Surveillance is the first step to preventing injury among fast jet aircrew: results of a 2-year prospective cohort study.
Injury surveillance is imperative for injury prevention but difficult in military populations. Our objective was to accurately describe the pattern of musculoskeletal complaints among Royal Australian Air Force (RAAF) fast jet aircrew (FJA) using the validated University of Canberra Fast Jet Aircrew Musculoskeletal Questionnaire (UC-FJAMQ) over a 2-year period, and determine injury burden on the workforce and operational capability. 306 RAAF FJA were monitored over a 2-year period (4×5 month reporting periods). Musculoskeletal complaint episodes (MCEs) were captured weekly using the UC-FJAMQ. Time loss episodes (TLEs) were captured from the UC-FJAMQ and injury registers completed by embedded physiotherapists. Cumulative severity and operational impact scores from the UC-FJAMQ, and time loss duration, were used to describe severity and calculate burden. Mean weekly UC-FJAMQ response rate was 62%. 1012 MCEs were captured, with a mean weekly prevalence of 14.9% (95% CI 14.2-15.6), and incidence of 4.1 episodes per person-year (95% CI 3.9-4.4). A total of 145 TLEs were captured, with a mean 5-month prevalence of 12.4% (range 8.9-15.3%), and incidence of 0.37 episodes per person-year (95% CI 0.31-0.43). Spinal regions accounted for 81% of MCEs and contributed 76% and 85% of burden in relation to cumulative severity and operational impact, respectively. 57% of TLE burden came from spinal regions. Despite modest weekly UC-FJAMQ response rates, musculoskeletal complaints were shown to be widespread and negatively impact operational capability. Future injury prevention efforts among FJA should focus on spinal regions, particularly the neck.


Knowledge and Beliefs Regarding Breast and Cervical Cancer Screening Among Mexican-Heritage Latinas.
Lower participation rates in mammography and Papanicolaou test are common among Latinas compared with other ethnic groups. Suboptimal screening rates are attributed to lack of knowledge, access to services, and cultural influences. The purpose of this study is to qualitatively examine an alternative framework for examining cultural influences on Mexican-heritage Latinas' understandings of breast and cervical cancer screening and how to leverage their beliefs to positively influence screening practices. The study is based on the analysis of 4 focus groups with 47 Latinas residing in greater Phoenix, Arizona. Iterative qualitative analyses identified 5 major themes: (1) knowledge and beliefs about cancer cause and risk in general, (2) knowledge and beliefs specific to breast and cervical cancer screening, (3) experiences with breast and cervical cancer screening, (4) facilitators and barriers to breast and cervical screening, and (5) desired information about cancer and screening. Rather than focusing on Latinas' knowledge and/or misconceptions of breast and cervical cancer in screening-related education, researchers must examine what Latinas believe and leverage those convictions to expand their perceptions and behaviors related to breast and cervical cancer prevention practices. Practitioners should recognize that Latinas may differ in beliefs from other minorities, and that even within-group, there may be cultural differences that influence cancer screening behaviors.


Consistency of associations of systolic and diastolic blood pressure with white matter hyperintensities: A meta-analysis.
White matter hyperintensities are the commonest manifestation of cerebral small vessel disease, associated with stroke, functional impairment, and cognitive decline. They are commonly preceded by hypertension, but the magnitude and clinical importance of this association is unclear. Quantify the relationship between blood pressure and white matter hyperintensities across studies. PubMed and EMBASE were searched for studies reporting associations between concurrent or historic blood pressure and white matter hyperintensities. Beta coefficients from linear models were extracted, whether standardized, unstandardized, unadjusted or adjusted for age, sex, and cardiovascular risk factors. Beta-coefficients were combined by fixed and random effects meta-analysis, combining standardized beta-coefficients or unstandardized coefficients measured by consistent methods. Twenty-five of 3230 papers were eligible, including 53,392 participants. Systolic blood pressure was significantly associated with white matter hyperintensity volume (WMHV) after maximal adjustment (standardized beta 0.096, 95%CI 0.06-0.133, p < 0.001, I2 = 65%), including for concurrent readings (b = 0.106, p < 0.001) or readings five years previously (b = 0.077, p < 0.001), and for younger or older populations (mean age < 65: b = 0.114; >65 b = 0.069). Unstandardized, adjusted associations were similar for raw WMHV, log-transformed WMHV, or WMHV as percentage of intracranial volume. Unadjusted associations with systolic blood pressure (SBP) were greater (standardized beta = 0.273, 0.262-0.284, p < 0.0001). However, while associations with DBP were weaker than SBP (standardized beta = 0.065, p < 0.001), they were minimally affected by adjustment for age. A standard deviation increase in SBP is associated with 10% of a standard deviation increase in WMHV, providing the current best estimate of the potential reduction in progression of white matter hyperintensities expected with good control of blood pressure.


Paul Dudley White International Lecture: cardiac performance as viewed through the pressure-volume window.
Viewing canine left ventricular performance through the pressure-volume (P-V) window, I proposed a new index of ventricular contractility (Emax: end-systolic P-V ratio or maximum elastance) in my doctoral thesis at the University of Tokyo in 1969. After I joined Dr. Kiichi Sagawa (deceased in 1989) at Johns Hopkins University, we firmly established the Emax concept during 1971-1978. The concept was extended to derive the systolic P-V area (PVA) as a new measure of the total mechanical energy generated by ventricular contraction in 1978. Experiments have revealed that PVA closely correlates with cardiac oxygen (O2) consumption (VO2) under various loading conditions at a constant Emax, the VO2-PVA relation changes its elevation with Emax, and the O2 costs of PVA and Emax characterize the mechanoenergetics of cardiac contraction under various normal and abnormal conditions in an innovative manner (Suga: Physiol Rev 70: 247-277, 1990). Emax and PVA can also evaluate the ventriculo-arterial hydraulic and energetic matching in normal and failing hearts. Emax and PVA have thus widely opened the P-V window to the extent that human and animal normal and failing cardiac performance can be characterized in a physiologically sound manner.


Challenges of talent development in alpine ski racing: a narrative review.
Alpine ski racing is one of the most popular sports in many countries; nevertheless, selection disadvantages and severe injuries result in high dropout rates. In this review we summarize existing knowledge about the specific challenges associated with selection bias and injuries, and their effects on talent development in ski racing. The relative age effect (RAE) appears in all age categories of national Austrian and international alpine ski racing. Relatively younger athletes seem to only have a chance for selection if they are early maturing. Talent selection processes should consider both the biological maturity status as well as the relative age; additionally, a competition system based on a rotating cut-off date might contribute to a reduction of RAE. Youth and adolescent ski racers report lower injury rates compared to World Cup athletes. The knee was the most affected body part in relation to traumatic injuries. The most frequently reported overuse injuries were knee pain (youth) and low back pain (adolescent level). Athlete-related modifiable risk factors were core strength, neuromuscular control, leg extension strength and limb asymmetries. Based on these findings, prevention measures should be expanded to contribute to long-term injury prevention. In future research more multi-disciplinary, longitudinal studies should be performed.


[Ischemic postconditioning and its application in organ transplantation].
The concept of "ischemic postconditioning" was first raised in 2002, and the following 5 year research shows that it can protect organs from reperfusion injury. Although the mechanism of ischemic postconditioning is similar to ischemic preconditioning in many ways, it still has its own characteristics. Reperfusion injury is an inevitable problem in organ transplantation. It may accelerate the function recovery of the transplants to lessen the reperfusion injury. So ischemic postconditioning may have a fine prospect in organ transplantation for its good controllability during reperfusion. This article is going to briefly introduce the distinct mechanisms of ischemic postconditioning to protect organs from reperfusion injury and approach the possibilities of its application in organ transplantation.


[Treatment of curved canals: from stainless steel to nickel titanium].
Endodontic treatment of curved canals is always more difficult than straight canals, especially for the apical zone preparation: root canals may present several curvatures in different space directions. From an anatomical point of view root canals with accentuated curvatures are a very frequent event (more than we might think); radiological exams, in fact, give us only a 2D image, and we can observe mesial or distal curvatures but not those in the oral or buccal direction. However, all root canals have curvatures of some degrees; even those that appear straight. Because of this, endodontitis have made many attempts to overcome these problems and manage to have a good preparation in curve canal. The authors analyse all endodontic techniques (step back, step down, crown down, balanced forces) codified in the course of the years, to prepare curved canals; they both in shape or in materials. It's fundamental for the endodontist to have a specific technique to treat curved canals to allow a good, wide preparation; in this way it's possible to make a better and tridimensional filling of the endodontic space above all in the tipical zone.


The impact of stocking on the genetic integrity of Arctic charr (Salvelinus) populations from the Alpine region.
There is a long tradition of artificially stocking lakes and rivers with fish in the hope to increase the quality and amount of fish that can be harvested. The animals used for stocking often originate in distant hatcheries or hatcheries that breed fish from remote regions. This stocking practice could have effects on the genetic integrity of resident populations. We have analysed here a case of the influence of stocking on Alpine populations of the Arctic charr (usually included into Salvelinus alpinus, but revised to Salvelinus umbla Kottelat 1997) within a unique geographical and historical setting. The Königssee in the Bavarian Alps (Berchtesgaden) was heavily stocked several times during the last century. However, a sample of the ancestral Königssee population still exists in the Grünsee, which lies close to Königssee, but 1000 m higher. To trace the influence of stocking in Königssee we have analysed more than 300 individuals from 10 lake populations, including the source populations of the fish used for stocking. From these we have sequenced a part of the mitochodrial control region and have typed them at six microsatellite loci. The differential distribution of haplotypes, as well as assignment tests, show that the influence of stocking on the genetic integrity of the Königssee population has been negligible. However, our data reveal that in another lake included in our study (Starnberger See), the ancestral population was apparently replaced completely by the populations used for stocking. The major difference between the lakes is the relative preservation of ecological integrity. Königssee was ecologically stable in the past, whereas Starnberger See was heavily polluted at one point, with charr approaching extinction. Interestingly, in a lake neighbouring Starnberger See, the Ammersee, which was also subject to strong pollution but not stocked, the ancestral population has recovered. Our data suggest that the practice of artificial stocking should be reconsidered, or at least monitored for effectiveness.


KIR haplotypes are associated with late-onset type 1 diabetes in European-American families.
Classical human leukocyte antigens (HLA) genes confer the strongest, but not the only, genetic susceptibility to type 1 diabetes. Killer cell immunoglobulin-like receptors (KIR), on natural killer (NK) cells, bind ligands including class I HLA. We examined presence or absence, with copy number, of KIR loci in 1698 individuals, from 339 multiplex type 1 diabetes families, from the Human Biological Data Interchange, previously genotyped for HLA. Combining family data with KIR copy number information allowed assignment of haplotypes using identity by descent. This is the first disease study to use KIR copy number typing and unambiguously define haplotypes by gene transmission. KIR A1 haplotypes were positively associated with T1D in the subset of patients without the high T1D risk HLA genotype, DR3/DR4 (odds ratio=1.29, P=0.0096). The data point to a role for KIR in type 1 diabetes risk in late-onset patients. In the top quartile (age of onset>14), KIR A2 haplotype was overtransmitted (63.4%, odds ratio=1.73, P=0.024) and KIR B haplotypes were undertransmitted (41.1%, odds ratio=0.70, P=0.0052) to patients. The data suggest that inhibitory 'A' haplotypes are predisposing and stimulatory 'B' haplotypes confer protection in both DR3/DR4-negative and late-onset patient groups.


The IMPROVEDD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score to Improve Venous Thromboembolism Risk Stratification.
Background The IMPROVE score is a validated venous thromboembolism (VTE) assessment tool to risk stratify hospitalized, medically ill patients based on clinical variables. It was hypothesized that addition of D-dimer measurement to derive a new IMPROVEDD score would improve identification of at risk of VTE. Methods The association of the IMPROVE score and D-dimer ≥ 2 × the upper limit of normal (ULN) with the risk of symptomatic deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was evaluated in 7,441 hospitalized, medically ill patients randomized in the APEX trial. Based on the Cox regression analysis, the IMPROVEDD score was derived by adding two points to the IMPROVE score if the D-dimer was ≥ 2 × ULN. Results Baseline D-dimer was independently associated with symptomatic VTE through 77 days (adjusted HR: 2.22 [95% CI: 1.38-1.58], p = 0.001). Incorporation of D-dimer into the IMPROVE score improved VTE risk discrimination (ΔAUC: 0.06 [95% CI: 0.02-0.09], p = 0.0006) and reclassification (continuous NRI: 0.34 [95% CI: 0.17-0.51], p = 0.001; categorical NRI: 0.13 [95% CI: 0.03-0.23], p = 0.0159). Patients with an IMPROVEDD score of ≥2 had a greater VTE risk compared with those with an IMPROVEDD score of 0 to 1 (HR: 2.73 [95% CI: 1.52-4.90], p = 0.0007). Conclusion Incorporation of D-dimer into the IMPROVE VTE risk assessment model further improves risk stratification in hospitalized, medically ill patients who received thromboprophylaxis. An IMPROVEDD score of ≥2 identifies hospitalized, medically ill patients with a heightened risk for VTE through 77 days.


Virulence Role of the GlcNAc Side Chain of the Lancefield Cell Wall Carbohydrate Antigen in Non-M1-Serotype Group A Streptococcus.
Classification of streptococci is based upon expression of unique cell wall carbohydrate antigens. All serotypes of group A Streptococcus (GAS; Streptococcus pyogenes), a leading cause of infection-related mortality worldwide, express the group A carbohydrate (GAC). GAC, the classical Lancefield antigen, is comprised of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc) side chains. The immunodominant GlcNAc epitope of GAC is the basis of all rapid diagnostic testing for GAS infection. We previously identified the 12-gene GAC biosynthesis gene cluster and determined that the glycosyltransferase GacI was required for addition of the GlcNAc side chain to the polyrhamnose core. Loss of the GAC GlcNAc epitope in serotype M1 GAS resulted in attenuated virulence in two animal infection models and increased GAS sensitivity to killing by whole human blood, serum, neutrophils, and antimicrobial peptides. Here, we report that the GAC biosynthesis gene cluster is ubiquitous among 520 GAS isolates from global sources, representing 105 GAS emm serotypes. Isogenic ΔgacI mutants were constructed in M2, M3, M4, M28, and M89 backgrounds and displayed an array of phenotypes in susceptibility to killing by whole human blood, baby rabbit serum, human platelet releasate, human neutrophils, and antimicrobial peptide LL-37. The contribution of the GlcNAc side chain to GAS survival in vivo also varied by strain, demonstrating that it is not a prerequisite for virulence in the murine infection model. Thus, the relative contribution of GAC to virulence in non-M1 serotypes appears to depend on the quorum of other virulence factors that each strain possesses.IMPORTANCE The Lancefield group A carbohydrate (GAC) is the species-defining antigen for group A Streptococcus (GAS), comprising ~50% of the cell wall of this major human pathogen. We previously showed that the GlcNAc side chain of GAC contributes to the innate immune resistance and animal virulence phenotypes of the globally disseminated strain of serotype M1 GAS. Here, we use isogenic mutagenesis to examine the role of GAC GlcNAc in five additional medically relevant GAS serotypes. Overall, the GlcNAc side chain of GAC contributes to the innate immune resistance of GAS, but the relative contribution varies among individual strains. Moreover, the GAC GlcNAc side chain is not a universal prerequisite for GAS virulence in the animal model.


[Polymyalgia rheumatica: myalgic syndrome or occult vasculitis?].
Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder of unknown etiology which typically presents with symmetric myalgias in the shoulder and pelvic girdles. Other clinical signs include the rapid onset of symptoms and the almost exclusive manifestation in the elderly population. In around 20% of cases, PMR is associated with giant cell arteritis (GCA). However, new imaging techniques suggest that the prevalence of subclinical GCA (e. g. aortitis) in PMR is probably higher. Acute phase reactants like erythrocyte sedimentation rate and c-reactive protein are usually elevated. Myalgias are accompanied by synovitis and bursitis of the large proximal joints and can be visualized by ultrasound or magnetic resonance imaging. While the diagnosis of GCA can be verified by temporal artery biopsy, pathognomonic findings for PMR like specific autoantibodies are lacking. Typical for PMR is the rapid response to corticosteroids. Usually the therapy needs to be continued for at least 2 years. Due to adverse events in many cases a corticosteroid saving therapy like methotrexate is needed.


[Myelination, demyelination and re-myelination in the central nervous system].
The myelin sheaths that surround axons in the CNS are made and maintained by oligodendrocytes. These glial cells can form variable numbers of myelin segments (internodules): from 1 to 200 so that when one oligodendrocyte is destroyed with preservation of the axon, many internodules can be lost, constituting a demyelinating process. As a consequence of the destruction of myelin and sheath cells a rapid and abundant cell response takes place. The response is made up by resident (microglia) and haematogenous phagocytes which phagocytose myelin and cellular debris leaving the axons demyelinated. Demyelinated axons may either stay demyelinated and clumped together or they may be separated by astrocytic processes, yet they can be remyelinated. The occurrence of remyelination depends upon the intensity and time of exposition to the demyelinating agent. Remyelination in the CNS with complete restoration of conduction may be made by oligodendrocytes or Schwann cells which invade the CNS when astrocytes are destroyed.


Cold-inducible RNA-binding protein (CIRP) induces translation of the cell-cycle inhibitor p27Kip1.
The CDK inhibitor p27Kip1 plays a central role in controlling cell proliferation and cell-cycle exit. p27Kip1 protein levels oscillate during cell-cycle progression and are regulated by mitogen or anti-proliferative signaling. The abundance of the protein is frequently determined by post-transcriptional mechanisms including ubiquitin-mediated proteolysis and translational control. Here, we report that the cold-inducible RNA-binding protein (CIRP) selectively binds to the 5' untranslated region of the p27Kip1 mRNA. CIRP is induced, modified and relocalized in response to various stress stimuli and can regulate cell survival and cell proliferation particularly during stress. Binding of CIRP to the 5'UTR of the p27Kip1 mRNA significantly enhanced reporter translation. In cells exposed to mild hypothermia, the induction of CIRP correlated with increased translation of a p27Kip1 5'UTR reporter and with the accumulation of p27Kip1 protein. shRNA-mediated CIRP knockdown could prevent the induction of translation. We found that p27Kip1 is central for the decreased proliferation at lower temperature, since p27Kip1 KO mouse embryonic fibroblasts (MEFs) hardly increased their doubling time in hypothermic conditions, whereas wild-type MEFs significantly delayed proliferation in response to cold stress. This suggests that the CIRP-dependent p27Kip1 upregulation during mild hypothermia contributes to the cold shock-induced inhibition of cell proliferation.


Spatiotemporal distribution of vasoactive intestinal polypeptide receptor 2 in mouse suprachiasmatic nucleus.
Vasoactive intestinal polypeptide (VIP) signaling is critical for circadian rhythms. For example, the expression of VIP and its main receptor, VPAC2R, is necessary for maintaining synchronous daily rhythms among neurons in the suprachiasmatic nucleus (SCN), a master circadian pacemaker in animals. Where and when VPAC2R protein is expressed in the SCN and other brain areas has not been examined. Using immunohistochemistry, we characterized a new antibody and found that VPAC2R was highly enriched in the SCN and detectable at low levels in many brain areas. Within the SCN, VPAC2R was circadian, peaking in the subjective morning, and abundantly expressed from the rostral to caudal margins with more in the dorsomedial than ventrolateral area. VPAC2R was found in nearly all SCN cells including neurons expressing either VIP or vasopressin (AVP). SCN neurons mainly expressed VPAC2R in their somata and dendrites, not axons. Finally, constant light increased VIP and AVP expression, but not VPAC2R. We conclude that the circadian clock, not the ambient light level, regulates VPAC2R protein localization. These results are consistent with VPAC2R playing a role in VIP signaling at all times of day, broadly throughout the brain and in all SCN cells.


Chemically modified tetracyclines (CMT-3 and CMT-8) enable control of the pathologic remodellation of human aortic valve stenosis via MMP-9 and VEGF inhibition.
Tetracycline derivatives affect many cellular functions relevant to chronic cardiovascular pathologies, including cell proliferation, migration and matrix remodelling. Accordingly, we sought to determine whether they may modulate the pathologic characteristics known to be significantly involved in human aortic valve stenosis, such as gelatinase production, apoptosis, expression of vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNF-alpha). The effects of tetracycline derivatives (tetracycline and CMTs-3, -5, -8) on MMP-2 and -9 and their endogenous tissue inhibitor (TIMP-1 and -2) production profiles in explanted human aortic valve pieces were examined by means of gelatine zymography and reverse zymography. Chemiluminescent ELISA was performed to assess VEGF and TNF-alpha concentrations in the medium, and in order to evaluate programmed cell death, in situ labelling of the 3'-ends of the DNA fragments generated by apoptosis-associated endonucleases was performed. CMT-3 and -8 lowered the MMP-9 and VEGF levels significantly in a drug-, dose-, and time-dependent manner. MMP-2 and TIMPs remained unchanged, emphasizing the specificity of CMTs to MMP-9 production on the one hand and restoring the beneficial equilibrium of MMP-9 and TIMPs on the other. Tetracycline was the only drug with a significant impact on net gelatinolytic activity, suggesting that the effect of tetracycline is more extensive concerning total MMP activity. Tetracycline derivatives may have therapeutic effects on the pathologic remodellation of advanced human aortic stenosis through the inhibition of MMP-9 and VEGF production.


Staging of oesophageal carcinoma by endoscopic ultrasound: preliminary experience.
Endoscopic ultrasound (EUS) is a relatively recent imaging modality that is capable of visualizing oesophageal tissue layers and para-oesophageal structures. Current pre-operative staging of oesophageal cancer is less than satisfactory, and a modality which may improve pre-operative staging, thus allowing a more rational approach to choice of treatment, may be a welcome addition to current techniques. The purpose of the present study was to evaluate the accuracy of EUS in the staging of oesophageal carcinoma in a consecutive cohort of patients. Forty-three patients with oesophageal cancer were prospectively staged with EUS using the radial scanning Olympus EUM-3 echo-endoscope. In the 28 patients who underwent surgery EUS staging was correlated with operative and histological findings to evaluate the EUS accuracy rate of assessing tumour depth (T stage), and the presence of nodal involvement (N stage) using internationally accepted TNM staging criteria. Endoscopic ultrasound accuracy rates for overall T-staging was 61% whereas that of N-staging was 75%. The overall TNM pathological staging was 75% accurate by EUS. Compared to published literature figures for oesophageal staging by computed tomography scanning (39-54%) these results demonstrate that EUS has a reasonable accuracy rate for staging. Endoscopic ultrasound may prove to be a useful additional modality in the management of oesophageal cancer.


Polymorphic nature of nucleolus organizer regions in fishes.
An analysis of the nucleolar organizer region(NOR) by silver staining of five species of the order Gymnotiformes, Gymnotus carapo, Apteronotus albifrons, Sternopygus macrurus, Eigenmannia virescens, and Eigenmannia sp., is reported. The five species presented only one pair of homologs bearing NORs. In G. carapo, A. albifrons, and S. macrurus the silver-stained NORs were present as small black dots over the chromosomes. In E. virescens, the short arm of one of the largest chromosome pairs was entirely stained with silver. Eigenmannia sp. presented an intraspecific variability of the NOR-bearing pair and an increase in the length of this region, the larger one being about six times the size of the smaller. These findings suggest that an increase in the number of ribosomal genes in the NORs of certain species occurred during the evolution of this group.


Juvenile granulosa cell tumor of the testis: case report and review of literature.
Juvenile granulosa cell tumor of the testis is an infrequent tumor of the gonadal stroma characteristic of the pediatric age. It usually appears as a scrotal mass and less frequently as an abdominal or inguinal mass. It may be associated with ambiguous genitalia and/or abnormal sex chromosomes. The recommended treatment is orchiectomy alone because local recurrence or metastasis have never been observed. We describe a patient with a juvenile granulosa cell tumor of the testis and review the literature.


Potential of Circulating Proangiogenic MicroRNAs for Predicting Major Adverse Cardiac and Cerebrovascular Events in Unprotected Left Main Coronary Artery Disease Patients Who Underwent Coronary Artery Bypass Grafting.
This study aimed to explore the association of 14 proangiogenic microRNAs (miRNAs) with major adverse cardiac and cerebrovascular events (MACCE) occurrence in unprotected left main coronary artery disease (ULMCAD) patients who underwent coronary artery bypass grafting (CABG). A total of 196 ULMCAD patients who underwent first ever CABG were recruited. The peripheral blood samples were collected prior to CABG, and then plasma samples were separated to detect expressions of 14 proangiogenic miRNAs by the reverse transcription quantitative PCR. Patients were regularly followed up to MACCE occurrence or 36 months after CABG. MACCE occurrence at 1 year, 2 years, and 3 years was 7.1, 11.2, and 14.3%, respectively, and accumulating MACCE occurrence time was 32.7 (95% confidence interval: 31.5-33.9) months. Both Kaplan-Meier curves and univariate Cox's regression analyses displayed that miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 high expressions were associated with lower accumulating MACCE occurrence. Furthermore, forward stepwise multivariate Cox's regression disclosed that miR-let-7f high expression and miR-378 high expression independently predicted decreased accumulating MACCE occurrence, whereas BMI (>25.0 kg/m2), diabetes, previous stroke, and higher disease extent were independent predictive factors for elevated accumulating MACCE occurrence. Measurement of circulating proangiogenic miRNAs especially miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 helps predict MACCE risk in ULMCAD patients who underwent CABG.


Trigger Wrist Caused by a Rheumatoid Nodule on the Flexor Pollicis Longus Tendon.
Background: Trigger wrist is a rare condition. Previously reported cases have involved nodules or ganglion cysts affecting flexor digitorum profundus tendons; however, we found no reported cases of trigger wrist caused by a rheumatoid nodule on the flexor pollicis longus tendon. Case Report: A 57-year-old female presented with the complaint of chronic triggering of the right thumb and numbness in her fingers consistent with carpal tunnel syndrome. Corticosteroid injection did not provide symptom relief, so the patient was scheduled for surgery. A 3 × 1.5-cm lesion was removed from the flexor pollicis longus tendon distal to the carpal tunnel. Histopathologic examination demonstrated that the lesion was a rheumatoid nodule. Conclusion: Patients with rheumatoid arthritis who present with trigger finger symptoms of the thumb with concomitant carpal tunnel symptoms require careful evaluation to rule out trigger wrist before the condition progresses to Mannerfelt lesion.


Evaluation of the Safety of Early Compared to Late Enteral Nutrition in Canine Septic Peritonitis.
Septic peritonitis is a relatively common condition in the veterinary intensive care unit, with a classically high mortality rate. Early enteral nutrition (EEN) in critically ill humans can lead to improved outcome. This study was performed to determine the safety of early postoperative feeding in canine septic peritonitis. In this retrospective case series, 56 dogs were identified. Sixteen dogs received EEN, defined as nutrition within 24 hr of surgery; 27 received late enteral nutrition (LEN) defined as nutrition more than 24 hours following surgery; and 13 dogs had no enteral nutrition in hospital (NEN). Signalment, physical examination findings, and occurrence of pre-admission vomiting, regurgitation, and length of anorexia were the same amongst all groups. There was no significant difference in the number of gastrointestinal complications postoperatively between the EEN, LEN, and NEN groups or in the occurrence of vomiting/regurgitation postoperatively compared to preoperatively. There was no difference in the length of hospitalization between any group, although fewer dogs in the NEN group survived compared to the EEN/LEN combined group (46% [6/13] versus 81% [37/40]). This study indicates it is safe to initiate EEN without additional risk of gastrointestinal complications. Prospective studies are needed to evaluate the potential benefits of EEN in dogs with septic peritonitis.


Effect of zinc and polyphenols supplementation on antioxidative defense mechanisms and the frequency of microsatellite instability in chemically-induced mammary carcinogenesis in the rat.
The aim of the present study was to assess the effect of dietary supplementation (with zinc or zinc and polyphenolic compounds - resveratrol or genistein) on antioxidant enzymes (glutathione peroxidase - GPx, catalase - CAT and superoxide dismutase - SOD) and the frequency of microsatellite instability (MSI) in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA). The impact of selected compounds on the intensity of DMBA-induced carcinogenesis was also assessed. Sixty four Sprague-Dawley female rats were divided into study groups which, apart from the standard diet and DMBA, were treated with zinc, zinc and resveratrol or zinc and genistein via gavage for a period ranging from 40 days to 20 weeks of age. On the basis of the obtained results it can be said that synergistic reaction between Zn(II) and genistein causes a delay in cancer development as compared with the animals treated with DMBA but with no food supplementation. Supplementation with Zn(II) and polyphenolic compounds resulted in the occurrence of microsatellite instabilities in tumors. LOH (loss of heterozygosity) was found in tumor samples at microsatellite D1Mgh6 and D3Mgh9. DMBA treatment increased significantly the glutathione peroxidase activity whereas it had no effect on the SOD and CAT activities, as compared with control rats. Diet supplementation has an effect on the activity of selected antioxidant enzymes. Diet supplementation has an effect on the occurrence of microsatellite instabilities as well as on the intensity of the neoplastic process. The intensity of occurrence of microsatellite instabilities does not depend on the activity of selected antioxidant enzymes.


The crystal structure of the Calystegia sepium agglutinin reveals a novel quaternary arrangement of lectin subunits with a beta-prism fold.
The high number of quaternary structures observed for lectins highlights the important role of these oligomeric assemblies during carbohydrate recognition events. Although a large diversity in the mode of association of lectin subunits is frequently observed, the oligomeric assemblies of plant lectins display small variations within a single family. The crystal structure of the mannose-binding jacalin-related lectin from Calystegia sepium (Calsepa) has been determined at 1.37-A resolution. Calsepa exhibits the same beta-prism fold as identified previously for other members of the family, but the shape and the hydrophobic character of its carbohydrate-binding site is unlike that of other members, consistent with surface plasmon resonance analysis showing a preference for methylated sugars. Calsepa reveals a novel dimeric assembly markedly dissimilar to those described earlier for Heltuba and jacalin but mimics the canonical 12-stranded beta-sandwich dimer found in legume lectins. The present structure exemplifies the adaptability of the beta-prism building block in the evolution of plant lectins and highlights the biological role of these quaternary structures for carbohydrate recognition.


Identification of quorum-sensing-regulated genes of Burkholderia cepacia.
Quorum sensing is a regulatory mechanism (operating in response to cell density) which in gram-negative bacteria usually involves the production of N-acyl homoserine lactones (HSL). Quorum sensing in Burkholderia cepacia has been associated with the regulation of expression of extracellular proteins and siderophores and also with the regulation of swarming and biofilm formation. In the present study, several quorum-sensing-controlled gene promoters of B. cepacia ATCC 25416 were identified and characterized. A total of 28 putative gene promoters show CepR-C(8)-HSL-dependent expression, suggesting that quorum sensing in B. cepacia is a global regulatory system.


1.89 $ kg-1 Lake-Water-Based Semisolid Electrolytes for Highly Efficient Energy Storage.
Solid electrolytes with fast ion kinetics and superior mechanical properties are critical to electrochemical energy devices; however, how to design low-cost, high-performance solid electrolytes has become a critical challenge in the energy field, and significant progress has not been achieved until now. Here, lake-water-based semisolid electrolytes with a low cost of 1.89 $ kg-1 have been put forward for the purpose of market promotion. By virtue of the palygorskite dopants and lake water source, the electrolytes display satisfying mechanical, electrical, and electrochemical properties as well as economic benefits. The application potential of electrolytes has been demonstrated by employing a polyelectrolyte with ionic conductivity of 0.82 × 10-4 S cm-1 in flexible supercapacitors. The as-assembled devices give a high energy density of 54.72 Wh kg-1 and excellent cycling stability with a capacity retention of 94.8% over 20 000 cycles. The flexibility of devices has been verified through 5000 repetitive bending tests. Our work presents insight into the design of flexible solid electrolytes based on cheap and green raw materials.


[Reassessment of EWSR1 gene rearrangement-negative undifferentiated round cell sarcomas in bone and soft tissues by fluorescence in situ hybridization].
Objective: To unravel the CIC rearrangement sarcomas and BCOR-CCNB3 sarcomas from EWSR1 rearrangement-negative undifferentiated round cell sarcomas in the bone and soft tissues. Methods: Twenty-eight cases of EWSR1 rearrangement-negative undifferentiated round cell sarcomas of bone and soft tissues, tested for CIC rearrangement and BCOR rearrangement by fluorescence in situ hybridization and related immunostaining were analyzed, and some of the BCOR rearrangement cases were verified by reverse transcription-polymerase chain reaction. Results: Five of 28 (17.9%) tested cases were positive for CIC rearrangement and six (21.4%) for BCOR rearrangement. Histopathologically, CIC rearrangement sarcomas comprised nodular aggregates of round to polygonal cells, containing hyperchromatic nuclei, prominent nucleoli and moderate cytoplasm, with focal variable necrosis and myxoid stroma. BCOR-CCNB3 sarcomas mostly comprised diffusely arranged, round to oval to short spindly cells with angulated nuclei, vesicular chromatin, inconspicuous nucleoli and interspersed vessels. Immunohistochemically, five of six BCOR-CCNB3 sarcomas showed CCNB3 immunostaining, which could be helpful for diagnosis. Two patients with CIC rearrangement sarcoma died of the diseases in seven months and twenty-two months. One patient with BCOR-CCNB3 sarcoma died of the diseases in forty-six months. Conclusions: Overall, 39.3% of the EWSR1 rearrangement-negative undifferentiated round cell sarcomas are CIC rearrangement sarcomas and BCOR-CCNB3 sarcomas. Molecular testing is helpful for diagnosis.


Novel in vivo Assessment of Unruptured Intracranial Aneurysm Inflammatory Factors.
Background and Purpose: The growth and eventual rupture of intracranial aneurysms may be due to an underlying inflammatory process as evidenced by pathological examination of aneurysm walls. We hypothesize that unruptured aneurysms have an increased inflammatory milieu within their lumen in comparison to the rest of the cerebral arterial vascular system. Methods: Blood was sampled from unruptured aneurysms in patients presenting for aneurysm coil embolization and C3 and C4 complement values from this serum were compared with complement values in the parent artery. Results: Ten patients were enrolled over 32 months with a mean aneurysm size of 9.1 mm. Compared to control samples drawn from peripheral circulation, there were significant decreases of both C3 (p = 0.0003) and C4 (p = 0.0063) levels in aneurysmal blood samples. Conclusions: A state of decreased complement indicative of classic pathway activation was found in all tested aneurysms, thus providing evidence of an ongoing process of complement activation in the blood of live, unruptured aneurysm sacs.


Changes in expression and organization of smooth-muscle-specific alpha-actin during fibronectin-mediated modulation of arterial smooth muscle cell phenotype.
The spreading of freshly isolated arterial smooth muscle cells on a substrate of fibronectin is mediated by an integrin receptor on the cell surface. It is associated with organization of actin filaments in stress fibers and marked changes in cell morphology and function, collectively referred to as a transition from a contractile to a synthetic phenotype. To study further how extracellular matrix components affect smooth muscle phenotype, we have analyzed the expression and organization of smooth-muscle-specific alpha-actin in freshly isolated rat aortic smooth muscle cells cultured on a substrate of fibronectin under serum-free conditions. Northern-blot analysis showed that the expression of mRNA for smooth muscle alpha-actin, but not for nonmuscle actin, was strongly repressed during primary culture. On the other hand, the cellular content of alpha-actin was only moderately changed during the same period. Indirect immunofluorescence staining revealed that nonmuscle actin was rapidly organized in stress fibers, which did not stain with a monoclonal antibody against smooth muscle alpha-actin. Filament bundles containing alpha-actin were most prominent in the central parts of the cytoplasm and gradually disappeared as the spreading of the cells progressed. In contrast to the situation with nonmuscle actin, there was no apparent overlap in the staining for alpha-actin and the fibronectin receptor (alpha 5 beta 1), indicating that this receptor interacted with nonmuscle actin during the initial spreading process. Taken together, the results show that the expression and organization of smooth muscle alpha-actin are changed during interaction of the cells with fibronectin early in primary culture. They support the notion that integrin-mediated interactions between extracellular matrix components and arterial smooth muscle cells take part in the control of smooth muscle phenotype.


Performance of trigger tools in identifying adverse drug events in emergency department patients: a validation study.
Trigger tools are retrospective surveillance methods that can be used to identify adverse drug events (ADEs), unintended and harmful effects of medications, in medical records. Trigger tools are used in quality improvement, public health surveillance and research activities. The objective of the study was to evaluate the performance of trigger tools in identifying ADEs. This study was a sub-study of a prospective cohort study which enrolled adults presenting to one tertiary care emergency department. Clinical pharmacists evaluated patients for ADEs at the point-of-care. Twelve months after the prospective study's completion, the patients' medical records were reviewed using eight different trigger tools. ADEs identified using each trigger tool were compared with events identified at the point-of-care. The primary outcome was the sensitivity of each trigger tool for ADEs. Among 1151 patients, 152 (13.2%, 95% confidence intervals (CI) 11.4, 15.3%) were diagnosed with one or more ADEs at the point-of-care. The sensitivity of the trigger tools for detecting ADEs ranged from 2.6% (95% CI 0.7, 6.6%) to 15.8% (95% CI 10.6, 22.8%). Their specificity varied from 99.3% (95% CI 98.6, 99.7) to 100% (95% CI 99.6, 100%). The trigger tools examined had poor sensitivity for identifying ADEs in emergency department patients, when applied manually and in retrospect. Reliance on these methods to detect ADEs for quality improvement, surveillance, and research activities is likely to underestimate their occurrence, and may lead to biased estimates.


Factors associated with timing of umbilical cord clamping in tertiary hospital of Nepal.
Delayed umbilical cord clamping (DCC) (≥ 60 s) is recognized to improve iron status and neurodevelopment compared to early umbilical cord clamping. The aim of this study is to identify current umbilical cord clamping practice and factors determining the timing of clamping in a low-resource setting where prevalence of anemia in infants is high. A cross-sectional study design including 128 observations of clinical practice in a tertiary-level maternity hospital in Kathmandu, Nepal. Overall 48% of infants received DCC. The mean and median cord clamping times were 61 ± 33 and 57 (38-79) s, respectively. Univariate analysis showed that infants born during the night shift were five times more likely to receive DCC (OR 5.6, 95% CI 1.4-38.0). Additionally, infants born after an obstetric complication were 2.5 times more likely to receive DCC (OR 2.5, 95% CI 1.2-5.3), and babies requiring ventilation had a 65% lower likelihood of receiving DCC (OR 0.35, 95% CI 0.13-0.88). Despite the existence of standard protocols for cord clamping and its proven benefit, the lack of uniformity in the timing of cord clamping reveals poor translation of clinical guidelines into clinical practice. Clinical trial registration ISRCTN97846009.


Sucrose, sucrosyl oligosaccharides, and oxidative stress: scavenging and salvaging?
In nature, no single plant completes its life cycle without encountering environmental stress. When plant cells surpass stress threshold stimuli, chemically reactive oxygen species (ROS) are generated that can cause oxidative damage or act as signals. Plants have developed numerous ROS-scavenging systems to minimize the cytotoxic effects of ROS. The role of sucrosyl oligosaccharides (SOS), including fructans and the raffinose family oligosaccharides (RFOs), is well established during stress physiology. They are believed to act as important membrane protectors in planta. So far a putative role for sucrose and SOS during oxidative stress has largely been neglected, as has the contribution of the vacuolar compartment. Recent studies suggest a link between SOS and oxidative defence and/or scavenging. SOS might be involved in stabilizing membrane-associated peroxidases and NADPH oxidases, and SOS-derived radicals might fulfil an intermediate role in oxido-reduction reactions taking place in the vicinity of membranes. Here, these emerging features are discussed and perspectives for future research are provided.


Two bullets in the gun: combining immunotherapy with chemotherapy to defeat neuroblastoma by targeting adrenergic-mesenchymal plasticity.
Neuroblastoma (NB) is a childhood tumor that originates in the peripheral sympathetic nervous system and is responsible for 15% of cancer-related deaths in the pediatric population. Despite intensive multimodal treatment, many patients with high-risk NB relapse and develop a therapy-resistant tumor. One of the phenomena related to therapeutic resistance is intratumor heterogeneity resulting from the adaptation of tumor cells in response to different selective environmental pressures. The transcriptional and epigenetic profiling of NB tissue has recently revealed the existence of two distinct cellular identities in the NB, termed adrenergic (ADRN) and mesenchymal (MES), which can spontaneously interconvert through epigenetic regulation. This phenomenon, known as tumor plasticity, has a major impact on cancer pathogenesis. The aim of this review is to describe the peculiarities of these two cell states, and how their plasticity affects the response to current therapeutic treatments, with special focus on the immunogenic potential of MES cells. Furthermore, we will discuss the opportunity to combine immunotherapy with chemotherapy to counteract NB phenotypic interconversion.


Current challenges and future prospects in oral anticoagulant therapy.
The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.


[Masked depression: the rise and fall of a diagnosis].
The diagnosis of "masked depression" was very common in the 70'es and 80'es for patients with somatic complaints without an organic counterpart, when a psychic illness was assumed. Today this diagnosis does not play an important role any more - neither clinically nor scientifically. This article examines the background of the enormous initial importance of this diagnostic concept and of its final abandonment. Critical reflection of the literature. The main reason for the immense success of that diagnosis was the tempting possibility of subsuming patients with a multitude of only unsatisfactorily explicable and treatable somatic symptoms under one single concept. In addition, this concept allowed to derive a uniform treatment, i.e. pharmacotherapy with antidepressants. Several problems inherent in the diagnosis of masked depression finally led to the dropping of that concept: the expansion of that diagnosis onto a vast number of disorders, the continuing lack of clarity of the concept (disorder of recognition vs. disorder of communication; the positive proof of psychic symptoms as a prerequisite vs. the positive proof of psychic symptoms as an exclusion criterion for that diagnosis). Last but not least, the introduction of DSM-III and ICD-10 as operationalized, purely descriptive and rather theory-free systems of diagnostic classification supported that development. The present diagnoses for those patients re-emphasize the somatic symptomatology. Formerly "masked depressed" patients are now diagnosed as suffering from somatization disorder, somatoform disorder, psychosomatic disorder, conversion disorder, neurasthenia or hypochondriasis.


From chaos to cosmos: The telling of a life story reconsidered.
This paper is based on clinical work as a pastoral counsellor with 26 elderly chronic patients at one of the city hospitals in Helsinki. The author discusses how the patients experience chaos and cosmos and how the telling of their life stories encourages them to encounter the crisis. They asked: who am I in the midst of all these (cultural, social and physical) changes? Chaos was experienced as a feeling of alienation from oneself, of being unable to determine one's own living conditions, and of being unable to handle stress situations by the same means as before. The path from chaos to cosmos was discovered by telling one's life story, which proved to be a creative process relating and integrating the present with the past, and providing an overview of one's life cycle. The counsellor and the other social contacts willing to listen to and reflect upon the story facilitated the progress considerably as did a positive attitude towards religion and seeking of life satisfaction in spite of everything.


Hemoglobin F production in testicular malignancy.
The peripheral blood of 3 patients with testicular malignancy and elevated hCG levels was examined for Hb F production. Increases of percent chemically determined Hb F and/or F cell number were observed in each case when or soon after the hCG level was elevated. In these cases, Hb F production correlated with the degree of clinically evident malignancy. These observations suggest that the reactivation of Hb F synthesis may be applied to the evaluation of disease activity in patients with testicular malignancy.


Quantitative determination of human plasma erythropoietin using embryonic mouse liver erythroblasts.
An in vitro bioassay for the quantitative detection of erythropoietin (Ep) in human plasma is described. The method is based on the increased 3H-uridine incorporation into 12-day embryonic mouse liver erythroblasts due to Ep. It was found that 11 out of 12 anaemic patients showed high plasma Ep level, while 7 out of 8 patients suffering from polycythaemia revealed low Ep values. In 4 out of 8 patients with chronic renal failure the Ep level was within the normal range, whereas in the remaining 4 it was higher than normal. The relative simplicity of the method and the reproducibility of the results make it useful even in the routine laboratory.


Implant of permanent pacemaker during acute coronary syndrome: Mortality and associated factors in the ARIAM registry.
Patients with acute coronary syndrome complicated with high degree atrioventricular block still have a high mortality. A low percentage of these patients need a permanent pacemaker (PPM) but mortality and associated factors with the PPM implant in acute coronary syndrome patients are not known. We assess whether PPM implant is an independent variable in the mortality of acute coronary syndrome patients. Also, we explored the variables that remain independently associated with PPM implantation. This was an observational study on the Spanish ARIAM register. The inclusion period was from January 2001 to December 2011. This registry included all Andalusian acute coronary syndrome patients. Follow-up for global mortality was until November 2013. We selected 27,608 cases. In 62 patients a PPM was implanted (0.024%). The mean age in PPM patients was 70.71±11.214 years versus 64.46±12.985 years in patients with no PPM. PPM implant was associated independently with age (odds ratio (OR) 1.031, 95% confidence interval (CI) 1.007-1.055), with left ventricular branch block (OR 6.622, 95% CI 2.439-18.181), with any arrhythmia at intensive care unit admission (OR 2.754, 95% CI 1.506-5.025) and with heart failure (OR 3.344, 95% CI 1.78-8.333). PPM implant was independently associated with mortality (OR 11.436, 95% CI 1.576-83.009). In propensity score analysis PPM implant was still associated with mortality (OR 5.79, 95% CI 3.27-25.63). PPM implant is associated with mortality in the acute coronary syndrome population in the ARIAM registry. Advanced age, heart failure, arrhythmias and left ventricular branch block at intensive care unit admission were found associated factors with PPM implant in acute coronary syndrome patient.


Social Work Response to Elder Abuse in Uganda: Voices from Practitioners.
Social workers across the globe are at the forefront of tackling elder abuse, as they are committed to social justice, human rights, and respect for human diversity. However, research on social workers' response to elder abuse in Sub-Saharan Africa remains scarce. This qualitative study assessed how social workers in Uganda have responded to elder abuse. In-depth semi-structured interviews were used to collect data from 21 social workers. The findings suggest that social work in Uganda has not asserted itself in the fight against elder abuse. The few social work interventions aimed at reducing the risk of elder abuse are mostly anti-poverty undertakings. Social workers mainly discussed the drivers of elder abuse, correlating them with their interventions, and challenges such as the absence of a specific law for older people, ignorance of older people's rights, and the underreporting of elder abuse. This study found that advocacy is needed for specific laws that protect the rights of older people, along with public awareness campaigns and the establishment of a research center for aging and later life.


Influence of apoptosis (BCL2, FAS), cell cycle (CCND1) and growth factor (EGF, EGFR) genetic polymorphisms on survival outcome: an exploratory study in squamous cell esophageal cancer.
The study aimed at investigating whether genetic polymorphisms in BCL2, FAS, CCND1, EGF and EGFR genes influence the outcome of patients of esophageal squamous cell cancer treated with radiotherapy, with or without chemotherapy. Sixty nine histologically confirmed, previously untreated, patients with a squamous cell esophageal cancer were inducted into this study. Genotyping of BCL2 (ala43thr), FAS (A-670G), CCND1 (G870A), EGF (+61A/G) and EGFR (G497A) polymorphisms were determined using the polymerase chain reaction followed by restriction fragment length polymorphism methodology. Genotyped data was analyzed using univariate and multivariate logistic regression statistical tests for predicting the survival outcome. Genotypes of BCL2, FAS, CCND1 and EGFR polymorphisms independently did not influence outcome significantly. However, patients with EGF +61AG genotype had median survival of 25.5 months (95% CI = 5.2-45.5), whereas those with EGF +61GG genotype had survival of only 3.7 months (95% CI = 0.0-9.8, p = 0.006). In univariate cox-regression analysis, interaction of genotypes EGF+61GG*radiotherapy tumor dose (< or =50 Gy) and EGF +61GG *upper third tumor location showed high hazard of death, 6.6 (95% CI = 2.0-21.5, p = 0.002) and 26.8 (95% CI = 3.7-194.2, p = 0.001) while EGF+61AG*middle third tumor location had reduced hazard 0.20 (95%CI = 0.06-0.60, p = 0.004). The pilot study suggests that EGF +61AG and +61GG genotypes may predict clinical outcome in esophageal cancer patients treated with radiotherapy with or without chemotherapy. EGF +61AG genotype was associated with improved survival, however +61GG genotype adversely affected the outcome in patients particularly with upper third location of tumor and lower dose (< or =50) of radiotherapy.


Rhythmic masking release: contribution of cues for perceptual organization to the cross-spectral fusion of concurrent narrow-band noises.
The contribution of temporal asynchrony, spatial separation, and frequency separation to the cross-spectral fusion of temporally contiguous brief narrow-band noise bursts was studied using the Rhythmic Masking Release paradigm (RMR). RMR involves the discrimination of one of two possible rhythms, despite perceptual masking of the rhythm by an irregular sequence of sounds identical to the rhythmic bursts, interleaved among them. The release of the rhythm from masking can be induced by causing the fusion of the irregular interfering sounds with concurrent "flanking" sounds situated in different frequency regions. The accuracy and the rated clarity of the identified rhythm in a 2-AFC procedure were employed to estimate the degree of fusion of the interferring sounds with flanking sounds. The results suggest that while synchrony fully fuses short-duration noise bursts across frequency and across space (i.e., across ears and loudspeakers), an asynchrony of 20-40 ms produces no fusion. Intermediate asynchronies of 10-20 ms produce partial fusion, where the presence of other cues is critical for unambiguous grouping. Though frequency and spatial separation reduced fusion, neither of these manipulations was sufficient to abolish it. For the parameters varied in this study, stimulus onset asynchrony was the dominant cue determining fusion, but there were additive effects of the other cues. Temporal synchrony appears to be critical in determining whether brief sounds with abrupt onsets and offsets are heard as one event or more than one.


Effect of epigallocatechin-3-gallate, major ingredient of green tea, on the pharmacokinetics of rosuvastatin in healthy volunteers.
Previous in vitro studies have demonstrated the inhibitory effect of green tea on drug transporters. Because rosuvastatin, a lipid-lowering drug widely used for the prevention of cardiovascular events, is a substrate for many drug transporters, there is a possibility that there is interaction between green tea and rosuvastatin. The aim of this study was to investigate the effect of green tea on the pharmacokinetics of rosuvastatin in healthy volunteers. An open-label, three-treatment, fixed-sequence study was conducted. On Day 1, 20 mg of rosuvastatin was given to all subjects. After a 3-day washout period, the subjects received 20 mg of rosuvastatin plus 300 mg of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea (Day 4). After a 10-day pretreatment of EGCG up to Day 14, they received rosuvastatin (20 mg) plus EGCG (300 mg) once again (Day 15). Blood samples for the pharmacokinetic assessments were collected up to 8 hours after each dose of rosuvastatin. A total of 13 healthy volunteers were enrolled. Compared with the administration of rosuvastatin alone, the concomitant use at Day 4 significantly reduced the area under the concentration-time curve from time 0 to the last measurable time (AUClast) by 19% (geometric mean ratio 0.81, 90% confidence interval [CI] 0.67-0.97) and the peak plasma concentration (Cmax) by 15% (geometric mean ratio 0.85, 90% CI 0.70-1.04). AUClast or Cmax of rosuvastatin on Day 15 was not significantly different from that on Day 1. This study demonstrated that co-administration of EGCG reduces the systemic exposure of rosuvastatin by 19%, and pretreatment of EGCG can eliminate that effect of co-administration of EGCG.


PGcloser: Fast Parallel Gap-Closing Tool Using Long-Reads or Contigs to Fill Gaps in Genomes.
Assembled draft genomes usually contain many gaps because of the length limit of next-generation sequencing. Although many gap-closing tools have been developed, most of them still attempt to fill gaps on the basis of next-generation sequencing reads (always < 200 bp). Hence, the gap-filling effect is inferior. Several tools that use long-reads to close gaps have recently been created. However, they require extensive runtimes, which may not be suitable for large genomes. We describe a gap-closing tool called PGcloser, which supports parallel mode and adopts long-reads/contigs to fill gaps in genome sequences. Three tests show that PGcloser is faster than other tools but exhibits similar accuracy. PGcloser is free open-source software that is available at http://software.tobaccodb.org/software/pgcloser.


Efficacy of Smear Layer Removal of Human Teeth Root Canals Using Herbal and Chemical Irrigants: An In Vitro Study.
Objectives Over many years, many intracanal irrigants have removed smear layers during routine root canal therapy. The efficacies of conventional endodontic chemical irrigants are documented, but limited research is available on herbal irrigants' role in the endodontic therapy irrigation protocol. This study aimed to evaluate endodontic irrigants' smear layer removal efficacy, namely, 3% sodium hypochlorite (NaOCl), 17% ethylenediaminetetraacetic acid (EDTA), green tea extract, and Triphala extract, using scanning electron microscopy (SEM) analysis. Methods Fifty freshly extracted human permanent maxillary and mandibular single-rooted teeth were collected from the Oral Surgery Department of Regional Dental College (RDC), Guwahati, India. The samples were divided into five groups with 10 teeth each: Group A: sterile distilled water (negative control), Group B: 3% NaOCl, Group C: 17% EDTA, Group D: green tea, and Group E: Triphala (citric acid). Each tooth was then longitudinally split and prepared for SEM inspection under 1000X magnification. The comparison of smear layer removal scores between the groups was done by the Kruskal-Wallis test and Mann-Whitney test, with the significance level set at p<0.01. Results The comparison of the overall mean smear scores and those at different root portions shows that Group C has the lowest mean score, followed by Group E. The pairwise comparison shows that the difference in the mean smear scores between Group C and the other four groups is statistically significant (p-value<0.05). Moreover, the difference in the overall, coronal, middle, and apical mean smear scores between Group A and Group E was highly significant (p-value<0.001). Conclusions The highest smear layer removal efficacy was observed in the samples treated with 17% EDTA. Moreover, the clearing efficacy of Triphala is significantly better than that of distilled water in smear layer removal.


Reconfigurable opto-thermoelectric printing of colloidal particles.
We have developed a new optical technique - opto-thermoelectric printing - to print colloidal particles with reconfigurable patterns on substrates via light-controlled thermoelectric fields.


Development of high resolution Michelson interferometer for stable phase-locked ultrashort pulse pair generation.
We developed a high resolution Michelson interferometer with a two-frequency He-Ne laser positioning system in order to stabilize the relative phase of a pulse pair. The control resolution corresponded to a 12 as time resolution or a phase of 1.5 degrees at 900 nm. This high resolution Michelson interferometer can generate a phase-locked pulse pair either with a specific relative phase such as 0 or pi radians or with an arbitrary phase. Coherent control of an InAs self-assembled quantum dot was demonstrated using the high resolution Michelson interferometer with a microspectroscopy system.


Treatment of premenstrual mastalgia with tamoxifen.
Thirty-four women with normal menstrual cycles but suffering from severe premenstrual mastalgia were randomly treated with either tamoxifen (10 mg daily) (18 women) or placebo (16 women) from cycle day 5 to 24 for six consecutive cycles. At the end of the treatment, 89% of the tamoxifen-treated patients were free from the symptoms and the remainder experienced partial alleviation. In contrast, six patients treated with placebo showed only partial alleviation (38%) (p less than 0.001). Twelve months after the end of tamoxifen treatment, 53% of the medicated women were still free of symptoms as compared with none of the placebo-treated patients. These results suggest that tamoxifen is highly effective for the management of severe premenstrual mastalgia and should be useful for the treatment of this disorder.


Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC delta-independent mechanism in human malignant tumor cells.
Rottlerin has been shown to induce antiproliferation and apoptosis of human cancer cell lines. In this study, we demonstrate a novel mechanism of rottlerin-induced apoptosis via death receptor (DR) 5 upregulation. We found that treatment with rottlerin significantly induces DR5 expression both at its messenger RNA and protein levels. Downregulation of DR5 expression with small-interfering RNA (siRNA) efficiently attenuated rottlerin-induced apoptosis, showing that the critical role of DR5 in this cell death. Rottlerin-induced DR5 upregulation was accompanied by CCAAT/enhancer-binding protein-homologous protein (CHOP) protein expression and rottlerin-induced increase of DR5 promoter activity was diminished by mutation of a CHOP-binding site of DR5 promoter. Although rottlerin is known to be as an inhibitor of novel isoforms of protein kinase C (PKC), specifically PKC delta, not only suppression of PKC delta expression by siRNA but also overexpression of wild-type-PKC delta or dominant-negative-PKC delta did not affect the rottlerin-mediated induction of DR5 in our study. These results suggest that rottlerin induces upregulation of DR5 via PKC delta-independent pathway. Furthermore, subtoxic dose of rottlerin sensitizes human cancer cells, but not normal cells, to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Thus, DR5-mediated apoptosis, which is induced by rottlerin alone or by the combined treatment with rottlerin and TRAIL, may offer a new therapeutic strategy against cancer.


Solvent Mediated Excited State Proton Transfer in Indigo Carmine.
Excited state proton transfer (ESPT) is thought to be responsible for the photostability of biological molecules, including DNA and proteins, and natural dyes such as indigo. However, the mechanistic role of the solvent interaction in driving ESPT is not well understood. Here, the electronic excited state deactivation dynamics of indigo carmine (InC) is mapped by visible pump-infrared probe and two-dimensional electronic-vibrational (2DEV) spectroscopy and complemented by electronic structure calculations. The observed dynamics reveal notable differences between InC in a protic solvent, D2O, and an aprotic solvent, deuterated dimethyl sulfoxide (dDMSO). Notably, an acceleration in the excited state decay is observed in D2O (<10 ps) compared to dDMSO (130 ps). Our data reveals clear evidence for ESPT in D2O accompanied by a significant change in dipole moment, which is found not to occur in dDMSO. We conclude that the ability of protic solvents to form intermolecular H-bonds with InC enables ESPT, which facilitates a rapid nonradiative S1 → S0 transition via the monoenol intermediate.


[Rimantadine in the prevention and treatment of influenza A].
Although the antiviral properties of rimantadine specifically directed against influenza A viruses have been known for more than 25 years, this compound has not been widely used owing to its narrow specificity. The drug is active and has low toxicity. It should play a major role in the fight against the medical, epidemiological and economic effects of influenza A, but it can only be used under a number of conditions: accurate identification of the circulating virus and early administration of the drug (these two prerequisites being somewhat contradictory), selection of the right targets (contacts of recognized cases, subjects constantly exposed to contagion, etc.) and respect of certain contraindication. On the other hand, the theoretical advantages of this type of prophylaxis are important: it may limit contagion (morbidity) or at least reduce the severity of the cases (mortality); it may also prevent an epidemic from penetrating the population treated and thus reduce the severity and costs of the epidemic. The therapeutic use of rimantadine has not yet been officially recommended, but it already seems very promising. Rimantadine should be used as an adjuvant treatment, side by side with immunization against influenza which it cannot replace.


An evolutionary perspective of AMPK-TOR signaling in the three domains of life.
AMPK and TOR protein kinases are the major control points of energy signaling in eukaryotic cells and organisms. They form the core of a complex regulatory network to co-ordinate metabolic activities in the cytosol with those in the mitochondria and plastids. Despite its relevance, it is still unclear when and how this regulatory pathway was formed during evolution, and to what extent its representations in the major eukaryotic lineages resemble each other. Here we have traced 153 essential proteins forming the human AMPK-TOR pathways across 412 species representing all three domains of life-prokaryotes (bacteria, archaea) and eukaryotes-and reconstructed their evolutionary history. The resulting phylogenetic profiles indicate the presence of primordial core pathways including seven proto-kinases in the last eukaryotic common ancestor. The evolutionary origins of the oldest components of the AMPK pathway, however, extend into the pre-eukaryotic era, and descendants of these ancient proteins can still be found in contemporary prokaryotes. The TOR complex in turn appears as a eukaryotic invention, possibly to aid in retrograde signaling between the mitochondria and the remainder of the cell. Within the eukaryotes, AMPK/TOR showed both a highly conserved core structure and a considerable plasticity. Most notably, KING1, a protein originally assigned as the γ subunit of AMPK in plants, is more closely related to the yeast SDS23 gene family than to the γ subunits in animals or fungi. This suggests its functional difference from a canonical AMPK γ subunit.


An Assessment of Program Eligibility Among Participants in Day Reporting Centers.
Day reporting centers (DRCs) vary considerably in how participant eligibility is determined and to date, there is little to no knowledge whether criteria for DRC eligibly are appropriately applied in program entrance. This study examines a statewide sample of individuals in community supervision settings and compares DRC eligibility criteria between DRC and non-DRC participants to examine differences between DRC participants and non-participants. Using a propensity score matched sample of 1,554 participants, study findings suggest that DRC participants show higher risk, need, and responsivity factors, consistent with the DRC programing model. These results suggest many individuals appear to be appropriately matched to DRCs, which may in turn, may influence their likelihood of program success, among other factors.


Dysregulation and Dislocation of SFPQ Disturbed DNA Organization in Alzheimer's Disease and Frontotemporal Dementia.
SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD.


Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy.
To determine whether a pathologic fracture in osteosarcoma of long bones has prognostic importance, and limb salvage can be safely performed in such cases, we reviewed the surgical treatment and oncologic results in 46 patients with nonmetastatic osteosarcoma of the extremity and pathologic fracture at presentation who had been treated in our Institution with neoadjuvant chemotherapy, between 1983 and 1999. Neoadjuvant chemotherapy was given according to 6 consecutive protocols. Surgery consisted of limb salvage (34 patients), amputation (11 patients) and rotationplasty (1 patient). The average follow-up was 11 (3-20) years. 28 patients remained continuously disease-free, 17 patients relapsed and 1 died of chemotherapy-related toxicity. Despite the high rate of limb salvage, only 2 local failures occurred, 1 after amputation and 1 after limb salvage. The 5-year disease-free survival and overall survival rates were 59% and 65%, respectively, with no differences between amputated and resected patients. These results are similar to those obtained in 689 contemporary patients having an osteosarcoma without a pathologic fracture treated in our Institution, and using the same protocols for chemotherapy. We conclude that with neoadjuvant chemotherapy, osteosarcoma patients presenting with a pathologic fracture can be surgically treated like those with no fracture, and that limb salvage procedures do not increase the risk of local recurrence or death of these patients.


Acute and residual mood and cognitive performance of young adults following smoked cannabis.
To examine acute and residual mood and cognitive performance in young adult regular cannabis users following smoked cannabis. Ninety-one healthy young adults completed this double-blind, placebo-controlled, parallel-groups study. Participants were randomized to receive active (12.5% THC) or placebo cannabis with a 2:1 allocation ratio, and mood [Profile of Mood States (POMS)] and cognitive performance [Hopkins Verbal Learning Test - Revised (HVLT-R), Digit Symbol Substitution Test (DSST), Continuous Performance Test (CPT), grooved pegboard (GPB)] were assessed before and 1, 24, and 48 (h) after smoking cannabis ad libitum. High and Low THC groups were based on blood THC concentrations. One hour after smoking cannabis, compared to Placebo, in both the High and Low THC groups, there were increases in POMS Arousal and Positive Mood, and in the High THC group only, increases in Confusion, Friendliness, and Elation, and a decrease in Fatigue. Increases in Friendliness and Elation in the High THC group remained significant for 24 h. The only significant acute effect of cannabis on cognition was a decrease in the percent of words retained in the HVLT-R in the High THC group compared to Placebo (mean difference = 15.8%, 95% CI = 3.6-28.0%, p = 0.006). Unexpectedly, compared to Placebo, both the High and Low THC groups improved in DSST performance at 48 h (p ≤ 0.016). Under the present experimental conditions, in young regular cannabis users, smoking cannabis ad libitum had significant effects on mood, some of which persisted 24 h later, yet minimal effects on cognition, and no evidence of residual cognitive impairment.


Therapeutic Effects and Molecular Mechanism of Chlorogenic Acid on Polycystic Ovarian Syndrome: Role of HIF-1alpha.
Chlorogenic acid (CGA) is a powerful antioxidant polyphenol molecule found in many diets and liquid beverages, playing a preventive and therapeutic role in various diseases caused by oxidative stress and inflammation. Recent research has found that CGA can not only improve clinical symptoms in PCOS patients but also improve follicular development, hormone status, and oxidative stress in PCOS rats, indicating the therapeutic effect of CGA on PCOS. Notably, our previous series of studies has demonstrated the expression changes and regulatory mechanisms of HIF-1alpha signaling in PCOS ovaries. Considering the regulatory effect of CGA on the HIF-1alpha pathway, the present article systematically elucidates the therapeutic role and molecular mechanisms of HIF-1alpha signaling during the treatment of PCOS by CGA, including follicular development, steroid synthesis, inflammatory response, oxidative stress, and insulin resistance, in order to further understand the mechanisms of CGA effects in different types of diseases and to provide a theoretical basis for further promoting CGA-rich diets and beverages simultaneously.


Associations between social connections and cognition: a global collaborative individual participant data meta-analysis.
Poor social connections (eg, small networks, infrequent interactions, and loneliness) are modifiable risk factors for cognitive decline. Existing meta-analyses are limited by reporting aggregate responses, a focus on global cognition, and combining social measures into single constructs. We aimed to investigate the association between social connection markers and the rate of annual change in cognition (ie, global and domain-specific), as well as sex differences, using an individual participant data meta-analysis. We harmonised data from 13 longitudinal cohort studies of ageing in North America, South America, Europe, Africa, Asia, and Australia. Studies were eligible for inclusion if they had baseline data for social connection markers and at least two waves of cognitive scores. Follow-up periods ranged from 0 years to 15 years across cohorts. We included participants with cognitive data for at least two waves and social connection data for at least one wave. We then identified and excluded people with dementia at baseline. Primary outcomes were annual rates of change in global cognition and cognitive domain scores over time until final follow-up within each cohort study analysed by use of an individual participant data meta-analysis. Linear mixed models within cohorts used baseline social connection markers as predictors of the primary outcomes. Effects were pooled in two stages using random-effects meta-analyses. We assessed the primary outcomes in the main (partially adjusted) and fully adjusted models. Partially adjusted models controlled for age, sex, and education; fully adjusted models additionally controlled for diabetes, hypertension, smoking, cardiovascular risk, and depression. Of the 40 006 participants in the 13 cohort studies, we excluded 1392 people with dementia at baseline. 38 614 individual participants were included in our analyses. For the main models, being in a relationship or married predicted slower global cognitive decline (b=0·010, 95% CI 0·000-0·019) than did being single or never married; living with others predicted slower global cognitive (b=0·007, 0·002-0·012), memory (b=0·017, 0·006-0·028), and language (b=0·008, 0·000-0·015) decline than did living alone; and weekly interactions with family and friends (b=0·016, 0·006-0·026) and weekly community group engagement (b=0·030, 0·007-0·052) predicted slower memory decline than did no interactions and no engagement. Never feeling lonely predicted slower global cognitive (b=0·047, 95% CI 0·018-0·075) and executive function (b=0·047, 0·017-0·077) decline than did often feeling lonely. Degree of social support, having a confidante, and relationship satisfaction did not predict cognitive decline across global cognition or cognitive domains. Heterogeneity was low (I2=0·00-15·11%) for all but two of the significant findings (association between slower memory decline and living with others [I2=58·33%] and community group engagement, I2=37·54-72·19%), suggesting robust results across studies. Good social connections (ie, living with others, weekly community group engagement, interacting weekly with family and friends, and never feeling lonely) are associated with slower cognitive decline. EU Joint Programme-Neurodegenerative Disease Research grant, funded by the National Health and Medical Research Council Australia, and the US National Institute on Aging of the US National Institutes of Health.


Descending necrotizing mediastinitis: a fatal complication of neglected esophageal foreign body.
Descending necrotising mediastinitis due to a neglected esophageal foreign body is uncommon. It is a lethal disease if it develops with full blown clinical picture. A case is reported of descending necrotising mediastinitis caused by a foreign body in oesophagus which is rarely reported in world literature. It is emphasized that prompt diagnosis and aggressive surgical mediastinal drainage is very important for the survival of these patients. Delayed diagnosis and treatment in our case may have been the cause of death of the patient. Delayed diagnosis in our case is due to the unavailability proper health facility in remote area in developing countries like Nepal.


Perflubron emulsion improves hepatic microvascular integrity and mitochondrial redox state after hemorrhagic shock.
Hemorrhagic shock is associated with decreased systemic oxygen delivery, but also with impaired microvascular perfusion, which can result in diminished local oxygen availability even in the presence of adequate cardiac output after resuscitation. Beside surgical interventions to control blood loss, transfusion of stored packed red blood cells represents the current standard of care in the management of severe hemorrhagic shock. Because stored red blood cells are less deformable and show a higher O2 affinity that affects the O2 off-load to tissues, perfluorocarbon-based artificial oxygen carriers might improve local O2 delivery under these conditions. To test this, rats were subjected to hemorrhagic shock (1 h, mean arterial pressure [MAP] 30-35 mmHg) and were resuscitated with fresh whole blood, pentastarch, stored red blood cells, perflubron emulsion (2.7 and 5.4 g/kg body weight) together with pentastarch, or stored red blood cells together with 2.7 g/kg perflubron emulsion. Hepatic microcirculation, tissue oxygenation, and mitochondrial redox state were investigated by intravital microscopy. In addition, hepatocellular function and liver enzyme release were determined. After hemorrhagic shock and resuscitation with perflubron emulsion, volumetric sinusoidal blood flow was significantly increased compared with resuscitation with stored red blood cells. Furthermore, resuscitation with perflubron emulsion resulted in higher hepatic tissue PO2 and normalized mitochondrial redox potential, which was accompanied by lessened hepatocellular injury as well as improved liver function. These results indicate that, in this model of hemorrhagic shock, asanguineous fluid resuscitation with addition of perflubron emulsion is superior to stored blood or pentastarch alone with respect to increased local O2 availability on the cellular level. This effect is primarily due to improved restoration of hepatic microcirculatory integrity.


Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation.
Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl](2)/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.


Prognostic factors for outcome in patients with refractory and relapsed acute lymphocytic leukemia treated with inotuzumab ozogamicin, a CD22 monoclonal antibody.
Inotuzumab ozogamicin was found to be highly active in patients with refractory-relapsed acute lymphocytic leukemia (ALL), with an overall response rate of 58% and a median survival of 6.3 months. Identifying factors associated with different outcomes on inotuzumab therapy may help select patients for this treatment and advice of prognosis. A total of 89 patients treated with inotuzumab on previous studies were analyzed. Inotuzumab was given at 1.3-1.8 mg/m(2) intravenously (IV) × 1 every 3-4 weeks or weekly (0.8 mg/m(2) day 1, 0.5 mg/m(2) days 8 and 15) every 3-4 weeks. Pretreatment factors associated with achieving marrow complete response (CR) and with survival were analyzed using standard statistical methods. The median survival of patients with at least marrow CR was 9.2 months versus 3.4 months for those without marrow CR (P < 0.001). By multivariate analysis, a high peripheral blood absolute blast count and low platelet count were independently associated with a lower likelihood of achieving at least marrow CR. Baseline characteristics independently associated with worse survival included adverse cytogenetics [complex karyotype, translocation (4;11), translocation (9;22), abnormal chromosome 17], disease beyond first salvage, and high peripheral blood absolute count. Patients with 0, 1-2, or 3 adverse factors had a median survival of 39+, 7.5, and 2.4 months, respectively. Our current analyses identified a subset of adult patients with ALL in whom outcome of therapy with inotuzumab ozogamicin can be differentially predicted.


Copper(II) bromide and copper(II) acetate complexes of 4,4'-(p-phenylene)bipyridazine.
4,4'-(p-Phenylene)bipyridazine, C(14)H(10)N(4), (I), and the coordination compounds catena-poly[[dibromidocopper(II)]-mu-4,4'-(p-phenylene)bipyridazine-kappa(2)N(2):N(2')], [CuBr(2)(C(14)H(10)N(4))](n), (II), and catena-poly[[[tetrakis(mu-acetato-kappa(2)O:O')dicopper(II)]-mu-4,4'-(p-phenylene)bipyridazine-kappa(2)N(1):N(1')] chloroform disolvate], {[Cu(2)(C(2)H(3)O(2))(4)(C(14)H(10)N(4))].2CHCl(3)}(n), (III), contain a new extended bitopic ligand. The combination of the p-phenylene spacer and the electron-deficient pyridazine rings precludes C-H...pi interactions between the lengthy aromatic molecules, which could be suited for the synthesis of open-framework coordination polymers. In (I), the molecules are situated across a center of inversion and display a set of very weak intermolecular C-H...N hydrogen bonds [3.399 (3) and 3.608 (2) A]. In (II) and (III), the ligand molecules are situated across a center of inversion and act as N(2),N(2')-bidentate [in (II)] and N(1),N(1')-bidentate [in (III)] long-distance bridges between the metal ions, leading to the formation of coordination chains [Cu-N = 2.005 (3) A in (II) and 2.199 (2) A in (III)]. In (II), the copper ion lies on a center of inversion and adopts CuN(2)Br(4) (4+2)-coordination involving two long axial Cu-Br bonds [3.2421 (4) A]. In (III), the copper ion has a tetragonal pyramidal CuO(4)N environment. The uncoordinated pyridazine N atom and two acetate O atoms provide a multiple acceptor site for accommodation of a chloroform solvent molecule by trifurcated hydrogen bonding [C-H...O(N) = 3.298 (5)-3.541 (4) A].


Advances in Applications of Metabolomics in Pluripotent Stem Cell Research.
Stem cells undergo extensive metabolic rewiring during reprogramming, proliferation and differentiation, and numerous studies have demonstrated a significant role of metabolism in controlling stem cell fates. Recent applications of metabolomics, the study of concentrations and fluxes of small molecules in cells, have advanced efforts to characterize and maturate stem cell fates, assess drug toxicity in stem cell tissue models, identify biomarkers, and study the effects of environment on metabolic pathways in stem cells and their progeny. Looking to the future, combining metabolomics with other -omics approaches will provide a deeper understanding of the complex regulatory mechanisms of stem cells.


Pretreatment with β-Boswellic Acid Improves Blood Stasis Induced Endothelial Dysfunction: Role of eNOS Activation.
Vascular endothelial cells play an important role in modulating anti-thrombus and maintaining the natural function of vascular by secreting many active substances. β-boswellic acid (β-BA) is an active triterpenoid compound from the extract of boswellia serrate. In this study, it is demonstrated that β-BA ameliorates plasma coagulation parameters, protects endothelium from blood stasis induced injury and prevents blood stasis induced impairment of endothelium-dependent vasodilatation. Moreover, it is found that β-BA significantly increases nitric oxide (NO) and cyclic guanosine 3', 5'-monophosphate (cGMP) levels in carotid aortas of blood stasis rats. To stimulate blood stasis-like conditions in vitro, human umbilical vein endothelial cells (HUVECs) were exposed to transient oxygen and glucose deprivation (OGD). Treatment of β-BA significantly increased intracellular NO level. Western blot and immunofluorescence as well as immunohistochemistry reveal that β-BA increases phosphorylation of enzyme nitric oxide synthase (eNOS) at Ser1177. In addition, β-BA mediated endothelium-dependent vasodilatation can be markedly blocked by eNOS inhibitor L-NAME in blood stasis rats. In OGD treated HUEVCs, the protective effect of β-BA is attenuated by knockdown of eNOS. In conclusion, the above findings provide convincing evidence for the protective effects of β-BA on blood stasis induced endothelial dysfunction by eNOS signaling pathway.


Vascular responses to leukotriene B4, C4 and D4 following FPL 55712, indomethacin, saralasin, phentolamine and verapamil in the conscious rat.
The pressor and vascular permeability effects of leukotrienes B4 (LTB4), C4 and D4 were investigated in conscious unrestrained rats. Leukotrienes C4 and D4 (3.2-51 nmol kg-1 i.v.) caused an acute dose-dependent elevation of the mean arterial pressure, which was maximal after 2 min and returned to control levels within 14 min. Heart rate was significantly reduced by the higher doses of LTC4 and LTD4. LTB4 (up to a dose of 51 nmol kg-1) was essentially inactive. These effects of LTC4 and LTD4 were abolished by FPL 55712, a putative antagonist of sulphidopeptide leukotrienes and by verapamil, a calcium channel blocker. Indomethacin, phentolamine or saralasin pretreatment failed to modify the pressor response to LTC4 and LTD4. LTC4 and LTD4 furthermore caused an increase in haematocrit values, which was significantly attenuated by FPL 55712, indomethacin and verapamil. The present findings show that the pressor effect of LTC4 and LTD4 is not related to prostanoid release and can be reversed by calcium channel blockade; whereas the effect on vascular permeability seems to require the presence of both cyclo-oxygenase product(s) and calcium.


DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers.
In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.


Intravascular perfusion of carbon black ink allows reliable visualization of cerebral vessels.
The anatomical structure of cerebral vessels is a key determinant for brain hemodynamics as well as the severity of injury following ischemic insults. The cerebral vasculature dynamically responds to various pathophysiological states and it exhibits considerable differences between strains and under conditions of genetic manipulations. Essentially, a reliable technique for intracranial vessel staining is essential in order to study the pathogenesis of ischemic stroke. Until recently, a set of different techniques has been employed to visualize the cerebral vasculature including injection of low viscosity resin, araldite F, gelatin mixed with various dyes (i.e. carmine red, India ink) or latex with or without carbon black. Perfusion of white latex compound through the ascending aorta has been first reported by Coyle and Jokelainen. Maeda et al. have modified the protocol by adding carbon black ink to the latex compound for improved contrast visualization of the vessels after saline perfusion of the brain. However, inefficient perfusion and inadequate filling of the vessels are frequently experienced due to high viscosity of the latex compound. Therefore, we have described a simple and cost-effective technique using a mixture of two commercially available carbon black inks (CB1 and CB2) to visualize the cerebral vasculature in a reproducible manner. We have shown that perfusion with CB1+CB2 in mice results in staining of significantly smaller cerebral vessels at a higher density in comparison to latex perfusion. Here, we describe our protocol to identify the anastomotic points between the anterior (ACA) and middle cerebral arteries (MCA) to study vessel variations in mice with different genetic backgrounds. Finally, we demonstrate the feasibility of our technique in a transient focal cerebral ischemia model in mice by combining CB1+CB2-mediated vessel staining with TTC staining in various degrees of ischemic injuries.


[Ileal leiomyosarcoma presenting with an episode of acute massive intestinal bleeding].
The aim of this article was to present a case of gastrointestinal stromal tumour (GIST) presenting with acute intestinal bleeding. The Authors outline the histogenetic, clinical, diagnostic and prognostic profile of this pathology. Technical progress in immuno-histochemical and ultrastructural diagnostics has made possible to go beyond the old definition of gastrointestinal stromal tumours and identify several subgroups of such tumours on the basis of nervous and/or muscular phenotypic differentiation. The histopathological and structural variety of GIST accounts for their different clinical manifestations and variable and unpredictable biological behaviour. Histological criteria are by no means of absolute value: tumours considered benign on the basis of histology may present a malignant behaviour in the course of time, with the development of metastases and recurrences. In this regard, a number of predictive malignancy indices have been identified such as the patient's age, tumour size, presence of haemorrhage and necrotic areas, high mitotic index (> 5 mitoses/50 HFP), and kit-gene mutations. The Authors stress the diagnostic importance of 99m Tc-RBC scintigraphy in the case reported and agree with the literature as to the appropriate therapy, consisting in intestinal resection. The therapy of active GIST is essentially surgical and consists in resection of the intestinal tract affected by the tumour: lymphadenectomy must be performed only in case of need, because GIST metastasis preferably via the blood stream. As far as therapy is concerned, the demonstration of kit-gene mutation, expressed by the more aggressive forms, has made it possible to produce an inhibitor of protein tyrosine kinase Ber-Abl, which causes selective inhibition of cellular proliferation both in vitro and in vivo and induces apoptosis of Ber-Abl positive cell lines.