Management of ruptured aneurysmal subarachnoid hemorrhage with multiple basilar trunk aneurysms using a flow-diverter stent: A case report.

Ruptured aneurysmal subarachnoid hemorrhage associated with multiple basilar trunk aneurysms represents a rare clinical condition. Endovascular intervention stands as the preferred therapeutic approach. We present the case of a 35-year-old patient with subarachnoid hemorrhage and three consecutive basilar trunk aneurysms. Utilizing a flow-diverter stent, we achieved simultaneous occlusion of all 3 aneurysms, performed 2 hours post dual antiplatelet therapy (comprising salicylic acid 300 mg and ticagrelor 180 mg). Sustained resistance to clopidogrel necessitated the subsequent 3 months, followed by single antiplatelet therapy. At the 1-month follow-up, the patient demonstrated a favorable clinical course, devoid of cerebral infarction, and evidenced unobstructed stent patency upon brain magnetic resonance imaging.

Joint Asian Pacific Association of Gastroenterology (APAGE)-Asian Pacific Society of Digestive Endoscopy (APSDE) clinical practice guidelines on the use of non-invasive biomarkers for diagnosis of colorectal neoplasia.

Screening for colorectal cancer (CRC) is effective in reducing CRC related mortality. Current screening methods include endoscopy based and biomarker based approaches. This guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society of Digestive Endoscopy (APSDE), developed in response to the increasing use of, and accumulating supportive evidence for the role of, non-invasive biomarkers for the diagnosis of CRC and its precursor lesions. A systematic review of 678 publications and a two stage Delphi consensus process involving 16 clinicians in various disciplines was undertaken to develop 32 evidence based and expert opinion based recommendations for the use of faecal immunochemical tests, faecal based tumour biomarkers or microbial biomarkers, and blood based tumour biomarkers for the detection of CRC and adenoma. Comprehensive up-to-date guidance is provided on indications, patient selection and strengths and limitations of each screening tool. Future research to inform clinical applications are discussed alongside objective measurement of research priorities. This joint APAGE-APSDE practice guideline is intended to provide an up-to-date guide to assist clinicians worldwide in utilising non-invasive biomarkers for CRC screening; it has particular salience for clinicians in the Asia-Pacific region.

Modified Folfox6 as Adjuvant Chemotherapy in Vietnamese Patients With Colorectal Cancer.

Colorectal cancer is the third most common cancer and the second leading cause of death from cancer worldwide. In Vietnam, the disease is the fifth leading cancer (8.9%), with 14 733 new cases in 2018. In recent years, the mFolfox6 regimen has been indicated commonly as the adjuvant chemotherapy after curative resection for patients with colorectal cancer. However, the efficacy of the regimen in Vietnamese patients has not been assessed and reported. In this retrospective study, we reviewed medical records of 83 patients with stage II or stage III colorectal cancer who received mFOLFOX6 regimen in order to investigate simultaneously survival and safety of this chemotherapy regimen. Three-year overall and disease-free survival were 84.3% and 79.5%, respectively. Our data revealed that postoperative Carcinoma Embryonic Antigen (CEA) level was a significant prognostic factor for survival, with hazard ratio of 3.83 and 3.67, respectively (P < .05), for overall survival and disease-free survival in the elevated CEA level group when compared to the normal CEA level group. The regimen also demonstrated to be well tolerated and can be used in routine practice as an adjuvant chemotherapy.

Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology.

Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology.

Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications.

SIGNIFICANCE: Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. RECENT ADVANCES: We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. CRITICAL ISSUES: Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. FUTURE DIRECTIONS: Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic.

Pharmacology and Clinical Drug Candidates in Redox Medicine.

SIGNIFICANCE: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. RECENT ADVANCES: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. CRITICAL ISSUES: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. FUTURE DIRECTIONS: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine.

Stability of murine bradykinin type 2 receptor despite treatment with NO, bradykinin, icatibant, or C1-INH.

BACKGROUND: Little is known about factors which trigger and/or contribute to hereditary angioedema or ACE-inhibitor-mediated angioedema including variations in bradykinin type 2 receptor (B2R) expression and activity. METHODS: Protein and mRNA expression of B2R and the increase of intracellular calcium (iCa) in response to bradykinin were monitored in porcine and murine endothelial cells in response to NO donors or bradykinin. B2R protein expression was evaluated in skin, heart, and lung of (i) mice with endothelial-specific overexpression of eNOS (eNOS(tg) ), (ii) in eNOS(-/-) mice and (iii) in C57BL/6 mice treated with the NO donor pentaerythritol tetranitrate (PETN), the NOS inhibitor l-nitroarginine (L-NA), plasma pool C1-INH, and the B2R antagonist icatibant. Aortic reactivity to bradykinin was investigated including eNOS(-/-) mice. RESULTS: B2R protein and mRNA expression remained unchanged in cells subjected to L-NA, NO donors, and bradykinin in a time- and concentration-dependent manner. Likewise, increases of iCa in murine brain endothelial cells remained unchanged. B2R protein levels were similar in eNOS(tg) and eNOS(-/-) as compared to transgene-negative littermates. Likewise, treatment of C57BL/6 mice with PETN, L-NA, C1-INH or icatibant did not change B2R protein expression. In aortic rings of C57BL/6 mice, bradykinin induced B2R-dependent constrictions which were attenuated by endothelial NO and abolished by diclofenac indicating the functional importance of B2R-induced activation of endothelial NO synthase and cyclooxygenase. CONCLUSION: These data suggest that alterations of B2R protein expression induced by NO, bradykinin, C1-INH, or icatibant unlikely contribute to bradykinin-induced angioedema. This finding does not rule out a role for NO in bradykinin-induced extravasation and/or angioedema.

SFRR-E Young Investigator AwardeeNOXing out stroke: Identification of NOX4 and 5as targets in blood-brain-barrier stabilisation and neuroprotection.

Stroke is the second leading cause of death with high blood pressure and female gender being the main risk factors. However, only one treatment is available and with many contraindications, which leaves more than 80% of patients untreated. Over a thousand experimental stroke treatments have remained unsuccessful in the clinic. In preclinical research, low reproducibility and publication bias have been suggested as causes of low translatability success. NADPH oxidases might be key players in stroke via their unique role as a major and/or early source of reactive oxygen species (ROS). To clarify the role of the different NOX isoforms (1, 2, 4, and 5) we analysed different KO and KI models. Previous literature claimed a role for NOX2. Using both a meta-analytical and a blinded randomised controlled trial approach, we however find that NOX2 plays only a minor role and publication bias and lack of power perturbed the published literature. We earlier showed a detrimental role of NOX4 in stroke and extend this based on cell-specific KO animals that endothelial but not vascular smooth muscle cells are the major source of NOX4 in stroke. Mice do not express the human NOX5 gene. Using a NOX5 KI model, we show that endothelial NOX5 induces hypertension and increased stroke risk, particularly in females. In human hypertension, NOX5 is upregulated, and women have a higher stroke risk. Thus NOX5 might be a missing link in this context. In conclusion, NOX4 and NOX5, but not NOX2, are promising targets for the development of new neuroprotective therapies for ischemic stroke. A priori power and sample size calculation as well as reporting of also negative data is essential with respect to preclinical validation of therapeutic targets.

Toward one Giga frames per second--evolution of in situ storage image sensors.

The ISIS is an ultra-fast image sensor with in-pixel storage. The evolution of the ISIS in the past and in the near future is reviewed and forecasted. To cover the storage area with a light shield, the conventional frontside illuminated ISIS has a limited fill factor. To achieve higher sensitivity, a BSI ISIS was developed. To avoid direct intrusion of light and migration of signal electrons to the storage area on the frontside, a cross-sectional sensor structure with thick pnpn layers was developed, and named "Tetratified structure". By folding and looping in-pixel storage CCDs, an image signal accumulation sensor, ISAS, is proposed. The ISAS has a new function, the in-pixel signal accumulation, in addition to the ultra-high-speed imaging. To achieve much higher frame rate, a multi-collection-gate (MCG) BSI image sensor architecture is proposed. The photoreceptive area forms a honeycomb-like shape. Performance of a hexagonal CCD-type MCG BSI sensor is examined by simulations. The highest frame rate is theoretically more than 1Gfps. For the near future, a stacked hybrid CCD/CMOS MCG image sensor seems most promising. The associated problems are discussed. A fine TSV process is the key technology to realize the structure.

Type-1.5 superconductivity.

We demonstrate the existence of a novel superconducting state in high quality two-component MgB2 single crystalline superconductors where a unique combination of both type-1 (lambda{1}/xi{1}<1/sqrt[2]) and type-2 (lambda{2}/xi{2}>1/sqrt[2]) superconductor conditions is realized for the two components of the order parameter. This condition leads to a vortex-vortex interaction attractive at long distances and repulsive at short distances, which stabilizes unconventional stripe- and gossamerlike vortex patterns that we have visualized in this type-1.5 superconductor using Bitter decoration and also reproduced in numerical simulations.

Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase.

BACKGROUND AND PURPOSE: The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment. EXPERIMENTAL APPROACH: We investigated whether high dose isosorbide mononitrate (ISMN) or pentaerythrityl tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg(-1) d(-1) for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg(-1) d(-1) for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite. KEY RESULTS: Western blots of rabbit aortic rings showed similar protein levels of sGC alpha1- (P=0.2790) and beta1-subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN-treated mice (P=0.0961 for alpha1 and P=0.3709 for beta1). The activities of isolated sGC in response to SNAP (1 microM-1 mM) were identical in aortae of ISMN-treated rabbits (P=0.0775) and lungs of PETN-treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN. CONCLUSIONS AND IMPLICATIONS: These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo.

Synthesis and cytotoxicity of gossypol related compounds.

Gossypol, gossypolone, reduced gossypol and new Schiff's bases of racemic gossypol and gossypolone were extracted or synthesized. Their cytotoxic activities on KB human cancer cells were determined. Gossypolone and the ethylamine derivative of gossypolone were the most active compounds (IC(50) in the micromolar range in both cases). The cytotoxicity of gossypol and gossypolone was increased when the tests were performed in the absence of serum and decreased when catalase as well as mannitol were added to the culture medium.

Three-dimensional (87)Rb NMR imaging and spectroscopy of K(+) fluxes in normal and postischemic pig hearts.

K(+) uptake rates were measured in the anterior (An) and posterior (Pos) LV walls of pig hearts before and after regional ischemia and reperfusion using Rb(+) as a K(+) congener and 3D (87)Rb NMR imaging and spectroscopy as detection methods. The hearts were perfused by the Langendorff method with Krebs-Henseleit (KH) buffer and loaded with Rb(+) (4.7 mM, Rb-KH) after 120-min ischemia and 60-min reperfusion. A second protocol involved Rb(+) loading prior to ischemia. Ischemia was produced by occlusion of the left anterior descending artery, which after 110 min of reperfusion resulted in infarction in the An wall (24 +/- 6% of the LV mass) determined by triphenyltetrazolium chloride staining. At the end of reperfusion pressure-rate product and oxygen consumption rate decreased to 58 +/- 10 and 74 +/- 4% of their preischemic values, respectively. Phosphocreatine, ATP, and intracellular pH (pHi), measured by (31)P NMR spectroscopy in the infarcted area, decreased to 59 +/- 17, 32 +/- 6%, and 6.7 +/- 0.36 (from 7.05 +/- 0.13), respectively. Serial (87)Rb images were acquired according to both protocols. Rate constants (k x 10(3), min(-1)), relative amount of intracellular Rb(+) (A, %) and relative fluxes (F = kA, %/min) for the An and Pos walls were determined from the images. Before ischemia, F and k were comparable in the Pos and An walls. Ischemia + reperfusion decreased F in the An wall (from 4.4 +/- 0.3 to 1.4 +/- 0.85) due to a decrease in A (20 vs. 73) and increased F in Pos wall (from 3.2 +/- 0.6 to 6.6 +/- 0.23) due to an increase in k (from 42 +/- 3 to 93 +/- 6). The intensities of the Rb images correlated with the Rb(+) content measured in tissue samples. Magn Reson Med 44:83-91, 2000. Published 2000 Wiley-Liss, Inc.

MutS and MutL activate DNA helicase II in a mismatch-dependent manner.

MutS, MutL, and DNA helicase II are required for the mismatch-provoked excision step that occurs during Escherichia coli methyl-directed mismatch repair. In this study MutL is shown to enhance the unwinding activity of DNA helicase II more than 10-fold on a conventional helicase substrate in which a 35-residue oligonucleotide is annealed to a M13 circular single-stranded phage DNA under conditions where the two proteins are present at approximately molar stoichiometry with respect to the substrate. MutS- and MutL-dependent activation of DNA helicase II has also been demonstrated with a model substrate in which a 138-residue oligonucleotide was hybridized to a 138-nucleotide gap in an otherwise duplex 7,100-base pair circular DNA. Displacement of the oligonucleotide requires MutS, MutL, DNA helicase II, and ATP and is dependent on the presence of a mismatch within the hybrid region. Although DNA helicase II and Rep helicase share substantial sequence homology and features of mechanism, Rep helicase is inactive in this reaction.

Mismatch-, MutS-, MutL-, and helicase II-dependent unwinding from the single-strand break of an incised heteroduplex.

Escherichia coli MutS, MutL, and DNA helicase II are sufficient to initiate mismatch-dependent unwinding of an incised heteroduplex (Yamaguchi, M., Dao, V., and Modrich, P. (1998) J. Biol. Chem., 273, 9197-9201). We have studied unwinding of 6.4-kilobase circular G-T heteroduplexes that contain a single-strand incision, 808 base pairs 5' to the mismatch or 1023 base pairs 3' to the mispair as viewed along the shorter path between the two DNA sites. Unwinding of both substrates in the presence of MutS, MutL, DNA helicase II, and single-stranded DNA binding protein was mismatch-dependent and initiated at the single-strand break. Although unwinding occurred in both directions from the strand break, it was biased toward the shorter path linking the strand break and the mispair. MutS and MutL are thus sufficient to coordinate mismatch recognition to the orientation-dependent activation of helicase II unwinding at a single-strand break located a kilobase from the mispair.

Ribosome binding of DNA analogs of tRNA requires base modifications and supports the "extended anticodon".

The efficiency of translation depends on correct tRNA-ribosome interactions. The ability of chemically synthesized yeast tRNA(Phe) anticodon domains to effectively inhibit the binding of native yeast tRNA(Phe) to poly(U)-programmed Escherichia coli 30S ribosomal subunits was dependent on a Mg(2+)-stabilized stem and an open anticodon loop, both facilitated by base modifications. Analysis of tRNA sequences has revealed that base modifications which negate canonical hydrogen bonding are found in 95% of those tRNA anticodon loop sequences with the potential to form two Watson-Crick base pairs across the loop. Therefore, we postulated that a stable anticodon stem and an open loop are prerequisites for ribosome binding. To test this hypothesis, DNA analogs of the yeast tRNA(Phe) anticodon domain were designed to have modification-induced, Mg(2+)-stabilized stems and open loops. The unmodified DNA analog neither bound to poly(U)-programmed 30S ribosomal subunits nor inhibited the binding of native tRNA(Phe). However, specifically modified DNA analogs did bind to ribosomal subunits and effectively inhibited tRNA(Phe) from binding. Thus, modification-dependent Mg(2+)-stabilized anticodon domain structures with open loops have evolved as the preferred anticodon conformations for ribosome binding.

A magnesium-induced conformational transition in the loop of a DNA analog of the yeast tRNA(Phe) anticodon is dependent on RNA-like modifications of the bases of the stem.

Two single-stranded DNA heptadecamers corresponding to the yeast tRNA(Phe) anticodon stem-loop were synthesized, and the solution structures of the oligonucleotides, d(CCAGACTGAAGATCTGG) and d(CCAGACTGAAGAU-m5C-UGG), were investigated using spectroscopic methods. The second, or modified, base sequence differs from that of DNA by RNA-like modifications at three positions; dT residues were replaced at positions 13 and 15 with dU, and the dC at position 14 with d(m5C), corresponding to positions where these nucleosides occur in tRNA(Phe). Both oligonucleotides form intramolecular structures at pH 7 in the absence of Mg2+ and undergo monophasic thermal denaturation transitions (Tm = 47 degrees C). However, in the presence of 10 mM Mg2+, the modified DNa adopted a structure that exhibited a biphasic "melting" transition (Tm values of 23 and 52 degrees C) whereas the unmodified DNA structure exhibited a monophasic denaturation (Tm = 52 degrees C). The low-temperature, Mg(2+)-dependent structural transition of the modified DNA was also detected using circular dichroism (CD) spectroscopy. No such transition was exhibited by the unmodified DNA. This transition, unique to the modified DNA, was dependent on divalent cations and occurred most efficiently with Mg2+; however, Ca2+ also stabilized the alternative conformation at low temperature. NMR studies showed that the predominant structure of the modified DNA in sodium phosphate (pH 7) buffer in the absence of Mg2+ was a hairpin containing a 7-nucleotide loop and a stem composed of 3 stable base pairs. In the Mg(2+)-stabilized conformation, the loop became a two-base turn due to the formation of two additional base pairs across the loop.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of 5-methylcytidine in the anticodon arm of yeast tRNA(Phe): site-specific Mg2+ binding and coupled conformational transition in DNA analogs.

The tDNA(Phe)AC, d(CCAGACTGAAGAU13m5C14U15GG), with a DNA sequence similar to that of the anticodon stem and loop of yeast tRNA(Phe), forms a stem and loop structure and has an Mg(2+)-induced structural transition that was not exhibited by an unmodified tDNA(Phe)AC d(T13C14T15) [Guenther, R. H., Hardin, C. C., Sierzputowska-Gracz, H., Dao, V., & Agris, P. F. (1992) Biochemistry (preceding paper in this issue)]. Three tDNA(Phe)AC molecules having m5C14, tDNA(Phe)AC d(U13m5C14U15), d(U13m5C14T15), and d(T13,5C14U15), also exhibited Mg(2+)-induced structural transitions and biphasic thermal transitions (Tm approximately 23.5 and 52 degrees C), as monitored by CD and UV spectroscopy. Three other tDNA(Phe)AC, d(T13C14T15), d(U13C14U15), and d(A7;U13m5C14U15) in which T7 was replaced with an A, thereby negating the T7.A10 base pair across the anticodon loop, had no Mg(2+)-induced structural transitions and only monophasic thermal transitions (Tm of approximately 52 degrees C). The tDNA(Phe)AC d(U13m5C14U15) had a single, strong Mg2+ binding site with a Kd of 1.09 x 10(-6) M and a delta G of -7.75 kcal/mol associated with the Mg(2+)-induced structural transition. In thermal denaturation of tDNA(Phe)AC d(U13m5C14U15), the 1H NMR signal assigned to the imino proton of the A5.dU13 base pair at the bottom of the anticodon stem could no longer be detected at a temperature corresponding to that of the loss of the Mg(2+)-induced conformation from the CD spectrum. Therefore, we place the magnesium in the upper part of the tDNA hairpin loop near the A5.dU13 base pair, a location similar to that in the X-ray crystal structure of native, yeast tRNA(Phe).(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Sm autoantibodies of systemic lupus erythematosus cross react with dietary plant proteins.

Cross reactivity of patient lupus autoantibodies to the small nuclear ribonucleoprotein particles of many different types of animals is well documented. The aim of our research was to determine if any level of cross reactivity existed between proteins of common dietary plants and anti-Sm autoantibodies of lupus patient's sera, as has been found for scleroderma patient sera (Agris et al., Exptl. Cell Res. 189, 276-279, 1990). Protein extracts from soy bean, corn, spinach, and carrot were analyzed. At least one protein (molecular weight approximately 28,000 daltons) common to all the above protein extracts was recognized by most of the anti-Sm sera tested. Affinity purified antibody eluted from the 28 kilodalton plant protein specifically recognized the Sm proteins of a HeLa cell protein extract. Recognition of the 28 kilodalton dietary plant protein was found to be unique to anti-Sm lupus sera.