated the influence of normal aging upon equilibrium and kinematics features during a whole-body task. Eight young (23+/-1.51 years) and eight elderly (74.5+/-4.5 years) adults reached from a standing position an object placed in front of them on the ground. The authors found smaller Center of Masse (CoM) and Center of Pressure (CoP) antero-posterior displacements in elderly than in young adults. Wrist paths were curved in young but straight in elderly adults. Wrist peak velocity and duration were respectively lower and greater in elderly compared to young adults. However, Principal-Component-Analysis did not reveal differences in angle coordination between the two groups, suggesting so that modifications in equilibrium and wrist kinematics reflect an adaptation process that compensates age-related physiological changes. The authors hypothesized that equilibrium preservation in elderly contributes to wrist kinematics modifications. The authors verified this premise by placing young adults under equilibrium restrictions (reduced base of support) and observing that they reproduced the behavior of elderly adults. The authors propose that wrist kinematics is equilibrium dependent and that such a strategy is included in the motor plan of elderly adults.


A method for evaluating treatment quality using in vivo EPID dosimetry and statistical process control in radiation therapy.
Purpose Due to increasing complexity, modern radiotherapy techniques require comprehensive quality assurance (QA) programmes, that to date generally focus on the pre-treatment stage. The purpose of this paper is to provide a method for an individual patient treatment QA evaluation and identification of a "quality gap" for continuous quality improvement. Design/methodology/approach A statistical process control (SPC) was applied to evaluate treatment delivery using in vivo electronic portal imaging device (EPID) dosimetry. A moving range control chart was constructed to monitor the individual patient treatment performance based on a control limit generated from initial data of 90 intensity-modulated radiotherapy (IMRT) and ten volumetric-modulated arc therapy (VMAT) patient deliveries. A process capability index was used to evaluate the continuing treatment quality based on three quality classes: treatment type-specific, treatment linac-specific, and body site-specific. Findings The determined control limits were 62.5 and 70.0 per cent of the χ pass-rate for IMRT and VMAT deliveries, respectively. In total, 14 patients were selected for a pilot study the results of which showed that about 1 per cent of all treatments contained errors relating to unexpected anatomical changes between treatment fractions. Both rectum and pelvis cancer treatments demonstrated process capability indices were less than 1, indicating the potential for quality improvement and hence may benefit from further assessment. Research limitations/implications The study relied on the application of in vivo EPID dosimetry for patients treated at the specific centre. Sampling patients for generating the control limits were limited to 100 patients. Whilst the quantitative results are specific to the clinical techniques and equipment used, the described method is generally applicable to IMRT and VMAT treatment QA. Whilst more work is required to determine the level of clinical significance, the authors have demonstrated the capability of the method for both treatment specific QA and continuing quality improvement. Practical implications The proposed method is a valuable tool for assessing the accuracy of treatment delivery whilst also improving treatment quality and patient safety. Originality/value Assessing in vivo EPID dosimetry with SPC can be used to improve the quality of radiation treatment for cancer patients.


Chromatographic enantioseparation by cycloalkylcarbamate derivatives of cellulose and amylose.
Cyclopentyl and (+/-)-exo-2-norbornylcarbamates of cellulose and amylose were prepared and their chiral recognition abilities as chiral stationary phases for high-performance liquid chromatography (HPLC) were evaluated. Among these carbamates, cellulose tris(cyclopentylcarbamate) and amylose tris((+/-)-exo-2-norbornylcarbamate) showed particularly high chiral recognition, which is comparable to that of several well-known phenylcarbamate derivatives. The chiral recognition mechanism of cellulose tris(cyclohexylcarbamate), which was previously found to be an effective chiral stationary phase for HPLC, was investigated using NMR spectroscopy. The derivative dissolved in chloroform exhibited the chiral discrimination of several enantiomers in NMR as well as in HPLC. For example, the 1,1'-bi-2-naphthol enantiomers were distinctly discriminated in the (1)H, (13)C, and 2D-NOESY spectra.


Romantic Relationships from Adolescence to Established Adulthood.
This 15-year longitudinal study investigated with follow-up data how romantic patterns from ages 16 to 24 are associated with romantic involvement and turnover (ages 25-30), romantic dispositions (age 30) and romantic relationships characteristics (age 30). A sample of 255 individuals (60.8% women) identified all their romantic partners between the ages of 16 and 24. Between ages 25 and 30, participants identified all their romantic partners and the length of each relationship. At age 30, they also completed a series of questionnaires regarding romantic dispositions and if it applied, characteristics of their current romantic relationship. Results indicated continuity in the romantic sphere from adolescence to established adulthood. At age 30, romantic patterns were associated with: avoidance of intimacy, jealousy, global romantic satisfaction, relationship status and the duration of the current romantic relationship. Together, these results bring new information on romantic development from adolescence to established adulthood.


[Analysis of a 452C/T single nucleotide polymorphism in γ-glutamyl hydrolase gene in children with acute leukemia].
To investigate the distribution of γ-glutamyl hydrolase gene (GGH) 452C/T genotype and allele frequency in children with acute leukemia (AL) and healthy children. Bone marrow samples from 92 children with AL and peripheral blood samples from 124 healthy children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for a GGH 452C/T polymorphism by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis (RT-PCR-DGGE) and direct sequencing. The frequencies of the AL patients with TT, CT and CC genotypes were 2.2%, 13.0% and 84.8%, and the frequencies of the control children were 1.6%, 16.9% and 81.5%, respectively. There was no significant difference in GGH genotype or T allele frequency between the two groups (P> 0.05). However, the T allele frequency in Han Chinese children was significantly different from those reported in Japanese, Mexican and African-American populations. The frequency of 452C/T polymorphism of GGH gene in Han Chinese children has been determined. The results suggested that an ethnic difference may exist.


[Desmoid tumor: report of a case].
The desmoid tumor is a solid tumor with soft parts and with various possible locations. It is not very frequent and of unknown presentation in our medium. We presented the case of a patient who was treated of extrinsic duodenal obstruction. A compression of the third section of the duodenum was found. The diagnosis was made by pathological anatomy.


Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model.
It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice. The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 microg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells. These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.


Time course of supine and standing shifts in total body, intracellular and extracellular water for a sample of healthy adults.
Traditional tetrapolar bioimpedance spectroscopy (BIS) is performed with the participant supine for 10 min. New vertical analyzers are penetrating clinical, home and fitness markets, but have body water values that differ from supine reference measures. The minimum time standing prior to assessment does not appear in the literature. We investigated the time course of body water shifts in healthy adults undergoing 30-min assessments in supine and vertical positions. While seated, participants were prepped for standard tetrapolar electrode placement. Starting position was counterbalanced and body water measurements were taken every 5 min for 30 min in both positions. Participants sat for 2 min prior to switching positions. Of the 64 participants, three were unable to stand for 30 min; their data were excluded. Body size differences were minimized via computation of relative (%) change between time intervals for total body water (TBW), extracellular water (ECW) and intracellular water (ICW). ECW and ICW shifted in opposite directions while participants were supine; as ECW decreased at each time point, ICW increased (P<0.0125). Likewise, when participants stood, ECW increased incrementally (P<0.0125), but the decreases in ICW were not significant. At each time interval, the changes in supine ECW and ICW differed from the standing values (P<0.05). No postural or time differences were found for %change TBW. For TBW, 5 min appears sufficient for fluid stabilization in either position. Supine ECW and ICW stabilization require more than 30 min as does standing ECW.


The effects of colchicine on milk secretion, mammary metabolism and blood flow in the goat.
Mammary function in the conscious goat was studied during colchicine-induced depression of milk secretion in one mammary gland. Milk yield of the treated gland was reduced to approximately a quarter of previous, while there were significant increases in afternoon milk yield from the untreated glands on the 2nd and 3rd days after treatment in goats in late lactation. Milk composition in the untreated glands was not significantly affected. In the treated gland, milk [Na+], [Cl-], [citrate] and [protein] increased while [K+] and [lactose] decreased, although the time course of these changes differed; milk [fat] was unaffected. Mammary extractions ((A-V)/A) of glucose, acetate and most amino acids were significantly decreased during the period of maximal inhibition of secretion. There were no significant changes in arterial plasma concentrations of glucose, acetate or any essential amino acids. In another series of experiments, mammary blood flow increased and then returned to normal after colchicine treatment even though milk yield and mammary glucose uptake decreased markedly; oxygen uptake was not significantly affected. The results are discussed in relation to the actions of colchicine on the mammary secretory cell, to the normal control of mammary blood flow and to the mechanism of compensation by the untreated gland.


Hardware-accelerated interactive data visualization for neuroscience in Python.
Large datasets are becoming more and more common in science, particularly in neuroscience where experimental techniques are rapidly evolving. Obtaining interpretable results from raw data can sometimes be done automatically; however, there are numerous situations where there is a need, at all processing stages, to visualize the data in an interactive way. This enables the scientist to gain intuition, discover unexpected patterns, and find guidance about subsequent analysis steps. Existing visualization tools mostly focus on static publication-quality figures and do not support interactive visualization of large datasets. While working on Python software for visualization of neurophysiological data, we developed techniques to leverage the computational power of modern graphics cards for high-performance interactive data visualization. We were able to achieve very high performance despite the interpreted and dynamic nature of Python, by using state-of-the-art, fast libraries such as NumPy, PyOpenGL, and PyTables. We present applications of these methods to visualization of neurophysiological data. We believe our tools will be useful in a broad range of domains, in neuroscience and beyond, where there is an increasing need for scalable and fast interactive visualization.


An Endoscopic Transcanal Transpromontorial Approach for Vestibular Schwannomas using a Computer-Based Three-Dimensional Imaging System.
A 2D monocular endoscope has been used in transcanal transpromontory vestibular schwannoma surgery instead of craniotomy. However, the absence of depth perception is the limitation of this approach. With the loss of depth perception, the surgeon will be not able to perform delicate and particularly complicated surgery. A binocular endoscope has been developed to provide stereoscopic vision with better depth perception for complicated anatomic structures and has been applied in some endoscopic surgeries. However, the diameter of the endoscope is a limitation in the performance of transcanal otologic surgeries. A small diameter endoscope facilitates easier surgery in a restricted space. A computer-based 3D imaging system can obtain 3D images in real-time using a small monocular endoscope. In this study, to evaluate the feasibility of a computer-based 3D imaging system for endoscopic lateral skull base surgery, we applied this 3D imaging system in a transcanal transpromontorial approach in two patients with vestibular schwannomas. The surgical procedure was completed without complication in these two cases. There was no mortality, perioperative complications, nor notable postoperative complications. Using this computer-based 3D imaging system, a better depth perception and stereoscopic vision was observed compared to a conventional 2D endoscope. The improvement in depth perception offers superior management of the complicated surgical anatomy.


Oral mucosal lesions in systemic lupus erythematosus--a clinical, histopathological and immunopathological study.
The oral mucosa was investigated in 51 patients with systemic lupus erythematosus (SLE). Lesions were seen in 23 patients (45%). Most lesions were of discoid type or erythemas; only 3 were seen in 23 patients (45%). Most lesions were of discoid type or erythemas; only 3 were ulcerations. The hard palate, buccal mucosa and vermilion border were the most frequent sites of involvement. The overall prevalence was not related to disease activity, but discoid lesions and ulcerations were only seen in patients with active disease. Histopathological investigation showed liquefactive degeneration in 6 biopsies of 10 lesions. Immunofluorescence examination was positive in all cases.


Ditopic ambiphilicity of an anionic dimetalloborylene complex.
In early reports, the boron atom of the anionic borido complexes [{(η(5)-C(5)H(4)R)(OC)(2)Mn}(2)B](-) (R = H, Me) showed nucleophilic behavior in the presence of electrophiles such as methyl iodide and group 11 metal chlorides, akin to the ground-breaking boryl lithium of Yamashita and Nozaki. Later, a reaction with the well-known transition metal Lewis base [Pt(PCy(3))(2)] suggested the possibility of boron-centered electrophilicity. In this paper we elucidate a third reactivity profile of the anion, nucleophilic substitution on heavier halides of group 14 metals by a manganese center. Meanwhile, other group 11 halides were found to interact with the boron center, but form structures different from those seen with gold. The basis of the discrimination of the anion between main group and transition metal halides is explored computationally, and the ditopic, ambiphilic reactivity of the anions is discussed.


[High-sensitivity C-reactive protein: a new risk factor of coronary disease].
CRP is an acute-phase protein released after an infection or an inflammation. Atherosclerosis is actually believed to result from the combination of lipid deposits in the arterial wall together with inflammatory cells. Numerous prospective studies have shown that the serum level of CRPhs is a strong predictor of future coronary events. The risk of such events is twice as high in patients with mean CRPhs values of 2.4 mg/l than in patients with values of 1 mg/l. Serum levels of CRPhs have been measured in 265 of our patients with normal sedimentation rate. Mean levels were 1.5 + 1.5 mg/l in men and 1.64 + 1.5 mg/l in women. Levels were higher in obese and diabetic patients. CRP levels can be slightly increased in arthritis. Serum levels double in women treated by oral estrogens after menopause. CRP should be measured at least 4 weeks after an infection such as a viral rhinitis. CRP levels decrease by 15 to 30% after treatment with glitazone (rosiglitazone) and with statins. The effect of aspirin is controversial. The magnitude of the preventive effect of aspirin and of statins on coronary risks could depend on the basal level of CRPhs. If these data are confirmed, it would be easier to select those patients who would be the most likely to benefit from the antiinflammatory treatments.


Adaptation of cardiac myocyte contractile properties to exercise training.
Recent work suggests that chronic exercise induces alterations in the contractile properties of cardiac myocytes. These alterations include increased sensitivity to activation by Ca, changes in the force-length relationship, and increased power output. A recently observed shift in expression of myosin light chain 1 subunit isoforms induced by training may provide a molecular mechanism for these contractile alterations.


Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review.
Intensivists' clinical decision making pursues two main goals for patients: to decrease mortality and to improve quality of life and functional status in survivors. Patient-important outcomes are gaining wide acceptance in most fields of clinical research. We sought to systematically review how well patient-important outcomes are reported in published randomized controlled trials (RCTs) in critically ill patients. Literature search was conducted to identify eligible trials indexed from January to December 2013. Articles were eligible if they reported an RCT involving critically ill adult patients. We excluded phase II, pilot and physiological crossover studies. We assessed study characteristics. All primary and secondary outcomes were collected, described and classified using six categories of outcomes including patient-important outcomes (involving mortality at any time on the one hand and quality of life, functional/cognitive/neurological outcomes assessed after ICU discharge on the other). Of the 716 articles retrieved in 2013, 112 RCTs met the inclusion criteria. Most common topics were mechanical ventilation (27%), sepsis (19%) and nutrition (17%). Among the 112 primary outcomes, 27 (24%) were patient-important outcomes (mainly mortality, 21/27) but only six (5%) were patient-important outcomes besides mortality assessed after ICU discharge (functional disability = 4; quality of life = 2). Among the 598 secondary outcomes, 133 (22%) were patient-important outcomes (mainly mortality, 92/133) but only 41 (7%) were patient-important outcomes besides mortality assessed after ICU discharge (quality of life = 20, functional disability = 14; neurological/cognitive performance = 5; handicap = 1; post-traumatic stress = 1). Seventy-three RCTs (65%) reported at least one patient-important outcome but only 11 (10%) reported at least one patient-important outcome besides mortality assessed after ICU discharge. Patient-important outcomes are rarely primary outcomes in RCTs in critically ill patients published in 2013. Among them, mortality accounted for the majority. We promote the use of patient-important outcomes in critical care trials.


Wilton Marion Krogman, Ph.D. (1903-1987): the end of an era.
Dr. Wilton Marion Krogman was one of the major founders of physical and forensic anthropology in the United States. His extraordinary career spanned nearly six decades, and he was universally admired and respected for his scholarship, teaching, research, wit, and humanity. While studies based on human skeletal remains have long been used to assist the medicolegal system, the late Dr. Krogman can be credited with uniting these areas into the discipline of forensic anthropology. His "Guide to the Identification of Human Skeletal Material" (1939) in the F.B.I. Law Enforcement Bulletin became the foundation of this discipline; his monumental book The Human Skeleton in Forensic Medicine (updated with the author in 1986) solidified its establishment. The purpose of this paper is to pay tribute to this great man and outline his influence on the development and advancement of forensic anthropology.


Effect of the prostacyclin analogue iloprost on K+ permeability in the smooth muscle cells of the canine carotid artery.
The present contribution deals with the electro- and tracerphysiological correlations to vasodilatation observed under prostacyclin or O2 deficiency. Because of the extreme chemical instability of native PGI2, we used iloprost, a stable carbacyclin analogue. At concentrations between 10(-9) and 10(-6) mol/l, iloprost hyperpolarized the resting membrane of normal tone (V = -63.4 mV) and noradrenaline predepolarized vascular smooth muscle cells (V = -55.2 mV) of the canine carotid artery by 7.4 and 16.9 mV, respectively, in a concentration-dependent manner. Correspondingly, the isometric tension was decreased. In both experimental series, the half-maximal effect was attained at a concentration of 2 x 10(-8) mol/l. The coupling ratios developed tension versus membrane potential were 1.079 mV/mN in normal tone and noradrenaline treated preparations. Hyperpolarization and relaxation in the latter group, however, were much larger for the same iloprost concentrations. 42K+ efflux was stimulated by 250% with iloprost (10(-6) mol/l), whereas 24Na+ efflux was increased only by 50%. This resulted in an augmentation of K+ permeability by 340% and of Na+ permeability by 40%, respectively. The ratio PK/PNa rose from 16 to 49 with iloprost. These results lead to the conclusion that iloprost should be classified as a K+ channel opener.


[A retrospective analysis of infection after corneal transplantation].
We studied retrospectively the background of postoperative infection after corneal transplantation. We reviewed the records of 753 eyes that had undergone corneal transplantation at Kyoto Prefectural University of Medicine or the Baptist Eye Clinic over a period of 6 years from April 1994 to March 2000. Patients who developed microbial keratitis after corneal transplantation were evaluated for the incidence of infection, age, the interval between transplantation and infection, microbiological etiology, the use of topical steroids, therapy, and complications. Follow-up after keratoplasty averaged 43.2+/-25.6 months (mean+/-standard deviation). Among 753 eyes examined, microbial keratitis developed in 27 eyes (3.6%), 14 eyes had bacterial, and 13 had fungal infections. The ages at presentation were 51.4+/-21.5 years for bacterial infections, and 66.5+/-11.1 for fungal infections. The time intervals between transplantation and the onset of infection averaged 7.8+/-7.9 months for bacterial infections, and 24.2+/-17.2 for fungal infections. Infections in 7 (50.0%) of the bacterial eyes were caused by methicillin-resistant Staphylococcus aureus (MRSA) or epidermidis (MRSE), and 9 (69.2%) of the fungal infections by yeast type fungus (8 were Candida species). At onset of keratitis, 3 (21.4%) of the bacterial eyes and 6 (46.2%) of the fungal eyes were treated with fluorometholone, and 11 (78.6%) of the bacterial eyes and 7 (53.8%) of the fungal eyes were treated with betamethazone or dexamethasone. The treatment duration until the focus of disappeared was 32.8+/-19.7 days for bacterial eyes, and 74.8+/-56.3 for fungal eyes. Major complications associated with infection included corneal perforation in 2 eyes of both the bacterial (14.3%) and fungal (15.4%) eyes, graft rejection in 4 (28.6%) bacterial eyes and 1 (7.7%) fungal eye, there was no recurrence of infection in the bacterial eyes but there were 3 (23.1%) cases of recurrence in the fungal eyes. Infection after corneal transplantation is opportunistic. Fungal infections occurred later than bacterial infections. Also in fungal infections, the mean age at presentation was higher and the recurrence of infection was more frequent.


Ab therapy of AML: native anti-CD33 Ab and drug conjugates.
MAb have become an important treatment modality in cancer therapy.Genetically engineered chimeric and humanized Ab have demonstrated activity against a variety of tumors. While the humanized anti-CD33MAb lintuzumab has only modest single-agent activity against overt AML, it can eliminate minimal residual disease detectable by reverse transcription-PCR in acute promyelocytic leukemia. Targeted chemotherapy with the anti−CD33−calicheamicin construct gemtuzumab ozogamicin has produced remissions in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.


Effectiveness of Mulligan mobilization and Kinesio-taping technique on the anterior innominate dysfunction in females.
To determine the effects of Mulligan mobilisation with Kinesio Tex tape on pain and disability in anterior innominate dysfunction in females. The quasi-experimental study was conducted from March to August 2018 at the Allied Hospital and Javeed Medical Complex, Faisalabad, Pakistan, and comprised women with anterior innominate dysfunction. The subjects were divided into group A, which was treated with therapeutic ultrasound, Mulligan mobilisation and Kinesio taping, and group B, which was treated with therapeutic ultrasound and Mulligan mobilisation. Data was taken at baseline and after 10 days to measure pain and disability using visual analogue scale and Modified Oswestry Disability Questionnaire. Data was analysed using SPSS 20. Of the 30 women, there were 15(50%) in group A with a mean age of 32.80±6.02 years and 15(50%) in group B with a mean age of 34.20±6.51 years. Both groups showed significant improvement in pain and disability post-treatment (p<0.05), with group A showing more improvement than group B in terms of disability (p=0.001), but not in terms of pain (p=0.20). Both Mulligan mobilisation along with Kineso Tex tape and Mulligan mobilisation alone were found to be effective in reducing pain and disability, with the tape showing better improvement in pain and disability compared to those receiving mobilisation alone.


Ethanol-induced signal transducing mechanism associated with a transient antiviral state in human amniotic cells.
Short-term effects of ethanol on human amnion cells were investigated by studying the cellular signaling processes and the replication of vesicular stomatitis virus. Treatment of human amniotic cells with ethanol transiently triggers the breakdown of inositol phospholipids, stimulates intracellular [Ca2+]i mobilization and activates the translocation of protein kinase C. Activation of this signal transduction mechanism is associated with the development of an antiviral state, as proven by studying 3H-uridine incorporation into the RNA of vesicular stomatitis virus. Induction of the antiviral state in human amniotic cells correlates with the solubility of the alcohols in the lipid membrane of the cells.


Diagnostic and therapeutic dilemmas in periampullary lesions.
Periampullary lesions often present diagnostic and therapeutic dilemmas. This study is to clarify the justification of pancreaticoduodenectomy for the resectable periampullary lesion without histological confirmation of malignancy. Clinical data for periampullary lesions with presumed malignancy were retrieved from our prospectively-collected computer database. The surgical risks and test performance characteristics in diagnosis were determined. There were 636 patients undergoing pancreaticoduodenectomy, including 572 with malignancy and 64 (10.1% false positive rate) with benign lesions. No resection was attempted for 32 patients, but 8 (25% false negative rate) eventually turned out to be malignant. Our data showed a sensitivity of 98.6% (572/580), a specificity of 27% (24/88) and an accuracy of 89.2% (596/668) in detecting periampullary malignancy. The surgical risks after pancreaticoduodenectomy were significantly lower in the benign group, with 28.1% morbidity (vs. 43.7% in the malignant group), no pancreatic leakage (vs. 11.5% in malignant group) and no surgical mortality (vs. 7.3% in the malignant group). Pancreaticoduodenectomy is justified for a periampullary lesion without histological confirmation whenever malignancy is suspected. Moreover, a nihilistic approach could be associated with a significant false negative rate (25%) if left unresected and might preclude a patient with periampullary malignancy from cure.