Nanoparticle Internalization Promotes the Survival of Primary Macrophages.
Macrophages, a class of tissue resident innate immune cells, are responsible for sequestering foreign objects through the process of phagocytosis, making them a promising target for immune-modulation via particulate engineering. Here, we report that nanoparticle (NP) dosing and cellular internalization via phagocytosis significantly enhances survival of ex vivo cultures of primary bone marrow-derived, alveolar, and peritoneal macrophages over particle-free controls. The enhanced survival is attributed to suppression of caspase-dependent apoptosis and is linked to phagocytosis and lysosomal signaling. Uniquely, poly(ethylene glycol)-based NP treatment extended cell viability in the absence of macrophage polarization and enhanced expression of pro-survival B cell lymphoma-2 (Bcl-2) protein in macrophages following multiple routes of in vivo administration. The enhanced survival phenomenon is also applicable to NPs of alternative chemistries, indicating the potential universality of this phenomenon with relevant drug delivery particles. These findings provide a framework for extending the lifespan of primary macrophages ex vivo for drug screening, vaccine studies, and cell therapies and has implications for any in vivo particulate immune-engineering applications.


Identification of Catalytic Sites for Oxygen Reduction in Metal/Nitrogen-Doped Carbons with Encapsulated Metal Nanoparticles.
The development of metal-N-C materials as efficient non-precious metal (NPM) catalysts for catalysing the oxygen reduction reaction (ORR) as alternatives to platinum is important for the practical use of proton exchange membrane fuel cells (PEMFCs). However, metal-N-C materials have high structural heterogeneity. As a result of their high-temperature synthesis they often consist of metal-Nx sites and graphene-encapsulated metal nanoparticles. Thus it is hard to identify the active structure of metal-N-C catalysts. Herein, we report a low-temperature NH4 Cl-treatment to etch out graphene-encapsulated nanoparticles from metal-N-C catalysts without destruction of co-existing atomically dispersed metal-Nx sites. Catalytic activity is much enhanced by this selective removal of metallic nanoparticles. Accordingly, we can confirm the spectator role of graphene-encapsulated nanoparticles and the pivotal role of metal-Nx sites in the metal-N-C materials for ORR in the acidic medium.


Microwave-assisted UV-digestion procedure for the accurate determination of Pd in natural waters.
A procedure was developed for the selective determination of Pd in environmental aquatic solutions. The method is based on a preliminary microwave-assisted UV-digestion for the degradation of dissolved organic material, and the subsequent determination of Pd using a recently presented enrichment procedure with ETAAS detection. Due to the simultaneous use of microwave and UV irradiation only extremely small quantities of hydrogen peroxide were necessary to yield a quantitative degradation of interfering organic ligands. Thus the on-line pre-concentration of Pd in the digested samples using the complexing agent N,N-diethyl-N'-benzoylthiourea was possible without any further sample pre-treatment. Using a sample volume of 1.57 ml for FI-ETAAS analysis a limit of detection of 15 ng l(-1) was obtained for the combined procedure, with a relative standard deviation being not more than 4.9%. The method was applied to quantify the water-soluble fraction of Pd in urban road dust. Extractions with a rain sample of pH 5.9 revealed that an average of 2.2% (n=8) of the total Pd present in urban road dust was water soluble.


Role of apolipoprotein B-derived radical and alpha-tocopheroxyl radical in peroxidase-dependent oxidation of low density lipoprotein.
The peroxidation of low density lipoprotein (LDL) may play an important role in the modification of the lipoprotein to an atherogenic form. The oxidation of LDL by peroxidases has recently been suggested as a model for in vivo transition metal ion-independent oxidation of LDL (Wieland, E., S. Parthasarathy, and D. Steinberg. 1993. Proc. Natl. Acad. Sci. USA. 90: 5929-5933). It is possible that in vivo the peroxidase activities of proteins, such as prostaglandin synthase and myeloperoxidase, promote LDL oxidation. We have used horseradish peroxidase (HRP) and H2O2 as a model of peroxidase-dependent oxidation of LDL and we observed the following during HRP/H2O2-initiated LDL oxidation. i) The oxidation of alpha-tocopherol occurred with the concomitant formation of alpha-tocopheroxyl radical. This was followed by the production of an apolipoprotein B (apoB)-derived radical. The apoB radical and the alpha-tocopheroxyl radical were formed under both aerobic and anaerobic conditions. ii) Inclusion of N-t-butyl-alpha-phenylnitrone (PBN) did not inhibit alpha-tocopheroxyl radical formation. The ESR spectrum of a PBN/LDL-lipid derived adduct was observed after prolonged incubation. iii) There was formation of conjugated dienes, lipid hydroperoxides and thiobarbituric acid reactive substances. Our data indicate that HRP/H2O2 oxidizes both alpha-tocopherol and apoB to the corresponding radicals and concomitantly initiates lipid peroxidation.


Randomized trial comparing dopamine and dobutamine in preterm infants.
The aim of this study was to compare the efficacy of two inotropic infusions in treating low BP in preterm neonates. Forty infants with median gestational age 27 weeks (range 23-33) were studied. At trial entry the infants, who all had a systolic BP < 40 mmHg despite receiving a colloid infusion, were randomized to receive either a dopamine or dobutamine infusion. The infusions were commenced at a rate of 5 micrograms/kg per min and, if necessary, this was increased over the 3 h study period to 15 micrograms/kg per min. There was no significant difference in the gestational or postnatal age or baseline BP of the 20 infants who received dopamine and those 20 who received dobutamine. Three hours after commencing the infusions, although there was no difference in the rate of inotrope infusion between the two groups, the infants who received dopamine had a significantly higher systolic BP, a median of 39 mmHg (range 30-58) compared to a median of 34 mmHg (range 21-46) in the dobutamine group, P < 0.05. In addition, 10 infants who received dopamine, but only 3 who received dobutamine, had a systolic BP > 40 mmHg (P < 0.05). We conclude that dopamine rather than dobutamine infusion is more efficacious in improving the BP of preterm neonates.


Bisphenol S induces Agrp expression through GPER1 activation and alters transcription factor expression in immortalized hypothalamic neurons: A mechanism distinct from BPA-induced upregulation.
The increasing prevalence of obesity around the world has brought concern upon ubiquitously present obesogenic environmental compounds, such as bisphenol A (BPA). Increasingly tightened regulations on the industrial use of BPA have prompted a transition to a structurally similar alternative, bisphenol S (BPS). BPS displays endocrine-disrupting behaviours similar to those of BPA and increases body weight, food intake and the hypothalamic expression of Agrp in vivo. However, the mechanisms behind this deleterious effect are unclear. Here, we report an increase in the mRNA level of Agrp at 4 h following BPS treatment in immortalized murine hypothalamic cell lines of embryonic and adult origin (mHypoE-41, mHypoA-59). BPS-induced changes in the expression of transcription factors and estrogen receptors that occurred concurrently with Agrp upregulation demonstrated similarities to BPA-induced changes, however, there were also changes that were unique to BPS. Specifically, while Chop, Atf3, Atf4, Atf6, Klf4, and Creb1 were upregulated and Gper1 was downregulated by both BPA and BPS, Esr1 mRNA levels were upregulated and Foxo1 and Stat3 levels remained unchanged by BPS. Finally, inhibition of GPER1 by G15 prevented BPS-mediated Agrp upregulation, independent of Atf3 and Klf4 upregulation. Overall, our results demonstrate the ability of BPS to increase Agrp mRNA expression through GPER1 signaling and to alter transcription factor expression in hypothalamic neurons, further elucidating the endocrine-disrupting potential of this alternative industrial chemical.


The Extent of Universal Health Coverage for Maternal Health Services in Eastern Uganda: A Cross Sectional Study.
Monitoring essential health services coverage is important to inform resource allocation for the attainment of the Sustainable Development Goal 3. The objective was to assess service, effective and financial coverages of maternal healthcare services and their equity, using health and demographic surveillance site data in eastern Uganda. Between Nov 2018 and Feb 2019, 638 resident women giving birth in 2017 were surveyed. Among them, 386 were randomly sampled in a follow-up survey (Feb 2019) on pregnancy and delivery payments and contents of care. Service coverage (antenatal care visits, skilled birth attendance, institutional delivery and one postnatal visit), effective coverage (antenatal and postnatal care content) and financial coverage (out-of-pocket payments for antenatal and delivery care and health insurance coverage) were measured, stratified by socio-economic status, education level and place of residence. Coverage of skilled birth attendance and institutional delivery was both high (88%), while coverage of postnatal visit was low (51%). Effective antenatal care was lower than effective postnatal care (38% vs 76%). Financial coverage was low: 91% of women made out-of-pocket payments for delivery services. Equity analysis showed coverage of institutional delivery was higher for wealthier and peri-urban women and these women made higher out-of-pocket payments. In contrast, coverage of a postnatal visit was higher for rural women and poorest women. Maternal health coverage in eastern Uganda is not universal and particularly low for postnatal visit, effective antenatal care and financial coverage. Analysing healthcare payments and quality by healthcare provider sector is potential future research.


Mycotic Aneurysm of the Extracranial Internal Carotid Artery Following Otitis Media.
Mycotic aneurysm of the internal carotid artery following otomastoiditis can manifest as a nasopharyngeal mass. This is a very rarely described condition. The case of a patient diagnosed with a retropharyngeal mycotic aneurysm of the left internal carotid artery following otitis media, treated with exclusion of the mycotic aneurysm from the circulation and transnasal drainage. Infection of the mastoid can spread to the parapharyngeal space of the nasopharynx and damage the carotid artery wall, resulting in an infected aneurysm. There are no guidelines on how to surgically approach those aneurysms. An endoscopic transnasal approach can be beneficial.


Binding mechanism of the matrix domain of HIV-1 gag on lipid membranes.
Specific protein-lipid interactions are critical for viral assembly. We present a molecular dynamics simulation study on the binding mechanism of the membrane targeting domain of HIV-1 Gag protein. The matrix (MA) domain drives Gag onto the plasma membrane through electrostatic interactions at its highly-basic-region (HBR), located near the myristoylated (Myr) N-terminus of the protein. Our study suggests Myr insertion is involved in the sorting of membrane lipids around the protein-binding site to prepare it for viral assembly. Our realistic membrane models confirm interactions with PIP2 and PS lipids are highly favored around the HBR and are strong enough to keep the protein bound even without Myr insertion. We characterized Myr insertion events from microsecond trajectories and examined the membrane response upon initial membrane targeting by MA. Insertion events only occur with one of the membrane models, showing a combination of surface charge and internal membrane structure modulate this process.


Effects of inspiratory muscle training in patients with hypertension: a meta-analysis.
To explore the effects of inspiratory muscle training (IMT) on hypertension and provide guidance for its clinical application as an auxiliary approach. Articles published prior to July 2022 were searched in Cochrane Library, Web of Science, PubMed, Embase, CNKI, and Wanfang databases. Included were randomized controlled studies that used IMT to treat individuals with hypertension. The mean difference (MD) was computed using the Revman 5.4 software. In individuals with hypertension, the effects of IMT on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and pulse pressure (PP) were compared and studied. There were found to be eight randomized controlled trials totaling 215 patients. According to a meta-analysis, the IMT reduced the SBP (MD: -12.55 mmHg, 95% CI: -15.78, -9.33), DBP (MD: -4.77 mmHg, 95% CI: -6.00, -3.54), HR (MD: -5.92 bpm, 95% CI: -8.72, -3.12), and PP (MD: -8.92 mmHg, 95% CI: -12.08, -5.76) in patients with hypertension. In subgroup analyses, low-intensity IMT showed a better reduction in SBP (MD: -14.47 mmHg, 95% CI: -17.60, -11.34), DBP (MD: -7.70 mmHg, 95% CI: -10.21, -5.18). IMT may become an auxiliary means to improve the four hemodynamic indexes (SBP, DBP, HR and PP) in patients with hypertension. In subgroup analyses, low-intensity IMT was more effective in regulating blood pressure than medium-high-intensity IMT. https://www.crd.york.ac.uk/prospero/, identifier: CRD42022300908.


Network-based global inference of human disease genes.
Deciphering the genetic basis of human diseases is an important goal of biomedical research. On the basis of the assumption that phenotypically similar diseases are caused by functionally related genes, we propose a computational framework that integrates human protein-protein interactions, disease phenotype similarities, and known gene-phenotype associations to capture the complex relationships between phenotypes and genotypes. We develop a tool named CIPHER to predict and prioritize disease genes, and we show that the global concordance between the human protein network and the phenotype network reliably predicts disease genes. Our method is applicable to genetically uncharacterized phenotypes, effective in the genome-wide scan of disease genes, and also extendable to explore gene cooperativity in complex diseases. The predicted genetic landscape of over 1000 human phenotypes, which reveals the global modular organization of phenotype-genotype relationships. The genome-wide prioritization of candidate genes for over 5000 human phenotypes, including those with under-characterized disease loci or even those lacking known association, is publicly released to facilitate future discovery of disease genes.


A novel neuroendocrine gene product: selective VGF8a gene expression and immuno-localisation of the VGF protein in endocrine and neuronal populations.
The VGF8a gene was recognised on the basis of its inducibility by NGF in rat pheochromocytoma (PC12) cells. Using immunocytochemistry, we have localised the corresponding VGF protein product in various neuronal groups, including primary sensory and enteric neurons, and in endocrine cells of the adrenal medulla, adenohypophysis and gut. VGF8a gene expression, as detected by RNAse protection analysis, largely correlated with such distribution.


Specialization of the sting venom and skin mucus of Cathorops spixii reveals functional diversification of the toxins.
Cathorops spixii is the most common venomous fish on the Brazilian coast. Apart from the involvement with defense against pathogens, the possible contribution of skin mucus components to the development of injuries caused by venomous fish species has not been investigated. Thus, the present study was conducted to gain a better understanding of the peptide and protein components of fish skin mucus and the sting venom from the catfish C. spixii. Our results show that sting venom and skin mucus have distinct constituents that distinguished them like structural proteins, chaperones, ion transport, carbohydrate metabolism, oxidoreductase, cell cycle and protein binding present in sting venom and like tropomyosin 3 isoform 2 and energy metabolim proteins in skin mucus. But in a group of common 13 proteins we identified and isolated a WAP65 protein. The peptide fractions caused more harmful effects, such as venular stasis, hemorrhage and changes in the arteriolar wall diameter, and the protein fractions produced a typical inflammatory process in post-capillary venules. And finally we showed for the first time the presence WAP65 in sting venom and skin mucus of C. spixii using LC/MS/MS and also we purified this protein in the sting venom. Wap65 shows inflammatory action, working at different doses inducing an increase in the number of leukocytes rolling and adhering to the endothelium.


Physico-chemical characteristics of the peloid mud from Morinje Bay (eastern Adriatic coast, Croatia): suitability for use in balneotherapy.
The study conducted in the Morinje Bay (Central Dalmatia, Croatia) included the investigation of the sedimentological, physico-chemical and geochemical properties of the Morinje Bay sediments in order to assess the suitability of the material for wellness-related purposes including medicinal use. The sedimentological characteristics of the Morinje mud are in accordance with the geological origin of the material; the sediment is fine grained, composed mostly of carbonates, quartz and clay minerals. The composition of the sediment determines the physico-chemical properties of the mud. The high content of carbonate minerals diminishes adsorbing the characteristics of the mud to some extent; however, they are still comparable to some commercial mud already successfully used for medicinal purposes. Geochemical analyses have shown that trace metals concentrations in the Morinje Bay samples were mostly in the range with similar material from unpolluted Adriatic environments. Only the concentrations of Cu, Pb, Zn and As were slightly higher than in the reference material, but still within acceptable limits.


Cellular Prion Protein Promotes Neuronal Differentiation of Adipose-Derived Stem Cells by Upregulating miRNA-124.
The cellular prion protein (PrP(C)) is a highly conserved glycoprotein anchored by glycosylphosphatidylinositol (GPI) to the cell surface and is also the source of pathogenic agent of scrapie prion protein (PrP(Sc)). Numerous researches have suggested putative physiological roles for PrP(C), including protection from ischemic and excitotoxic lesions, and participation in cell signaling and differentiation. Here, we demonstrated that PrP(C) positively regulates neuronal differentiation of mouse adipose-derived stem cells (ADSCs). The small C-terminal domain phosphatase 1 (SCP1) expression was knocked down by gene silencing. The mRNA expression of miRNA-124 and PrP(C) was measured with quantitative PCR. Western blot analysis was used to detect the protein levels of nestin, βIII-tubulin, and SCP1, and dual-luciferase reporter assay was performed to test the target of miRNA-124. The expression level of PrP(C) was found to increase steadily during neuron-like differentiation process, and PrP(C) knockout resulted in the reduction of neuron-like cell markers. We further showed that miRNA-124 could directly target SCP1-3'-untranslated region to decrease small C-terminal domain phosphatase 1 (SCP1) SCP1, and that miRNA-124 expression is regulated by PrP(C). Our results suggest that PrP(C) may play a key role in the neuronal differentiation of ADSC through modulating miRNA-124-SCP1 axis. To date, this is the first time strong evidence for the involvement of PrP(C) in the neuronal differentiation of ADSC is reported.


Pigmented Fungiform Papillae of the Tongue: A Single-center Experience and Review of Literature.
Pigmented fungiform papillae of the tongue (PFPT) is a rare benign pigmentary disorder of the tongue. In dark-skinned individuals, PFPT appears to be relatively common. However, limited data exist on PFPT in Korean patients. We aimed to investigate the clinical characteristics of PFPT in Korean patients. Patients diagnosed with PFPT between 1995 and 2021 at the Pusan National University Hospital were included. Clinical characteristics of PFPT, dermoscopic findings, and comorbidities were reviewed. A total of 19 patients diagnosed with PFPT were enrolled. The male to female ratio was approximately 1:5. The mean age at diagnosis was 41.1 years (range, 8~67 years). According to Holzwanger's classification, Type I was the most common (89.5%). PFPT was commonly concomitant with pigmentary disorders, including mucosal melanotic macules, Laugier-Hunziker syndrome, melasma, and melanonychia (6/19, 31.6%). Preceding oral infection or inflammatory lesions were found in four patients (21.1%), and systemic diseases and infectious diseases existed in two patients (10.5%). Dermoscopic examination was performed in seven patients; pigmented border with dichotomized vessels (rose petal pattern, 71.4%) and diffuse pigmentation (cobblestone pattern, 71.4%) were common findings. Our study shows PFPT can coexist with pigmentary disorders. Concomitant pigmentary disorder shows an association with sex hormone or susceptibility to abnormal pigmentation may be a possible cause of PFPT.


Wavelet basis selection and feature extraction for shift invariant ultrasound foreign body classification.
This paper proposes a novel technique for automatic ultrasound non-destructive foreign body (FB) detection and classification. A signal registration process is introduced to eliminate shift variations commonly encountered in ultrasound signals. Information theory based methods are then developed for wavelet basis selection and feature extraction to facilitate robust FB classification. Probabilistic neural networks are used for FB classification. Experimental results confirm that the wavelet basis selected by the proposed method improves the FB classification accuracy. It is concluded that low order wavelet bases have better ability to distinguish classes with great similarities than their higher order counterparts, while the reverse is true for more divergent classes.


Persulfurated Coronene and Its Chalcogenide Analogues: Insight into Effects of Peripheral Substitution.
The density functional theory (DFT) and time-dependent DFT methods have been used to investigate the persulfurated coronene (PSC) and its chalcogenide analogues (POC and PSeC), derived from the substitution of sulfur, oxygen, and selenium for all hydrogen atoms in coronene, respectively. The presence of peripheral S-S in PSC results in a σ-type lowest unoccupied molecular orbital and the dark low-lying states (S1 ∼ S15). The peripheral S-S bond is responsible for its electron capture, which maintains a planar configuration of the singly and doubly negative-charged PSC. POC is predicted to have the most stable saddle-shaped structure with the C═O group, and its bowl-shaped isomer with the O-O moiety is less stable by 279.2 kcal/mol energetically. PSeC has similar electronic and structural features with PSC, but its dimer is predicted to have much better hole mobility, compared to PSC. The present results indicate that the chalcogenide substitution at the periphery of the polycyclic aromatic hydrocarbons may remarkably change their electronic and spectroscopic properties as well as the carrier transport behavior of their molecular materials.


The formation of photoreceptor synapses in the retina of larval Xenopus.
The first appearance and early development of synapses between photoreceptors, bipolar cells and horizontal cells were studied in the retina of larval Xenopus, between stages 37/8 and 46. Synapse morphology was reconstructed from examination of serial sections. Additional data were obtained from E-PTA stained tissue, Photoreceptors initially contacted horizontal cell dendrites via ribbon synapses at the photoreceptor basal surface (stages 37/8--39). Later, horizontal cell dendrites penetrated the receptor as digitiform processes (stages 39--40) which subsequently expanded extensively within the invagination (stages 40--44). At stages 41--46, a photoreceptor ribbon generally was associated with two horizontal processes in a synaptic dyad complex; each ribbon participated in 1 or 2 such complexes. Bipolar cell dendrites made contact with receptors via superficial or invaginating basal-type junctions. Such junctions were observed first at stage 39, but increased greatly in number beginning at stage 42. Basal junctions were characterized by marked staining of the paramembranous receptor cell cytoplasm and a 9--13 nm wide cleft containing an electron-dense material. No association of bipolar cell dendrites with photoreceptor ribbons was noted. Junctional complexes presumed to be gap junctions first were observed at stage 39 between photoreceptor bases and basal processes emitted by neighbouring photoreceptors.


Effect of dietary vitamin E on ferric nitrilotriacetate-induced nephrotoxicity in rats.
The effect of dietary vitamin E on renal tissue damage and lipid peroxidation was investigated following treatment with ferric nitrilotriacetate (Fe-NTA) in rats. Almost 100% renal proximal tubular necrosis was observed in the vitamin E-deficient rats following Fe-NTA treatment (5 mgFe/kg body wt, ip) as early as 12 hr. In the vitamin E-supplemented rats, no injury was observed in the proximal convoluted (cortical) tubules, although some injury was seen in the medullary outer stripe (mostly pars recta of the proximal tubules) 24 hr after Fe-NTA treatment. The tissue lipid peroxidation was dose-dependently increased 1 hr after a single ip injection of Fe-NTA (1 to 10 mg Fe/kg body wt). Vitamin E-deficient animals had an increased tissue content of thiobarbituric acid-reactive substance following Fe-NTA treatment, whereas vitamin E-supplemented animals showed suppressed lipid peroxidation. This study indicates that vitamin E provides some protection against the nephrotoxicity and associated lipid peroxidation induced by Fe-NTA.


Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis.
We retrospectively analyzed our institutional incidence of hemorrhagic cystitis, identified risk factors, and examined associations of risk factors with disease severity and genitourinary complication rates. We reviewed charts of all consecutive pediatric patients treated from 1986 to 2010. We analyzed demographics, underlying diagnosis and treatment data to assess risk factors for hemorrhagic cystitis. We also correlated disease severity scores with clinical predisposing factors, and performed univariate and multivariate analyses to examine associations between risk factors and outcomes. Hemorrhagic cystitis was observed in 97 of 6,119 children (1.6%), most of whom (75%) had severity scores of II or III. Mean ± SD age was 12.2 ± 6.3 years for patients with hemorrhagic cystitis and 10.5 ± 7 years for patients without hemorrhagic cystitis (p = 0.017). On univariate analysis increased risk of hemorrhagic cystitis was significantly associated with age greater than 5 years, male gender, cyclophosphamide or busulfan chemotherapy, bone marrow or peripheral blood stem cell transplantation, pelvic radiotherapy and underlying diagnoses of rhabdomyosarcoma, acute leukemia and aplastic anemia. On multivariate analysis age greater than 5 years, allogeneic bone marrow or peripheral blood stem cell transplantation and pelvic radiotherapy were significantly associated with increased risk of hemorrhagic cystitis. Older age, late onset hemorrhagic cystitis, positive urine culture for BK virus and bone marrow or peripheral blood stem cell transplantation were associated with greater disease severity. Patients with higher severity scores more frequently experienced bladder perforation, hydronephrosis, overall hemorrhagic cystitis complications, and increased creatinine and blood urea nitrogen levels during followup. Older age, previous bone marrow or peripheral blood stem cell transplantation and BK virus in the urine are risk factors for hemorrhagic cystitis and are associated with a higher severity score. Higher severity scores are associated with increased rates of genitourinary complications and renal impairment.


Antibacterial and antioxidant activity and essential oil composition of Grammosciadium scabridum Boiss. from Iran.
The in vitro antibacterial and antioxidant activity of the essential oil and its two main components of Grammosciadium scabridum Boiss. (Apiaceae) growing wild in Iran, as well as the composition of its essential oil were studied. A total of 19 compounds representing 99.9% of the oil has been identified. Gamma-Terpinene (73.5%), p-cymene (14.2%) and (E)-beta-farnesene (5.3%) were characterized as the main components. The oil showed remarkable activity against three Gram-negative and four Gram-positive test bacteria, with minimal inhibitory concentration (MIC) values ranging from 0.31 to 10.00 mg/ml. The oil and its two main components were also subjected to screening for their possible antioxidant activity by using the 2,2-diphenyl-l-picrylhydrazyl (DPPH) assay. The free radical scavenging capacity of the oil was determined with an IC50 value of 6.6 mg/ml.


Why do cyclo-oxygenase-2 inhibitors cause cardiovascular events?
This report confirms evidence that selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as celecoxib, can lead to thrombotic cardiovascular events. Aspirin, a nonselective COX-1 (cyclo-oxygenase) and COX-2 inhibitor may result in gastric toxicity. For this reason, selective COX-2 inhibitors have been developed to reduce erosion of the gastric mucosa. Both selective and nonselective NSAIDs reduce prostacyclin formation in the infarcted heart; they accomplish this by tipping the balance of prostacyclin/thromboxane in favor of thromboxane, a prothrombotic eicosanoid. The relative increase in thromboxane, coupled with a diminution in prostacyclin in infarcted heart muscle, can lead to the development of thrombotic cardiovascular events. This may be prevented by the addition of a nitric oxide donor to NSAIDs.


Novel Mutations in CRLF1: Case Reports with Crisponi Syndrome.
Crisponi syndrome (CS) is a rare autosomal recessive syndrome, characterized by episodic facial muscle contraction with trismus, abundant salivation along with intermittent hyperthermia, feeding difficulties, characteristic facial dysmorphism, and camptodactyly. Here the authors report two South Indian neonates with confirmed diagnosis of Crisponi syndrome, caused by novel pathogenic variants in cytokine receptor-like factor 1 (CRLF1) gene. The classical clinical findings observed in the present cases were feeding difficulty, facial dysmorphism, tachypnea, contractures, camptodactyly, opisthotonus, hyperthermia, poor growth, and facial muscle contraction resembling probable tetanus. The patients with variants identified in the signal peptide domain had typical spasms from day one of life as compared to the variants in other domains who had later onset at neonatal period. The authors provide a review of the cases described, so far, from India highlighting that no common variants attribute to this rare syndrome. Recognizing this syndrome is crucial to differentiate it from infective conditions and for effective genetic counseling. Though tetanus is almost eradicated in developing countries, genetic causes should be suspected in new cases.


Identification of novel genes in the memory response to Brucella infection by cDNA arrays.
This study investigated memory responses in immune mice spleen cells to brucellosis by gene expression utilizing cDNA micro arrays. Out of a total of 1176 cDNA's 21 genes were differentially regulated in three independent experiments, and generally supported a Th1 type immune response. 10 genes were validated by real time PCR, and 3 genes (CD 86, CD 40 L and CD 132) were also analyzed by Flow Cytometry for surface protein expression. We extended these findings by studying the expression of five selected genes (IRF 1, SOCS 1, IL 2 R, IRF 7, and CXCR 4) in two independent groups of Brucella immunized mice. In this study we show the potential application of utilizing gene arrays to identify and establish new correlates of protection against a cell mediated immune response.


Dietary fish oil results in a greater bone mass and bone formation indices in aged ovariectomized rats.
Postmenopausal bone loss and the possible progression to osteoporosis is a major health concern. Until recently, hormone replacement therapy (HRT) was the standard for preventing the development of osteoporosis and possible hip fractures following menopause. However, because of some adverse effects of HRT, new therapies, lifestyle habits, and nutritional interventions are being developed and better characterized in their ability to prevent bone loss after menopause. One such option is to increase the amount of fish oil consumed in the diet. The goal of the current research was to determine the impact of fish oil supplementation on bone mass, density, formation, and resorption in an aged ovariectomized rat model. Twelve-month-old female retired breeder Sprague-Dawley rats were fed a control (Control) or fish oil (Fish) diet. Two weeks following the introduction of the diets, the rats were either sham-operated (Sham) or bilaterally ovariectomized (OVX). Ten weeks after surgery, indices of bone mass and bone histomorphometry were measured. Bone mineral content (BMC) of the whole femur was significantly higher in the Fish/OVX than in the Control/OVX, and the differences were most pronounced in the distal and proximal ends of the femur. However, the Fish/Sham and the Control/Sham did not differ in the measures of BMC. Although the Control/OVX had significantly lower cortical area and greater endosteal perimeter compared with the Control/Sham, the differences were not significant between the Fish/Sham and the Fish/OVX. In addition, the Fish/OVX had a significantly larger percent double-labeled surface and mineral apposition rate at the endocortical surface than the Control/OVX. Our findings suggest that fish oil supplementation has a positive effect on bone metabolism and might be a possible intervention to slow the loss of bone observed following menopause.


The Fes tyrosine kinase: a signal transducer that regulates myeloid-specific gene expression through transcriptional activation.
The c-fps/fes protooncogene encodes a 92-kDa protein tyrosine kinase that is involved in myeloid cell development and immune responses of granulocytes and macrophages. To help define its biological role and mechanism of action, we have developed a gain of function allele of Fes that has potent biological activity in myeloid cells. Introduction of constitutively active Fes into myeloid progenitors induced the appearance of fully differentiated macrophages or granulocytes depending on the lineage commitment of the transduced cells. We found that Fes-induced macrophage differentiation correlated with activation of the ets family transcription factor PU.1, which is essential for macrophage development. On the other hand, granulocyte differentiation by Fes was mediated through activation of CCAAT/enhancer-binding protein alpha (C/EBP-alpha) and STAT3, two transcription factors that are critical for granulocytic differentiation. We postulate that Fes transduces inductive signals for terminal macrophage and granulocyte differentiation, and that this biological activity is mediated through the activation of lineage-specific transcription factors.


Placental transport of riboflavin: differential rates of uptake at the maternal and fetal surfaces of the perfused human placenta.
The kinetics of riboflavin transfer across the perfused human placenta has been studied. With both circulations open, the transfer index (clearance of riboflavin: clearance of antipyrine) toward the fetus was 3.3 +/- 0.08 (+/- SD) versus 0.87 +/- 0.02 in the reverse direction (p less than 0.01). Galactoflavin reduced the materno-fetal transfer rate. The uptake of riboflavin and L-glucose after bolus injection into the maternal perfusate was 35% +/- 9.6% versus 3% +/- 16%, p = 0.005, which indicates an uptake rate in excess of diffusion. There was no significant difference in uptake at the fetal surface. With recirculation of either the maternal or fetal perfusate, the transplacental gradient that was established was lower at high concentrations of riboflavin, which indicates the saturability of this function. Riboflavin was concentrated in the intracellular space and partly metabolized to flavin mononucleotide and flavin adenine dinucleotide. An equilibrium was approximated when both perfusates were recirculated, with the concentration lowest in the maternal perfusate, highest in the placenta, and intermediate in the fetal perfusate. It is concluded that the major factor directing riboflavin toward the fetus is the difference in rates of uptake at the two surfaces of the placenta.


Very small embryonic-like (VSEL) stem cells: purification from adult organs, characterization, and biological significance.
In this review, we discuss current views of the bone marrow (BM) stem cell (SC) compartment and present data showing that BM contains heterogeneous populations of hematopoietic (H)SCs and non-HSCs. These cells are variously described in the literature as: endothelial progenitor cells (EPCs); mesenchymal (M)SCs; multipotent adult progenitor cells (MAPCs); marrow-isolated adult multilineage inducible (MIAMI) cells; and multipotent adult (MA)SCs. In some cases, it is likely that similar or overlapping populations of primitive SCs in the BM detected using various experimental strategies were assigned different names. Recently, we purified rare CXC chemokine receptor 4 expressing (CXCR4(+)) small SCs from the murine BM that express markers characteristic for embryonic (E)SCs, epiblast (EP)SCs, and primordial germ cells (PGCs). We named these primitive cells very small embryonic-like (VSEL) SCs. Our data indicate that VSELs may differentiate into cells from all three germ layers.


Editorial: The Name Game: Circumventing Quality Metrics by Categorizing Incomplete Colonoscopy as Sigmoidoscopy.
Cecal intubation rate (CIR) is an important metric for colonoscopy quality. Guidelines propose a minimum CIR of 90% for all indications, and 95% in screening procedures. In this issue, a study of three UK teaching hospitals demonstrated one-third of endoscopists inappropriately converted colonoscopies to flexible sigmoidoscopies, and several endoscopists only reached the 90% CIR benchmark because of these inappropriate conversions. Our professional societies and healthcare organizations must continue to work to improve the accurate assessment of colonoscopy quality in order to identify underperforming clinicians who should be provided with additional training for the benefit of their patients.


[Vascular anatomy of the right colon and vascular complications during laparoscopic surgery].
To analyze the vascular anatomy and complications of the right colon under laparoscope. Videotapes of 55 laparoscopic extended right hemicolectomy with D3 lymphadenectomy were reviewed and the anatomic relationship and bleeding vessels were determined. The superior mesenteric vein, superior mesenteric artery, ileocolic artery, and middle colic artery were present in all the patients. The right colic artery was present in 45.5%(25/55) of the patients. The incidence of the gastrocolic venous trunk was 74.5%. The overall incidence of intraoperative bleeding was 43.6%. Vessels in the pre-pancreatic region including the right gastroepiploic artery, the gastrocolic venous trunk, and its tributaries had a higher risk of bleeding than the middle colic vein and artery (16.4% vs. 14.5%). Intraoperative bleeding significantly prolonged the overall operative time and lymphadenectomy time. The vascular anatomy of the right colon is intricate and variable and laparoscopic extended right hemicolectomy with D3 lymphadenectomy is associated with a high risk of hemorrhage. Understanding the vessels anatomic relationship of the right colon is valuable to decrease vascular complication.


PKCγ promotes axonal remodeling in the cortico-spinal tract via GSK3β/β-catenin signaling after traumatic brain injury.
Traumatic brain injury (TBI) is a common cause of death and disability. Enhancing the midline-crossing of the contralateral corticospinal tract (CST) to the denervated side of spinal cord facilitates functional recovery after TBI. Activation of the gamma isoform of PKC (PKCγ) in contralateral CST implicates its roles in promoting CST remodeling after TBI. In this study, we deployed loss and gain of function strategies in N2a cells and primary cortical neurons in vitro, and demonstrated that PKCγ is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3β, PKCγ stabilizes the expression of cytosolic β-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKCγ in the corticospinal tract after unilateral TBI in vivo additionally showed that specifically delivery of active PKCγ mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKCγ-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKCγ mediates stability of β-catenin through the phosphorylation of GSK3β to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKCγ maybe a novel therapeutic target for physiological and functional recovery after TBI.


14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr.
Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G2,M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade. We found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 theta during Vprv-induced G2,M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3 theta association with Cdk1 and CyclinB1. Moreover, G2,M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3 theta binding to centrosomal proteins, Plk1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, Plk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin beta. Thus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins.


Clinical characteristics of adult patients with tics and/or Tourette's syndrome.
This study was conducted to describe the natural course of tic disorders over a long period of time in Japanese adults patients with Tourette's syndrome (TS) in terms of symptomatology. An extensive literature on TS cases was reviewed selectively and 31 TS patients (mean age: 31.4 years; sex: 28 males and 3 females) at our outpatient clinic were examined. The mean follow-up period of the patients was 7.6 years (SD: 8.1; 0 to 26). All the data available for this study, including medical charts, were examined systematically by two experienced child psychiatrists. The adult patients with tic disorders could be classified into the four groups: group A - tics only, group B - tics + comorbidities, group C - comorbidities only and group D - sub-clinical (remission) cases. Our 31 subjects consisted of 10 patients (32.3%) for group A, 14 (45.2%) for group B, 7 (22.6%) for group C, and 0 for group D. Further investigation into the natural course and clinical characteristics of adult TS needs to be done in order to acquire a better understanding of the broad spectrum of TS and to make improvements to the treatment for this illness.


The aluminum content of bone increases with age, but is not higher in hip fracture cases with and without dementia compared to controls.
Aluminum is considered a potentially toxic metal, and aluminum poisoning may lead to three types of disorders: aluminum-induced bone disease, microcytic anemia and encephalopathy. This is well known in patients with chronic renal failure, but since healthy subjects with normal renal function retain 4% of the aluminum consumed, they are also at risk of long-term low-grade aluminum intoxication. Included in this study were a total of 172 patients (age range 16-98 years) with the aim of examining whether aluminum accumulates in bone with increasing age. Additionally, we aimed to investigate whether the aluminum content of bone differs between controls and hip fracture cases with and without dementia, in particular in those with Alzheimer's disease. During operations for all cases, bone biopsies were taken with an aluminum-free instrument from the trabecular bone. The samples were measured for their content of aluminum using an inductively coupled mass spectrometer. We found an exponential increase in aluminum content of bone with age. The average aluminum values, adjusted for age, were similar in men and women (P=0.46). No significant differences in sex- and age-adjusted mean aluminum values between the controls and the hip fracture cases with (P=0.72) and without (P=0.33) dementia could be detected. The average aluminum concentration among cases with Alzheimer's disease was also similar to the values of hip fracture patients with other types of dementia (P=0.47). Odds ratios of hip fracture for each quartile of aluminum content in bone were also estimated to detect non-linear effects, but we did not find any statistically significant association remaining after age and sex adjustment. Thus, our results indicate that we accumulate aluminum in bone over our life span, but this does not seem to be of major pathogenetic significance for the occurrence of hip fracture or dementia.


Inhibitors and chemical probes for molecular chaperone networks.
The molecular chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and with their "client" proteins. Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation. The core chaperones, such as the heat shock proteins Hsp60, Hsp70, and Hsp90, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This possibility suggests that these PPIs, and perhaps not the individual chaperones themselves, could be compelling drug targets. Indeed, recent efforts have yielded small molecules that inhibit (or promote) a subset of inter-chaperone PPIs. These chemical probes are being used to study chaperone networks in a range of models, and the successes with these approaches have inspired a community-wide objective to produce inhibitors for a broader set of targets. In this Review, we discuss progress toward that goal and point out some of the challenges ahead.


Atheroprotective effect of myocardial bridge sustains in aging: Autopsy study on subjects with dual left anterior descending coronary artery type 3.
The atheroprotective role of the myocardial bridge (MB) on a tunneled segment is already demonstrated in subjects with dual left anterior descending coronary artery (dual LAD) type 3 anomaly, but the dynamics of changes and whether this protective effect sustains during aging is unknown. The retrospective autopsy study included cases of dual LAD type 3 anomaly identified over 18 years. The severity grade of atherosclerosis in branches of dual LAD was estimated by microscopy. The Spearman's correlation test and Receiver operator characteristics (ROC) curve analyses were performed to determine the relation of subjects' age with a degree of the protective role of the myocardial bridge. A total of 32 dual LAD type 3 cases were identified. The systematic heart examination revealed an anomaly prevalence of 2.1%. The age significantly positively correlated with the severity of atherosclerosis in the subepicardial dual LAD branch but not with the severity of atherosclerosis in the intramyocardial dual LAD branch. Subjects aged ≥38 years were likely to have a more severe degree of atherosclerosis in subepicardial than in intramyocardial LAD arteries (AUC 0.81 95% CI 0.59-1; sensitivity 100%, specificity 66.7%). In subjects aged ≥58 years, this difference was likely to be more pronounced (≥2 degree difference; AUC 0.75 95% CI 0.58-0.93; sensitivity 92.9%, specificity 66.7%). The atheroprotective effect of the myocardial bridge on tunneled segments usually becomes evident throughout the second half of the fourth decade of life and is most pronounced after about 60 years and ceases only in some.


The relation of patient satisfaction with complaints against physicians and malpractice lawsuits.
A small number of physicians generate a disproportionate share of complaints from patients and of malpractice lawsuits. If these grievances relate to patients' dissatisfaction with care, it might be possible to use commonly distributed patient satisfaction surveys to identify physicians at high risk of complaints from patients and of malpractice lawsuits. We sought to examine associations among patients' satisfaction survey ratings of physicians' performance and complaints from patients, risk management episodes, and rates of malpractice lawsuits. We examined 353 physicians at a large US teaching hospital whose inpatient performance was rated by 10 or more patients between January 1, 2001, and March 31, 2003. Physicians were divided into 3 tertiles according to satisfaction on a commercial survey instrument administered to recently discharged patients. Records of unsolicited complaints from patients (January 1, 2000, to March 31, 2003) and risk management episodes (January 1, 1983, to March 31, 2003) were analyzed after adjusting for the physician's specialty and panel characteristics of the physician's patients. Decreases in physicians' patient satisfaction survey scores from the highest to the lowest tertile were associated with increased rates of unsolicited complaints from patients (200 vs 243 vs 492 complaints per 100,000 patient discharges; P <0.0001) and risk management episodes (29 vs 43 vs 56 risk management episodes per 100,000 patient discharges; P = 0.007). Compared with physicians with the top satisfaction survey ratings, physicians in the middle tertile had malpractice lawsuit rates that were 26% higher (rate ratio [RR] = 1.26; 95% confidence interval [CI]: 0.72 to 2.18; P = 0.41), and physicians in the bottom tertile had malpractice lawsuit rates that were 110% higher (RR = 2.10; 95% CI: 1.13 to 3.90; P = 0.019). Patient satisfaction survey ratings of inpatient physicians' performance are associated with complaints from patients and with risk management episodes. Commonly distributed patient satisfaction surveys may be useful quality improvement tools, but identifying physicians at high risk of complaints from patients and of malpractice lawsuits remains challenging.


Bhattar Harichandra: The first commentator of Charaka Samhita.
Bhattar Harichandra was the first commentator who wrote 'Charakanyasa' commentary on Charaka Samhita after completion of redaction process by Dridhabala. Two manuscripts of this commentary are available with number 9290 and 13092 in Asiatic Society of Kolkata and Government East Library, Chennai respectively. Yadavji opines that Bhattar Harichandra belongs to the period of Chandragupta - II (375 A.D. - 413 A.D.) while Acharya Priyavrat Sharma considers the period of Yashodharaman (6 A.D.) as the period of Bhattar Harichandra. As far as external evidence is considered Banabhatta another notable Sanskrit poet quoted Bhattar Harichandra in his work Harshacharitam. Banabhatta was contemporary to Chandragupta. Charaka Samhita enjoyed much reputation during Chandragupta Mourya - II period. Agnivesha Tantra was redacted during the period of Kanishka (2 A.D.) and then onwards it was referred by titles like Sahasanka and Vikramaditya. Among Navaratna (Nine gems), Shanku and Vaitala Bhatta are included. But in the authors opinion it should be commented as "Shankuvaitala" and "Bhatta". The name Bhatta in his context may be referring to Bhattar Harichandra. Based on the external evidences it may be concluded that Bhattar Harichandra was contemporary to Chandragupta period i.e. 375 A.D. - 413 A.D. (4th to 5th century).


Functional Imaging of the Foot with Perfusion Angiography in Critical Limb Ischemia.
To report on the first clinical experience with perfusion angiography (PA) of the foot in patients with chronic critical limb ischemia. PA is a post-processing software algorithm and no extra digital subtraction angiography (DSA) has to be performed for this analysis. The data used to test the feasibility of PA were obtained from a consecutive group of 89 patients with CLI who were treated with standard below the knee angioplasty and 12 separate patients who were not suitable for endovascular revascularization. Motion artifacts in the dataset of the DSA made post-procedural analysis impossible in 10 % intervention. In the majority of patients (59/68) PA showed an increase in volume flow in the foot after successful angioplasty of the crural vessels. However, in 9/68 patients no increase was seen after successful angioplasty. With the use of a local administered competitive α-adrenergic receptor antagonist, it is also possible to test and quantify the capillary resistance index which is a parameter for the remaining functionality of the microcirculation in CLI patients. PA might be used as a new endpoint for lower limb revascularization and can also be used to test the functionality the microcirculation to identify sub-types of patients with CLI. Clinical evaluation and standardization of PA is mandatory before introduction in daily practice.


Detection by high-performance liquid chromatography of methotrexate and its metabolites in tumor tissue from osteosarcoma patients treated with high-dose methotrexate/leucovorin rescue.
Methotrexate (MTX) polyglutamates were detected in osteogenic sarcoma tumor samples obtained from patients 24 or 48 h after receiving high-dose MTX/leucovorin rescue therapy. Tumor samples were assayed by high-performance liquid chromatography, and polyglutamyl metabolites, along with MTX, were quantitated using both direct u.v. absorption at 313 nm and an enzyme titration assay. Good agreement between these two methods was found although the more sensitive enzyme assay detected peaks in some samples not detected by u.v. absorbance. A wide variation in MTX:MTX polyglutamate levels (1:1 to 25:1) was found among the six clinical samples studied. Also, no correlation between the extent of polyglutamate formation and plasma levels (determined at the time of tumor sampling) was observed. High intracellular levels of a derivative which appears to be the 7-hydroxy metabolite of MTX were also detected in four of six samples. This material coeluted with authentic standard, showed spectral properties like standard 7-OH-MTX, and did not inhibit dihydrofolate reductase.


Effects of semicarbazide on DNA, RNA and protein hepatic levels on four subsequent generations of Wistar rats.
1. The offspring (F1) of a parent generation (P) were mated on a brother-to-sister system to produce a second generation (F2), which was then mated in the same way to produce a third generation (F3). 2. Each of these generations were divided into two groups, controls and treated. 3. A single dose of 100 mg/kg of semicarbazide was administered to the treated Wistar rats on the 10th day of their pregnancy. 4. DNA, RNA and protein hepatic levels were measured in the livers of either 21-day-old foetuses or 1, 7, 15 or 30-day-old offspring. 5. These levels were also studied in the pregnant rats on day 21 of gestation. 6. Semicarbazide produced a significant decrease of these levels not only in the foetuses, offspring and pregnant rats but also in the controls, F2 and F3, from treated P and F1 respectively.


RhoA/ROCKs signaling is increased by treatment with TKI-258 and leads to increased apoptosis in SCC-4 oral squamous cell carcinoma cell line.
This study evaluated the effect of treatment with TKI-258 on apoptosis, involving Rho GTPases and their effectors in SCC-4 cells of oral squamous cell carcinoma. Markers of cell death and apoptosis were analyzed in control and TKI-258-treated SCC-4 cells by flow cytometry. The involvement of Rho GTPases and effectors in the induction of apoptosis by TKI-258 was evaluated by quantification of cleaved PARP. Also, gene expression analysis of those proteins was performed. The treatment with TKI-258 led to a significant increase in cell death (7-AAD) and apoptosis (annexin V and cleaved PARP). When Rho GTPases were stimulated with LPA and inhibited with toxin A Clostridium difficile, the percentage of apoptotic cells increased and decreased, respectively. A similar effect was found when the treatment was with TKI-258 combined with LPA and toxin A. Treatment with TKI-258 significantly increased RhoA gene expression, while RhoB, RhoC, Rac1, and Cdc42 decreased significantly. ROCKs inhibitors (Y-27632 and HA-1077) reduced apoptosis compared with control. TKI-258 combined with Y-27632 or HA-1077 led to an increase in apoptosis compared with inhibitors only. Treatment with TKI-258 led to an increase in ROCK1 and ROCK2 gene expression, and a decrease in PAK1 and PAK2 gene expression. TKI-258 stimulates apoptosis in SCC-4 cells of oral squamous cell carcinoma. Possibly, RhoA GTPase and their effectors ROCKs participate in the signaling pathway inhibited by TKI-258. Therapies with multi-target inhibitors, such as TKI-258, may be promising alternatives for the clinical treatment of oral squamous cell carcinoma.


Potential impact of application of Z0011 derived criteria to omit axillary lymph node dissection in node positive breast cancer patients.
The ACOSOG Z0011 trial, a randomized controlled trial among patients with sentinel node positive breast cancer treated with breast conserving therapy, concluded that axillary lymph node dissection (ALND) can be omitted in these patients. However, questions were raised on the general applicability if the results of the Z0011 trial. Therefore, the aim of this study was to assess the practice changing effect of the Z0011 trial by quantifying the proportion of all node positive breast cancer patients who meet the inclusion criteria which are based on the Z0011 trial, thus in whom an ALND could be omitted. A multicenter population based study including patients with clinical T1-2N0-1M0 invasive non-metastatic breast cancer, a positive sentinel node or ultrasound guided lymph node biopsy, treated with breast conserving therapy and adjuvant systemic therapy between January 2007 and December 2012. A total of 11,031 patients had invasive breast cancer including 3051 cases treated with breast conserving therapy and adjuvant systemic therapy. Subsequently, 916 cases with a positive nodal status underwent an ALND of whom 558 cases (60.9%), representing 5.1% of the total breast cancer population, would potentially have fulfilled the Z0011 criteria. Application of Z0011 based criteria is practice changing in nearly 61% of all node positive patients, which could result in omission of the ALND in a substantial number of patients in the future. Further research has to be performed on the applicability of these conclusions to other categories of breast cancer patients.


Detection of male genital schistosomiasis (MGS) by real-time TaqMan® PCR analysis of semen from fishermen along the southern shoreline of Lake Malawi.
Male genital schistosomiasis (MGS) is an underappreciated complication of schistosomiasis, first described in 1911. However, its epidemiology, diagnostic testing and case management are not well understood in sub-Saharan Africa. To shed new light on MGS prevalence in Malawi, a longitudinal cohort study was conducted among adult fishermen along the southern shoreline of Lake Malawi using detection of schistosome DNA in participants' semen by real-time TaqMan® PCR analyses. Upon recruitment of 376 participants, 210 submitted urine samples and 114 semen samples for parasitological tests. Thereafter, the available semen samples were subsequently analysed by real-time TaqMan® PCR. Praziquantel (PZQ) treatment was provided to all participants with follow-ups attempted at 1, 3, 6 and 12-months' intervals. At baseline, real-time PCR detected a higher MGS cohort prevalence of 26.6% (n = 64, Ct-value range: 18.9-37.4), compared to 10.4% by semen microscopy. In total, 21.9% of participants (n = 114) were detected with MGS either by semen microscopy and/or by real-time PCR. Subsequent analyses at 1-, 3-, 6- and 12-month follow-ups indicated variable detection dynamics. This first application of a molecular method, to detect MGS in sub-Saharan Africa, highlights the need for development of such molecular diagnostic tests which should be affordable and locally accessible. Our investigation also notes the persistence of MGS over a calendar year despite praziquantel treatment.


Free-base nicotine in tobacco products. Part II. Determination of free-base nicotine in the aqueous extracts of smokeless tobacco products and the relevance of these findings to product design parameters.
Reports in the peer-reviewed literature and popular press have alleged that smokeless tobacco product (STP) manufacturers increase the addictiveness of their products by adjusting formulae to increase the relative percentage of nicotine in STP that is not protonated. Such nicotine is more popularly, but incorrectly, known as free-base nicotine ("FBN") as it is a calculated amount as opposed to a real chemical species in the STP. Some regulators have mandated reporting of FBN as estimated by Henderson-Hasselbalch equation ("HHE") using the pH-value of an aqueous suspension (or extract) of STP. This is technically incorrect because the HHE is only valid in pure dilute aqueous solution of a single base and its conjugate acid. The aqueous suspensions (or extracts) of STP often contain high concentrations of salts and polymeric anions such as pectate and many other compounds, and there is a molar excess of ammonia over nicotine in some products. These are heretofore-unrecognized sources of error in use of the HHE to estimate relative amount of nicotine that is not protonated results in inaccurate FBN-values. Thus, it is not surprising that attempts to show the relevance of estimated value of FBN in STP to human physiology have failed.


Silymarin-loaded Eudragit(®) RS100 nanoparticles improved the ability of silymarin to resolve hepatic fibrosis in bile duct ligated rats.
Some nano-formulations of silymarin (SM), a drug commonly used for liver diseases, were developed to overcome its poor solubility and poor bioavailability; antifibrotic effect of these formulations has not been tested yet. In this study we aimed to formulate and evaluate silymarin-loaded Eudragit(®) RS100 nanoparticles (SMnps) and to test the capability of SMnps to reverse an established fibrosis model. SMnps were prepared by solvent evaporation and nano-precipitation techniques. The influence of drug:polymer ratio, concentration of surfactant in the aqueous phase on particle size, drug entrapment efficiency (EE) % and in vitro drug releases were investigated. For in vivo evaluation, bile duct ligated (BDL)-rats were treated with either SM or SMnps every other day (125mg/kg) orally for 3 weeks started 3 weeks after BDL. Liver function tests, oxidative stress and fibrosis/fibrogenesis process were evaluated using biochemical and histopathological techniques. The formulation No (F4) of SMnps showed an average particle size of 632.28±12.15nm, a drug EE% of 89.47±1.65% and released the drug in a prolonged manner over 24h. The prepared SMnps were nearly spherical with smooth surfaces. In BDL-rats, treatments with either SM or SMnps corrected liver function and oxidative stress. Only SMnps was able to reverse the induced fibrosis; SMnps significantly decreased serum tumor necrosis factor- α (TNF-α), serum transforming growth factor- β1 (TGF-β1), hepatic hydroxyproline and downregulated the hepatic expression of tissue inhibitor metalloproteinase-1 (TIMP-1) and cytokeratin-19 (CK-19), whilst increased hepatic hepatocytes growth factor (HGF) and upregulated the hepatic expression of matrix metalloproteinase-2 (MMP-2) and increased MMP-2/TIMP-1 ratio at mRNA level. Livers of rats treated with SMnps showed very little collagen in ECM and restored hepatic architecture as compared to either BDL rats or rats treated with SM. Formulation of silymarin as nanoparticles improved its ability to resolve cholestasis-induced liver fibrosis by restoring hepatic regenerative capabilities. Therefore, formulation of SMnps may represent a step forward in the field of anti-fibrotic drug development.


Self-destructive tendencies and depression as predictors of suicidal ideation in teenagers.
In male teenagers, scores on a self-destructive inventory were more strongly associated with the presence of suicidal ideation than scores on a depression inventory. For female teenagers, scores on the depression inventory were more strongly associated with suicidal ideation.


Direct synthesis of coated gold nanoparticles mediated by polymers with amino groups.
The single-step/single-phase synthesis of hybrid organic-inorganic core-shell gold nanoparticles (AuNPs), facilitated by amino-functionalized amphiphilic block copolymers that simultaneously play the roles of reductant and stabilizer, was investigated in this study. Experiments were devised with emphasis on the pH-responsive poly(ethylene oxide)-b-poly(2,3-dihydroxypropyl methacrylate)-b-poly[2-(diisopropylamino)ethyl methacrylate] triblock copolymer, which allows direct chemical cross-linking of the micellar structures to be performed. The polymer structure-reactivity relationship associated with the AuNP formation was established using a set of six structurally related macromolecules. AuNP formation was dependent on the aqueous dissociation equilibrium involving tertiary amino groups, the Au(III) speciation, and electrochemical redox potentials. The effects of these parameters on the synthesis of AuNPs change as the solution pH is increased from pH 3.3 (molecularly dissolved polymer chains; no AuNP formation) to 6.8 or higher (polymer chains self-assembled into spherical micelles; stable gold sols are produced), and Au(III) reduction potentials shift toward the cathodic region while the oxidation potential of deprotonated amino groups decreases. Sigmoidal nanoparticle growth kinetics was observed in all cases after a characteristic induction period. Stable, well-defined, uniform polymer-coated gold colloids with localized surface plasmon resonance centered at 53 0nm can be conveniently produced in one-pot, two-reactant, no work-up reactions when the stoichiometry is [N]/[Au]=3.5-25.0.


Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice.
In male coupling factor 6 (CF6)-overexpressing transgenic (TG) mice, a high-salt diet induces hypertension and cardiac systolic dysfunction with excessive reactive oxygen species generation. However, the role of gender in CF6-mediated pathophysiology is unknown. We investigated the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction and Rac1 activity, which activates radical generation and the mineralocorticoid receptor, in female TG mice. Fifteen-week-old male and female TG and wild-type (WT) mice were fed a normal- or high-salt diet for 60 weeks. Systolic and diastolic blood pressures were higher in the TG mice fed a high-salt diet than in those fed a normal-salt diet at 20-60 weeks in males but only at 60 weeks in females. The blood pressure elevation under high-salt diet conditions was concomitant with a decrease in left ventricular fractional shortening. In the WT mice, neither blood pressure nor cardiac systolic function was influenced by a high-salt diet. In the female TG mice, bilateral ovariectomy induced hypertension with cardiac systolic dysfunction 8 weeks after the initiation of a high-salt diet. The ratios of Rac1 bound to guanosine triphosphate (Rac1-GTP) to total Rac1 in the heart and kidneys were increased in the ovariectomized TG mice, and estrogen replacement abolished the CF6-mediated pathophysiology induced under the high-salt diet conditions. The overexpression of CF6 induced salt-sensitive hypertension, complicated by systolic cardiac dysfunction, but its onset was delayed in females. Estrogen has an important role in the regulation of CF6-mediated pathophysiology, presumably via the downregulation of Rac1.


Atrial receptors in the dog and rabbit.
1. Action potentials were recorded from slips of the cervical vagi in anaesthetized dogs and rabbits. Single functional units with atrial patterns of discharge (Paintal Type A, B and intermediate) were obtained and then attempts were made to alter (i.e. convert) their patterns of discharge. Finally the points of origin of these action potentials were located.2. Thirty unselected units were investigated in thirty dogs. Twenty-seven of these were located in the endocardium of the vein-atrial system and the ratio of the type A, type B and intermediate type receptors was 1:16:10; three units were located elsewhere in the chest. Conversion of the pattern of discharge was achieved in twenty of the twenty-seven units; conversion was achieved in the single type A unit.3. In a second series of experiments in dogs, eight Paintal Type A units were selectively studied in fifteen animals. Four of these were located in the endocardium and all were converted. The remaining four were located outside the endocardium and conversion could not be achieved in two of these. Thus in the entire investigation, the ;type A' units which could not be converted were all located at sites other than the atrial endocardium.4. In the corresponding unselected study in the rabbit, eleven units were studied in eleven animals. Nine of these units were located in the atrial endocardium and the ratio of the type A, type B and intermediate type receptors was 2:1:6. Conversion was achieved in both type A units, the sole type B unit and two of the intermediate units. One of the two units found outside the atrial endocardium was a ;type A' unit and could not be converted.5. The present investigation has shown that the atrial receptors with a Paintal Type A pattern of discharge are relatively rare in both dogs and rabbits. Conversion of the pattern of discharge is a relatively common phenomenon. Evidence for the proposition that there is one basic type of atrial receptor whose pattern of discharge is determined by its precise location in the vein-atrial system is discussed.


Numerical modelling of the effects of cold atmospheric plasma on mitochondrial redox homeostasis and energy metabolism.
A biochemical reaction model clarifies for the first time how cold atmospheric plasmas (CAPs) affect mitochondrial redox homeostasis and energy metabolism. Fundamental mitochondrial functions in pyruvic acid oxidation, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation involving the respiratory chain (RC), adenosine triphosphate/adenosine diphosphate (ATP/ADP) synthesis machinery and reactive oxygen species/reactive nitrogen species (ROS/RNS)-mediated mechanisms are numerically simulated. The effects of CAP irradiation are modelled as 1) the influx of hydrogen peroxide (H[Formula: see text]O[Formula: see text]) to an ROS regulation system and 2) the change in mitochondrial transmembrane potential induced by RNS on membrane permeability. The CAP-induced stress modifies the dynamics of intramitochondrial H[Formula: see text]O[Formula: see text] and superoxide anions, i.e., the rhythm and shape of ROS oscillation are disturbed by H[Formula: see text]O[Formula: see text] infusion. Furthermore, CAPs control the ROS oscillatory behaviour, nicotinamide adenine dinucleotide redox state and ATP/ADP conversion through the reaction mixture over the RC, the TCA cycle and ROS regulation system. CAPs even induce a homeostatic or irreversible state transition in cell metabolism. The present computational model demonstrates that CAPs crucially affect essential mitochondrial functions, which in turn affect redox signalling, metabolic cooporation and cell fate decision of survival or death.


Psychosocial work conditions before myocardial infarction in young men.
All male patients in the greater Stockholm area who had survived a myocardial infarction below the age of 45 were examined with regard to medical and psychosocial risk factors 3-6 months after the onset of the infarction. For each patient, a male control subject was randomly selected after matching with regard to age and residence area. In the patient group, coronary angiograms were performed and rated with regard to degree of coronary atherosclerosis. The psychosocial variables were not correlated with degree of coronary atherosclerosis. Excessive work demands combined with boredom at work ("variety" and "intellectual discretion") were significantly more often reported by the patients after adjustment had been made for life style factors. In the multivariate analysis a high LDL/HDL cholesterol ratio, a high cumulative tobacco consumption, high demands in relation to variety at work as well as high demands in relation to influence over work and finally a low alcohol consumption were significant independent predictors of case status. Excessive work demands in themselves did not differentiate cases from controls.


Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation.
We describe two brothers with mental retardation (MR) due to a c.428_451dup24 in the ARX gene. The mother did not apparently carry the mutation, as determined by dHPLC and by fragment size analysis. Using semiquantitative fluorescent PCR, we show however that 4% of her lymphocytes and 24% of her fibroblasts harbored the duplication. We thus show that the mother displays somatic mosaicism for the duplication thereby highlighting the need to reconsider the molecular screening in sporadic cases of MR.


Mobilization of CD34+ haematopoietic stem cells is associated with a functional inactivation of the integrin very late antigen 4.
The beta1 integrin very late antigen 4 (VLA-4) plays a central role in mobilization and homing of CD34+ cells. In this study, we examined the activation state of VLA-4 on CD34+ cells from bone marrow (BM) and peripheral blood (PB) by flow cytometry using a vascular cell adhesion molecule I-immunoglobulin (VCAM-I/IgG) fusion protein as soluble ligand. In an intraindividual analysis, we found a significantly reduced affinity and avidity of the VLA-4 receptor on CD34+ cells from PB during granulocyte colony-stimulating factor (G-CSF)-enhanced marrow recovery in comparison with steady-state BM. Moreover, the amount of circulating CD34+ cells during marrow recovery was inversely related to the activation state but not to the expression level of VLA-4, suggesting that a modulation of the functional state of VLA-4 is involved in the mobilization of CD34+ cells. Moreover, VLA-4 function on CD34+ cells from BM was associated with the maturation state of CD34+ cells as high-affinity VLA-4 receptors were observed on the vast majority of more primitive CD34+ cells. In addition, we found that Mg2+ ions as well as co-incubation of CD34+ cells with endothelial cells resulted in an activation of the VLA-4 receptor. In conclusion, modulation of the functional state of VLA-4 appears to be of relevance for the mobilization and homing of CD34+ haematopoietic stem cells.


Nucleostemin expression in squamous cell carcinoma of the head and neck.
This study presents initial data on presence of nucleostemin--a nucleolar protein typical of stem cells in the normal squamous epithelium of the oropharynx and larynx - in squamous cell carcinoma originating from these epithelia. Differentiation and proliferation markers such as keratins, beta-catenin, galectin-1, and Ki-67 were studied in parallel with nucleostemin for defining cell characteristics. Nucleostemin was detected in nucleoli of both proliferating basal cells and terminally differentiated suprabasal cells of normal epithelium and in tumor cells. Importantly, malignant transformation was connected with a significant enlargement of nucleostemin-positive nucleoli in these cell types. Detection of nucleostemin in head and neck cancer cells, together with the size of nucleoli, may be important in the evaluation of tumor differentiation and biology.


The impact of exercise-induced changes in intraventricular dyssynchrony on functional improvement in patients with nonischemic cardiomyopathy.
The assessment of dynamic intraventricular dyssynchrony has been reported to be feasible in a clinical setting. However, its prognostic implication in functional improvement has not yet been investigated. Symptom-limited, supine bicycle exercise was performed on 41 patients with nonischemic cardiomyopathy (52 +/- 12 years, ejection fraction < 40%). Using Doppler tissue imaging, the average of peak systolic velocities at 6 basal segments was obtained at rest and peak exercise. Dyssynchrony index (Ts-SD12) was defined as the SD of the time to peak systolic velocities at 12 left ventricular segments. The percent change of end-systolic volume (%Delta ESV) was calculated at follow-up. A 15% or greater reduction in end-systolic volume (%Delta ESV < -15%) was considered as functional improvement. During exercise, changes in dyssynchrony (Delta Ts-SD12) were individually variable. Average of peak systolic velocities (V) at 6 basal segments at peak exercise independently correlated with Ts-SD12 at peak exercise (beta = -0.541, P < .001). Follow-up echocardiography was performed on 35 patients after medical treatment for 13.0 +/- 4.9 months. There was significant association of %Delta ESV with the change in mitral regurgitation (r = 0.434, P = .009), disease duration (r = 0.343, P = .045), QRS interval (r = 0.347, P = .041), and Delta Ts-SD12 (r = 0.511, P = .002). Multivariate analysis identified Ts-SD12 measured at peak exercise as the strongest predictor for functional improvement (%Delta ESV: beta = 0.577, P < .001; and Delta ejection fraction: beta = -0.563, P < .001). In patients with heart failure, dynamic dyssynchrony can be assessed during exercise. Ts-SD12 at peak exercise may be an independent predictor for reverse remodeling with medical treatment.


Abnormal night sleep duration and inappropriate sleep initiation time are associated with elevated anxiety symptoms in Chinese rural adults: the Henan Rural Cohort.
Sleep problems have been demonstrated to cause mental symptoms, such as anxiety. However, research on the association of the night sleep duration and sleep initiation time on anxiety symptoms in rural China is still lacking. The current study, therefore, explored the independent and combined association of the night sleep duration and sleep initiation time on anxiety symptoms. This study included 28, 054 participants from the Henan Rural Cohort. Sleep was measured using the Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the two-item Generalized Anxiety Disorder scale (GAD-2). Multivariable logistic regression models and restricted cubic spline with anxiety symptoms as a dependent variable were fitted. Among the participants in this study, 11, 209 (39.96%) were males, and 16,845 (60.04%) were females, 1574 (5.61%) had anxiety symptoms. Both shorter and longer night sleep duration were significantly related to elevated prevalence of anxiety symptoms. Extreme sleep initiation time was also significantly associated with elevated anxiety symptoms. Additionally, night sleep duration and sleep initiation time had a combined effect on the prevalent anxiety symptoms. In conclusion, there was a dose-response association of night sleep duration and sleep initiation time with anxiety among Chinese rural population. Moreover, they might jointly increase the odds of prevalent anxiety.


Assessing the genotoxicity of urban air pollutants in Varanasi City using Tradescantia micronucleus (Trad-MCN) bioassay.
In the present study Tradescantia micronucleus (Trad-MCN) bioassay was performed to assess the genotoxicity of air pollutants in Varanasi City. The experiment was performed during October 2006 to April 2007. For Tradescantia micronucleus (Trad-MCN) bioassay four sites were selected, three in the city having different traffic characteristics and one control site virtually free from traffic intervention. Twenty young Tradescantia pallida inflorescences were collected from each sampling site during the study period and micronuclei frequencies were determined in early tetrads of pollen mother cells and expressed as MCN/100 tetrads. During the same period the concentration of different air pollutants were also measured. Tradescantia micronucleus (Trad-MCN) bioassay showed that the plants kept in areas having higher traffic emissions evidence higher micronuclei frequencies than samples kept at control site. The study indicates that in situ biomonitoring using higher plants may be useful for characterizing genotoxic air pollutants in areas even without any sophisticated instrument.


Impaired cytolytic activity in peripheral blood T cells from renal cell carcinoma patients.
Classic T lymphocyte cytotoxicity is mediated through the T cell receptor (TCR). Defects in TCR signal transduction and cytolytic activity have been reported in tumor infiltrating T lymphocytes. We hypothesized that impaired cytotoxicity occurs in peripheral blood T cells from renal cell carcinoma (RCC) that can be reversed by exposure to rhIL-2. Peripheral blood mononuclear cells (PBMC) from 29 RCC patients and 29 healthy volunteers were isolated and cultured in the absence or presence of 10 IU/ml rhIL-2. A redirected cytotoxicity assay that requires TCR signal transduction was used with chromium-labeled P815 target cells, effector PBMC and anti-CD3 antibody. Target cell lysis was measured in "lytic units" (LU). Mean LU from RCC patients was lower than that of healthy volunteers (105.8 LU vs. 194.6 LU, P = 0.025). Exposure to rhIL-2 increased T cell-mediated lysis in both groups. Disruption of T cell cytotoxicity in RCC patients can be overcome by exposure to rhIL-2.


Validity and Utility Testing of a Criteria-led Discharge Checklist to Determine Post-operative Recovery after Abdominal Surgery: an International Multicentre Prospective Cohort Trial.
Criteria-led discharge (CLD) has promising potential to reduce unnecessary hospital stay after abdominal surgery; however, the validity and utility of CLD is uncertain as studies are limited to small single-centre studies involving predominantly elective colorectal surgery. This prospective international multicentre cohort study explored the relationship between a CLD checklist, post-operative recovery, and hospital length of stay using patient-level data from four clinical trials involving 1071 adults undergoing all types of emergency and elective abdominal surgery at five hospitals across Australia and New Zealand. Patients were assessed daily for 21 post-operative days using a standardised CLD checklist. Surgeons and hospital clinicians were masked to findings. Criterion, construct, and content validity of the checklist to accurately reflect discharge decisions by surgical teams, assess physiological recovery, and encompass parameters signalling physiological readiness to discharge were tested. Potential utility of CLD to minimise unnecessary hospital stay was assessed by comparing day of readiness to discharge to actual day of discharge. The CLD checklist had concordance with existing discharge planning practices and accurately measured a longer post-operative recovery in more complex clinical situations. The CLD checklist in its current format did not detect all legitimate medical and surgical reasons necessitating a continued stay in hospital. Day of readiness to discharge was 0.8 days (95% CI 0.7 to 0.9, p < 0.001) less than actual day of discharge. A CLD checklist has excellent criterion and construct validity in measuring physiological recovery following all types of major elective and emergency abdominal surgery. Content validity could be improved. The use of CLD has the potential to reduce unnecessary hospital stay although the safety of discharging patients according to the criteria requires investigation prior to implementation. Trials were prospectively registered at the Australian New Zealand Clinical Trials Registry (LIPPSMAck POP 12613000664741, ICEAGE 12615000318583, PLASTIC 12619001344189, NIPPER PLUS 12617000269336).


Physician-assisted death. Opinions of Mexican medical students and residents.
To explore opinions of young residents and medical students on physician-assisted death (PAD). A questionnaire was answered by 140 residents at the beginning of their residency and 99 third- or fourth-year medical students (46 attended religiously administered medical schools [RAMS] and 53 lay-administered medical schools [LAMS]). Main questions were agreement with PAD, therapy withdrawal (TW) and personalized PAD (PPAD) on whether participants themselves would seek help to die. There were no differences of acceptance between residents and students but LAMS students had significantly higher agreement than RAMS students for PAD (68 vs. 33%), TW (79 vs. 39%) and PPAD (57 vs. 48%). LAMS students were also more willing to agree to a physician prescribe/inject a lethal drug, even if PAD were not legalized. However, legality was also an important issue, i.e., 25-58% of those unsure or opposed to PAD would reverse the decision if PAD were legalized, and 42-54% of those unwilling to TW would also reverse if written consent of the patient existed. Overall acceptance of residents and students was significantly higher than our previous study in nearly 1,000 older physicians (50 vs. 39% for PAD and 58 vs. 48% for TW). PAD and TW acceptability seems to be increasing in Mexico, probably as a result of evolving social attitudes that appeared to be counteracted by a more conservative upbringing at home in our young RAMS students.


Virtual occlusion in orthognathic surgery.
The aim of this retrospective study was to determine whether a virtually created occlusion is as accurate as a conventionally created occlusion. Seventeen orthognathic patients were included in the study, which was conducted in a university clinic. Plaster cast models were obtained and digitized. Two experienced observers created the conventional (gold standard) and virtual occlusion to assess inter-observer variability. One observer created the conventional and virtual occlusion a second time to assess the intra-observer variability. The criterion for accepting the virtual occlusion was that the difference between the gold standard and the virtual occlusion was not larger than the intra-observer variability for the gold standard. A non-parametric Kruskal-Wallis H test was performed to detect statistically significant differences between the intra- and inter-observer groups for both the conventional and virtual occlusion. No statistically significant differences were found between the different groups. The difference between the conventional and virtual occlusion group was 0.20mm larger than the intra-observer variability of the gold standard. The virtual occlusion tool presented here can be utilized in daily clinical practice and makes the use of physical dental models redundant.


Long-term Angiographic Results of the Low-profile Acandis Acclino Stent for Treatment of Intracranial Aneurysms : A Multicenter Study.
The low-profile Acandis Acclino is a self-expandable nitinol microstent for stent-assisted coiling of intracranial aneurysms. This article reports long-term clinical and angiographic outcome in a multicenter setting. In this study 98 consecutive patients (mean age 55.4 ± 13.5 years) were treated with the Acclino for 98 aneurysms (28 unruptured, 20 recurrent, 50 ruptured) at 3 German tertiary care centers within a 6-year period. The technical success, complications, clinical outcome and angiographic results were retrospectively analyzed. The technical success rate was 100% with immediate complete occlusion achieved in 89.8% of the patients. Among 65 patients (66.3%) available for a 6‑month follow-up, complete and near-complete occlusion rates were 92.3% and 98.5%, respectively. In 38 patients (38.8%) with long-term follow-up (mean: 21 months), complete and near-complete occlusion were achieved in 81.2% and 89.5%, respectively. Aneurysm recurrence between mid-term and long-term follow-up was observed in 14.3%. The retreatment rate was 11.3%. There were three thromboembolic events (3.1%), of which one resulted in ischemic stroke (1.0%). For unruptured aneurysms, the procedural and device-related morbidity rates were 2.1% and 0%, respectively. In the present study, the Acclino was associated with a low risk of thromboembolic complications and high aneurysm occlusion rates at long-term follow-up. Due to incomplete angiographic follow-up in this series, prospective studies will be necessary to confirm the results.


First report of furuncular myiasis caused by the larva of botfly, Dermatobia hominis, in a Taiwanese traveler.
A case of furuncular myiasis was reported for the first time in a 29-year-old young Taiwanese traveler returning from an ecotourism in Peru. Furuncle-like lesions were observed on the top of his head and he complained of crawling sensations within his scalp. The invasive larva of botfly, Dermatobia hominis, was extruded from the furuncular lesion of the patient. Awareness of cutaneous myiasis for clinicians should be considered for a patient who has a furuncular lesion and has recently returned from a botfly-endemic area.


Recruitment of young adult cancer survivors into a randomized controlled trial of an mHealth physical activity intervention.
Few studies have recruited young adult cancer survivors (YACS) from around the USA into remotely-delivered behavioral clinical trials. This study describes recruitment strategies used in the IMproving Physical Activity after Cancer Treatment (IMPACT) study, a 12-month randomized controlled trial of a mobile physical activity intervention for YACS. We conducted formative work to guide development of recruitment messages and used a variety of methods and channels to recruit posttreatment YACS (diagnosed ages 18-39, participating in < 150 min/week of moderate-to-vigorous intensity activity). We used targeted social media advertisements, direct mailings, clinical referrals, and phone calls to potentially eligible individuals identified through local tumor registries. We also asked community organizations to share study information and advertized at a national conference for YACS. The final sample of 280 participants (23% identified as racial/ethnic minority individuals, 18% male, mean 33.4 ± 4.8 years) was recruited over a 14-month period. About 38% of those who completed initial screening online (n = 684) or via telephone (n = 63) were randomized. The top recruitment approach was unpaid social media, primarily via Facebook posts by organizations/friends (45%), while direct mail yielded 40.7% of participants. Other social media (paid advertisements, Twitter), email, clinic referrals, and conference advertisements each yielded 3% or fewer participants. The most cost-effective methods per participant recruited were unpaid social media posts and direct mailings. The IMPACT trial successfully met enrollment goals using a national strategy to recruit physically inactive YACS. Our approaches can inform recruitment planning for other remotely-delivered intervention trials enrolling YACS. ClinicalTrials.gov NCT03569605 . Registered on 26 June 2018.


Undetected angle closure in patients with a diagnosis of open-angle glaucoma.
The aim of this study was to identify the proportion of patients referred to a tertiary glaucoma centre with a diagnosis of open-angle glaucoma (OAG) who were found to have angle closure glaucoma. Retrospective chart review. Consecutive new patients referred for glaucoma management to a tertiary centre between July 2010 and December 2011 were reviewed. Patients whose referrals for glaucoma assessment specified angle status as "open" were included. The data collected included glaucoma specialist's angle assessment, diagnosis, and glaucoma severity. The status of those with 180 degrees or more Shaffer angle grading of 0 was classified as "closed." From 1234 glaucoma referrals, 179 cases were specified to have a diagnosis of OAG or when angles were known to be open. Of these, 16 (8.9%) were found on examination by the glaucoma specialist to have angle closure. Pseudoexfoliation was present in 4 of 16 patients (25%) in the missed angle-closure glaucoma (ACG) group and 22 of 108 patients (13.5%) in the remaining OAG group. There was no difference found in demographic or ocular biometric parameters between those with confirmed OAG versus those with missed ACG. Almost 1 in 11 patients referred by ophthalmologists to a tertiary glaucoma centre with a diagnosis of OAG were in fact found to have angle closure. Given the different treatment approaches for ACG versus OAG, this study suggests a need to strengthen angle evaluations.


Elevated levels of circulating adhesion molecules in patients with active pulmonary tuberculosis.
Recent studies have indicated the importance of cell adhesion molecules in the pathogenesis of various inflammatory lung diseases. Our study was designed to determine whether five soluble adhesion molecules including soluble L-, E- and P-selectin (sL-, sE- and sP-selectin), intercellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in serum reflect the severity of active pulmonary tuberculosis (TB), and whether there is a distinct profile of these soluble molecules in this disease. Using enzyme-linked immunosorbent assays, we measured the serum levels of these five soluble adhesion molecules in 31 patients with active TB and 11 healthy volunteers. Serum levels of sE-selectin, sP-selectin and sICAM-1, but not sL-selectin or sVCAM-1, were significantly higher in patients with active TB than in the control subjects (P < 0.001, each). Significant correlations were detected only between serum levels of sE-selectin and sP-selectin, sE-selectin and sICAM-1, and sP-selectin and sICAM-1. There was a significant correlation between the Gaffky scale result (a scale assessing the number of mycobacteria bacilli present) and all of the above adhesion molecules, except for sL-selectin. Serum levels of sE-selectin, sL-selectin and sICAM-1 also correlated with the CXR radiological score. Higher levels of sL-selectin and sICAM-1 were detected in the serum of patients with radiological cavity formation compared to those without. The ESR, C-reactive protein and circulating neutrophil counts all correlated significantly with sE-selectin, sP-selectin, sICAM-1 and sVCAM-1. The results suggest that there is a distinct profile of soluble adhesion molecules in active pulmonary TB and that sE-selectin, sP-selectin, and especially sICAM-1 appear to be the most sensitive clinical measures of disease severity.


Convenient purification of gold clusters by co-precipitation for improved sensing of hydrogen peroxide, mercury ions and pesticides.
An effective separation process is developed to remove free protein from the protein-protected gold clusters via co-precipitation with zinc hydroxide on their surface. After dialysis, the purified clusters exhibit an enhanced fluorescence for improved sensitive detection and selective visualization.


Minimization of Surface Energies and Ripening Outcompete Template Effects in the Surface Growth of Metal-Organic Frameworks.
As well-oriented, surface-bound metal-organic frameworks become the centerpiece of many new applications, a profound understanding of their growth mode becomes necessary. This work shows that the currently favored model of surface templating is in fact a special case valid only for systems with a more or less cubic crystal shape, while in less symmetric systems crystal ripening and minimization of surface energies dominate the growth process.


Dose-finding and phase 2 study of weekly paclitaxel (taxol) and cisplatin combination in treating Chinese patients with advanced nonsmall cell lung cancer.
The aim of the present study is to evaluate the efficacy and toxicity of weekly paclitaxel combined with cisplatin as first-line chemotherapy in patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) and to identify the optimal dose of weekly paclitaxel to be administered safely and effectively. Chemonaive patients with NSCLC, stage 3B with malignant pleural effusion, or stage 4 were enrolled in this study. In the dose-finding study, patients took paclitaxel once weekly at an initial dose of 50 mg/m2 and 3 weeks followed by cisplatin on day 15 at a fixed dose of 80 mg/m2. The escalating dose for paclitaxel was 10mg/m2 for each level. In the phase 2 study, patients received paclitaxel at maximum tolerated dose (MTD). The MTD for paclitaxel was 60 mg/m2. Of the 47 eligible patients, 7 patients had a complete response and 15 achieved a partial response. The overall response was 46.8% (95% CI, 32.0% to 61.6%). The median survival was 16 months (95% CI, 13.4 to 18.6 months). Twenty-four patients (51.1%) completed 6 cycles of treatment. With regard to hematological toxicity, although grade 3/4 neutropenia was observed in 5 patients (10.6%), there was no febrile neutropenia. The major nonhematological toxicity was asthenia, which was observed in all patients (17 patients grade 1/2 and 30 patients with grade 3/4). Weekly paclitaxel combined with cisplatin on day 15 is a safe and effective regimen as a first-line chemotherapy in NSCLC. The MTD for this regimen was 60 mg/m.