Wnt5a promotes human colon cancer cell migration and invasion but does not augment intestinal tumorigenesis in Apc1638N mice.
Whereas aberrant activation of canonical Wnt/β-catenin signaling underlies the majority of colorectal cancer cases, the contribution of non-canonical Wnt signaling is unclear. As enhanced expression of the most extensively studied non-canonical Wnt ligand WNT5A is observed in various diseases including colon cancer, WNT5A is gaining attention nowadays. Numerous in vitro studies suggest modulating capacities of WNT5A on proliferation, differentiation, migration and invasion, affecting tumor and non-mutant cells. However, a possible contribution of WNT5A to colorectal cancer remains to be elucidated. We have analyzed WNT5A expression in colorectal cancer profiling data sets, altered WNT5A expression in colon cancer cells and used our inducible Wnt5a transgenic mouse model to gain more insight into the role of WNT5A in intestinal cancer. We observed that increased WNT5A expression is associated with poor prognosis of colorectal cancer patients. WNT5A knockdown in human colon cancer cells caused reduced directional migration, deregulated focal adhesion site formation and reduced invasion, whereas Wnt5a administration promoted the directional migration of colon cancer cells. Despite these observed protumorigenic activities of WNT5A, the induction of Wnt5a expression in intestinal tumors of Apc1638N mice was not sufficient to augment malignancy or metastasis by itself. In conclusion, WNT5A promotes adhesion sites to form in a focal fashion and promotes the directional migration and invasion of colon cancer cells. Although these activities appear insufficient by themselves to augment malignancy or metastasis in Apc1638N mice, they might explain the poor colon cancer prognosis associated with enhanced WNT5A expression.


Accuracy, precision, usability, and cost of free chlorine residual testing methods.
Chlorine is the most widely used disinfectant worldwide, partially because residual protection is maintained after treatment. This residual is measured using colorimetric test kits varying in accuracy, precision, training required, and cost. Seven commercially available colorimeters, color wheel and test tube comparator kits, pool test kits, and test strips were evaluated for use in low-resource settings by: (1) measuring in quintuplicate 11 samples from 0.0-4.0 mg/L free chlorine residual in laboratory and natural light settings to determine accuracy and precision; (2) conducting volunteer testing where participants used and evaluated each test kit; and (3) comparing costs. Laboratory accuracy ranged from 5.1-40.5% measurement error, with colorimeters the most accurate and test strip methods the least. Variation between laboratory and natural light readings occurred with one test strip method. Volunteer participants found test strip methods easiest and color wheel methods most difficult, and were most confident in the colorimeter and least confident in test strip methods. Costs range from 3.50-444 USD for 100 tests. Application of a decision matrix found colorimeters and test tube comparator kits were most appropriate for use in low-resource settings; it is recommended users apply the decision matrix themselves, as the appropriate kit might vary by context.


Identification and Characterization of a 25 kDa Protein That Is Indispensable for the Efficient Saccharification of Eisenia bicyclis in the Digestive Fluid of Aplysia kurodai.
The digestive fluid of the sea hare Aplysia kurodai can liberate approximately 2.5 mg of glucose from 10 mg of dried Eisenia bicyclis powder. Although laminaran, a major storage polysaccharide in E. bicyclis, is easily digested to glucose by the synergistic action of the 110 and 210 kDa A. kurodai β-glucosidases (BGLs), glucose is not liberated from E. bicyclis by direct incubation with these BGLs. To clarify this discrepancy, we searched for an Eisenia hydrolysis enhancing protein (EHEP) in the digestive fluid of A. kurodai. A novel 25 kDa protein that enhances E. bicyclis saccharification by β-glucosidases was purified to a homogeneous state from the digestive fluid of A. kurodai, and its cDNA was cloned from total cDNAs reverse-transcribed from hepatopancreas total RNA. The E. bicyclis extract strongly inhibited BGLs, suggesting some compound within this brown alga functioned as a feeding deterrent. However, when E. bicyclis was incubated with BGLs in the presence of EHEP, glucose production was markedly increased. As E. bicyclis is rich in phlorotannin, which are only found in brown algae, our study suggested that these compounds are the main BGL inhibitors in E. bicyclis extract. EHEP protects BGLs from phlorotannin inhibition by binding to phlorotannins and forming an insoluble complex with phloroglucinol and phlorotannins. These findings indicated that EHEP plays a key role in the saccharification of brown seaweeds containing phlorotannins in the digestive fluid of A. kurodai. This is the first report of EHEP as a phlorotannin-binding protein that protects BGLs from inhibition.


Particularities of Renal Manifestations in Chronic Viral Hepatitis.
Chronic viral hepatitis represent major health problems worldwide, with an evolution that is sometimes marked by a series of extrahepatic manifestations. Among these, kidney disease may occur, either as glomerulonephritis, and/or renal dysfunction. The purpose of this study was to achieve a complete assessment of the liver and kidney function in a series of patients diagnosed with chronic viral hepatitis, in order to identify a possible kidney disease in this context. 104 patients with chronic viral hepatitis B and C, aged between 25 and 80, were included in the study. These patients were assessed by a series of tests that allowed us to perform a complete evaluation of both liver and kidney function: liver cytolysis enzymes, serum bilirubin, markers of cholestasis, markers of viral infection, urinalysis, albuminuria, electrophoresis of urinary proteins, urea, creatinine, and abdominal ultrasound. Glomerular injury was a rare finding in patients with chronic hepatitis. Patients with chronic hepatitis B had glomerular disease in 5,88 % of cases, while 10 % of the patients with hepatitis C presented this type of renal disease. Acute kidney injury was not identified in our patient group. None of the patients in the hepatitis B study group presented chronic kidney disease. CKD was present in two patients with chronic hepatitis C that had no other associated conditions.


Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation.
The histone variant H3.3 is enriched at enhancers and active genes, as well as repeat regions such as telomeres and retroelements, in mouse embryonic stem cells (mESCs)1-3. Although recent studies demonstrate a role for H3.3 and its chaperones in establishing heterochromatin at repeat regions4-8, the function of H3.3 in transcription regulation has been less clear9-16. Here, we find that H3.3-specific phosphorylation17-19 stimulates activity of the acetyltransferase p300 in trans, suggesting that H3.3 acts as a nucleosomal cofactor for p300. Depletion of H3.3 from mESCs reduces acetylation on histone H3 at lysine 27 (H3K27ac) at enhancers. Compared with wild-type cells, those lacking H3.3 demonstrate reduced capacity to acetylate enhancers that are activated upon differentiation, along with reduced ability to reprogram cell fate. Our study demonstrates that a single amino acid in a histone variant can integrate signaling information and impact genome regulation globally, which may help to better understand how mutations in these proteins contribute to human cancers20,21.


Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea.
Non-specific beneficial as well as deleterious effects of childhood immunizations have been reported in areas of high mortality. This study aimed to determine the effects of diphtheria-tetanus-whole-cell-pertussis (DTP), BCG, hepatitis B, and measles vaccines on mortality in the highlands of Papua New Guinea (PNG). Demographic events for children born in 1989-1994 who were under monthly demographic surveillance in Tari were recorded from birth until age 2 years, out-migration, death, or the end of the study period. Data on BCG, hepatitis B, DTP, measles and pneumococcal polysaccharide vaccination were collected monthly from clinic records. To allow for different characteristics of immunized and non-immunized children, analysis included conditioning on a propensity score for vaccination, adjusting for differences in children's background characteristics. In all, 101/3502 children (3%) who had at least one vaccine died between ages 29 days and 24 months were compared to 112/546 (21%) who had none. BCG was associated with lower mortality in the 1-5 month age group (hazard ratio [HR] = 0.17, 95% CI: 0.09, 0.34), measles vaccine with lower mortality at age 6-11 months (HR = 0.42, 95% CI: 0.17, 1.01), and pneumococcal polysaccharide vaccine with lower mortality at age 12-23 months (HR = 0.42, 95% CI: 0.19, 0.93). One or more doses of DTP was associated with lower overall mortality (HR = 0.27, 95% CI: 0.16, 0.44), particularly in the 1-5 month age group (HR = 0.19, 95% CI: 0.10, 0.34), and also in those who had had prior BCG (HR = 0.45, 95% CI: 0.22, 0.91). Routine immunizations are effective in reducing overall mortality in young children in an area of high mortality. In particular, DTP, whether considered separately or in addition to BCG, was associated with a lowering of overall mortality, in contrast to findings reported from Guinea-Bissau.


Genetic characterization of canine parvovirus from dogs in Pakistan.
Canine parvoviruses (CPV) exist as antigenic variants with varying frequencies and genetic variabilities across the globe. Given the endemicity and high prevalence in Pakistan, we characterized the CPVs originating from dogs-population to elucidate viral diversity and evolution. Fecal samples from clinically diseased pups (n = 17) of different breeds and age (2-6 months) were processed for hemagglutination assay (HA), and later for partial amplification of VP2 gene sequence and amino acid analysis. A total of 11 samples (64.71%) were found positive both in hemagglutination and PCR assays. Phylogenetic and evolutionary analysis demonstrated higher genetic heterogeneity in studied strains and constituted seven clusters within the CPV-2a group, however, they shared high level of identity with Chinese strains. Further studies are necessary to elucidate genetic analysis and epidemiology of CPV variants across a wide geographical area of the country.


Enhanced Thrombolysis by Ultrasound-Assisted Catheter-Directed Thrombolysis and Microbubbles in an In Vitro Model of Iliofemoral Deep Vein Thrombosis.
There is a need to improve the efficacy and safety of catheter-directed thrombolysis (CDT) for thrombo-occlusive diseases, and ultrasound-assisted CDT (USAT) is a promising approach. We tested if thrombolysis efficacy of USAT can be improved by adding gaseous microbubbles (MB). We developed an in vitro dynamic overflow model for iliofemoral deep vein thrombosis, and added MB to an USAT system with ultrasound energy and dose of tissue plasminogen activator according to clinical practice. A total of 64 clots (mean baseline weight of 8.23 ± 1.12 g, generated from citrated human whole blood from 7 healthy male volunteers) were randomly assigned to 1 of 4 study protocols of 30 minutes' duration: negative control, CDT, USAT, and USAT + MB.Thrombolysis efficacy was assessed by measuring the change in D-dimer levels in the overflow liquid and the percentage of clot weight reduction. Compared to negative control, change in D-dimer increased by 62% (p = 0.017), 128% (p = 0.002), and 177% (p < 0.001) in the CDT, USAT, and USAT + MB groups, respectively. D-dimer increase was greater in the USAT than in the CDT group (p = 0.014), and greater in the USAT + MB than in the USAT group (p = 0.033). Compared to negative control, percentage of clot weight reduction increased by 123% (p = 0.016), 154% (p = 0.002), and 233% (p < 0.001) in the CDT, USAT, and USAT + MB groups, respectively. Percentage of clot weight reduction was greatest in the USAT + MB group (p < 0.05 compared with all other groups). In conclusion, our in vitro study suggests that the thrombolytic efficacy of USAT in human whole blood clots can be improved by local administration of MB.


Role of endogenous prostaglandins in gastric secretion and mucosal defense.
Prostaglandins are found in high concentration in the gastric mucosa and gastric juice. Exogenous prostaglandins inhibit acid secretion, stimulate mucus and bicarbonate secretion, alter mucosal blood flow, and provide dramatic protection against a wide variety of agents which cause acute mucosal damage. The physiological role of prostaglandins is still being elucidated. There is now strong evidence that endogenous prostaglandins modulate acid secretion by blocking the histamine-stimulated increase in cyclic AMP within the parietal cell. This function is probably controlled by intraluminal pH. It is likely that mucus and bicarbonate secretion by both stomach and duodenum are influenced by endogenous prostaglandins. A physiological role of prostaglandins in mucosal protection is less certain. Prostaglandins are released by trivial injury, and this probably serves a defensive function. A mucosa which is prostaglandin-depleted is more susceptible to damage, but does not spontaneously ulcerate. It is conceivable that peptic ulcer disease may be in part caused by an impaired mucosal prostaglandin response to food.


Unique reactivity of alpha,beta-unsaturated carboxylic acid imidazolides: catalytic asymmetric synthesis of alpha,beta-epoxy esters and alpha,beta-epoxy carboxylic acid derivatives.
Catalytic asymmetric synthesis of alpha,beta-epoxy esters and alpha,beta-epoxy carboxylic acid derivatives is described. Catalytic asymmetric epoxidation of alpha,beta-unsaturated carboxylic acid imidazolides using La-BINOL-Ph(3)As=O complex gave the corresponding alpha,beta-epoxy peroxy tert-butyl esters, which were directly converted to the alpha,beta-epoxy methyl esters by adding methanol to the reaction. This catalytic system had broad generality for epoxidation of various substrates. With the use of 5-10 mol% of the catalyst, both beta-aryl and beta-alkyl-substituted-alpha,beta-epoxy methyl esters were obtained in up to 91% yield and in up to 93% enantiomeric excess. In addition, efficient transformations of alpha,beta-epoxy peroxy tert-butyl esters into the alpha,beta-epoxy amides, alpha,beta-epoxy aldehydes, and gamma,delta-epoxy beta-keto esters are also reported.


Coinfection of individual leukocytes with human cytomegalovirus and human immunodeficiency virus is a rare event in vivo.
Infection with the human cytomegalovirus (HCMV) accelerates disease progression in human immunodeficiency virus 1 (HIV-1)-infected individuals. This has been attributed to the transaction of HIV-1 gene expression by HCMV gene products. For transactivation to be effective in vivo both viruses must be present in the same cell. We therefore examined blood samples from 13 HIV-1-infected patients with HCMV viremia for coinfection of individual leukocytes. In four of the patients lymph nodes were also examined. Multiple samples contained defined numbers (between 10 and 1000) of CD4+ lymphocytes or CD14+ monocytes were sorted by a FACS-based automated cell deposition unit. Samples were then analysed by a multiplex nested polymerase chain reaction, which can detect simultaneously HCMV and HIV DNA. The percentage of infected cells was calculated for each virus using the Poisson distribution. Between 0.43% and 6.2% of the CD4+ lymphocytes were infected with HIV and less than 0.15% with HCMV. The level of infection in CD14+ monocytes was always < or = 0.11% for HIV and ranged between < 0.05% and 0.58% for HCMV. Only seven of 1030 sorted samples from blood were positive for both viruses. In lymphnodes, none of the 144 samples tested were double-positive. This clearly shows that coinfection of individual human leukocytes with HIV and HCMV is a very rare event in vivo. Therefore, direct transactivation of HIV by HCMV in coinfected cells obtained from blood and lymphnodes may not explain the effect of HCMV on the prognosis of HIV-infected individuals.


Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding.
Myocardial infarction and stroke are caused by blood clots forming over a ruptured or denuded atherosclerotic plaque (atherothrombosis). Production of prostaglandin E(2) (PGE(2)) by an inflamed plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. Platelets express multiple G-protein coupled receptors, including receptors for ADP and PGE(2). ADP can mobilize Ca(2+) and through the P(2)Y(12) receptor can inhibit cAMP production, causing platelet activation and aggregation. Clopidogrel (Plavix), a selective P(2)Y(12) antagonist, prevents platelets from clotting but thereby increases the risk of severe or fatal bleeding. The platelet EP(3) receptor for PGE(2), like the P(2)Y(12) receptor, also inhibits cAMP synthesis. However, unlike ADP, facilitation of platelet aggregation via the PGE(2)/EP(3) pathway is dependent on co-agonists that can mobilize Ca(2+). We used a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP(3) antagonists. We show that DG-041, a selective EP(3) antagonist, inhibits PGE(2) facilitation of platelet aggregation in vitro and ex vivo. PGE(2) can resensitize platelets to agonist even when the P(2)Y(12) receptor has been blocked by clopidogrel, and this can be inhibited by DG-041. Unlike clopidogrel, DG-041 does not affect bleeding time in rats, nor is bleeding time further increased when DG-041 is co-administered with clopidogrel. This indicates that EP(3) antagonists potentially have a superior safety profile compared to P(2)Y(12) antagonists and represent a novel class of antiplatelet agents.


Melt-processable hydrophobic acrylonitrile-based copolymer systems with adjustable elastic properties designed for biomedical applications.
Acrylonitrile-based polymer systems (PAN) are comprehensively explored as versatile biomaterials having various potential biomedical applications, such as membranes for extra corporal devices or matrixes for guided skin reconstruction. The surface properties (e.g. hydrophilicity or charges) of such materials can be tailored over a wide range by variation of molecular parameters such as different co-monomers or their sequence structure. Some of these materials show interesting biofunctionalities such as capability for selective cell cultivation. So far, the majority of AN-based copolymers, which were investigated in physiological environments, were processed from the solution (e.g. membranes), as these materials are thermo-sensitive and might degrade when heated. In this work we aimed at the synthesis of hydrophobic, melt-processable AN-based copolymers with adjustable elastic properties for preparation of model scaffolds with controlled pore geometry and size. For this purpose a series of copolymers from acrylonitrile and n-butyl acrylate (nBA) was synthesized via free radical copolymerisation technique. The content of nBA in the copolymer varied from 45 wt% to 70 wt%, which was confirmed by 1H-NMR spectroscopy. The glass transition temperatures (Tg) of the P(AN-co-nBA) copolymers determined by differential scanning calorimetry (DSC) decreased from 58 degrees C to 20 degrees C with increasing nBA-content, which was in excellent agreement with the prediction of the Gordon-Taylor equation based on the Tgs of the homopolymers. The Young's modulus obtained in tensile tests was found to decrease significantly with rising nBA-content from 1062 MPa to 1.2 MPa. All copolymers could be successfully processed from the melt with processing temperatures ranging from 50 degrees C to 170 degrees C, whereby thermally induced decomposition was only observed at temperatures higher than 320 degrees C in thermal gravimetric analysis (TGA). Finally, the melt processed P(AN-co-nBA) biomaterials were sterilized with ethylene oxide and tested for cytotoxicity in direct contact tests with L929 cells according to the EN DIN ISO standard 10993-5. All tested samples exhibited non-toxic effects on the functional integrity of the cell membrane and the mitochondrial activity. However, the morphology of the cells on the samples was different from that observed on polystyrene as control, indicating slightly cytotoxic effects according to the evaluation guide of the US Pharmacopeial Convention. Thus, the melt-processable, hydrophobic P(AN-co-nBA) copolymers with adjustable mechanical properties are promising candidates for in vitro investigations of tissue growth kinetics.


Cross sectional study to determine chloroquine resistance among Plasmodium falciparum clinical isolates from Khartoum, Sudan.
Background: Malaria continues to present a global health threat; the World Health Organization (WHO) reported 214 million cases of malaria by the year 2015 with a death rate of 438000. Sudan is endemic to malaria with over 95% of malaria cases due to Plasmodium falciparum. Chloroquine is a well-established drug in the treatment of P. falciparum malaria although its use has declined since its introduction as the drug of choice in treatment of malaria in Sudan. The mechanism of resistance has been attributed to mutations in P. falciparum Chloroquine resistance transporter gene coding for a key food vacuole proteins. In current study we aimed at verifying the genetic cause of resistance to Chloroquine in field isolates of P. falciparum. Methods: Twenty P. falciparum cases were diagnosed from East Nile hospital in Khartoum and recruited in the investigation. Nested PCR was conducted to isolate mutation region in the PfCRT gene and the amplicons were sequenced using Sanger sequencing technique (Macrogen, Soule Korea). Results: 16/20 (80%) of the field isolates contained base pair mutation of codon 76 in the pfcrt gene thus being resistant to chloroquine treatment and only 4/20 (20%) did not contain such mutation. Conclusions: High treatment failures associated with Chloroquine treatment is evident of the high prevalence of mutant strains of P. falciparum field isolates thus suggesting the reduced relevance of Chloroquine as a treatment choice in the management of P. falciparum malaria.


Abdominal aortic calcification in patients newly diagnosed with essential thrombocythemia.
: Although atherosclerosis is likely to be involved in the development of arterial thrombotic events in patients with essential thrombocythemia (ET), abdominal aortic calcification (AAC) has rarely been investigated. We evaluated the prevalence and clinical relevance of AAC at the time of ET diagnosis. : This retrospective study included patients newly diagnosed with ET who underwent abdominal computed tomography (CT) at the time of diagnosis between January 2002 and December 2021 at Chungnam National University Hospital, Daejeon, Korea. CT images were reviewed and an aortic calcification score was assigned. : Of the 94 patients (median age, 62 yr; range, 18-90 yr), AAC was detected in 62 (66.0%). AAC was most commonly mild (33.0%), followed by moderate (22.7%) and severe (5.3%). Old age [odds ratio (OR)=34.37, 95% confidence interval (CI)=12.32-95.91, P<0.001] was an independent risk factor for AAC. The patients with AAC had a higher WBC count (11.8±4.7 vs. 9.7±2.9×109/L, P=0.017), higher neutrophil-to-lymphocyte ratio (4.3±2.7 vs. 3.1±1.5, P=0.039), and higher JAK2V617F positivity (81.5% vs. 58.8%, P=0.020) compared to those without AAC. AAC was an independent risk factor for arterial thrombotic vascular events that occurred before or at diagnosis of ET (OR=4.12, 95% CI=1.11-15.85, P=0.034). : AAC is common in patients with ET and is associated with arterial thrombotic events.


The added value of water footprint assessment for national water policy: a case study for Morocco.
A Water Footprint Assessment is carried out for Morocco, mapping the water footprint of different activities at river basin and monthly scale, distinguishing between surface- and groundwater. The paper aims to demonstrate the added value of detailed analysis of the human water footprint within a country and thorough assessment of the virtual water flows leaving and entering a country for formulating national water policy. Green, blue and grey water footprint estimates and virtual water flows are mainly derived from a previous grid-based (5 × 5 arc minute) global study for the period 1996-2005. These estimates are placed in the context of monthly natural runoff and waste assimilation capacity per river basin derived from Moroccan data sources. The study finds that: (i) evaporation from storage reservoirs is the second largest form of blue water consumption in Morocco, after irrigated crop production; (ii) Morocco's water and land resources are mainly used to produce relatively low-value (in US$/m3 and US$/ha) crops such as cereals, olives and almonds; (iii) most of the virtual water export from Morocco relates to the export of products with a relatively low economic water productivity (in US$/m3); (iv) blue water scarcity on a monthly scale is severe in all river basins and pressure on groundwater resources by abstractions and nitrate pollution is considerable in most basins; (v) the estimated potential water savings by partial relocation of crops to basins where they consume less water and by reducing water footprints of crops down to benchmark levels are significant compared to demand reducing and supply increasing measures considered in Morocco's national water strategy.


Strategies of patient care in acute coronary syndromes: rationale for the Global Registry of Acute Coronary Events (GRACE) registry.
An abundance of evidence is available from large, randomized clinical trials supporting the efficacy of therapies for the management of patients with acute coronary syndromes. For ST-segment elevation myocardial infarction (MI), a variety of databases can be used to assess how these therapies, both pharmacologic and invasive, are being integrated into real practice. Little information is available, however, with regard to how newer treatments are actually being implemented for patients with unstable angina and non-ST-segment elevation MI. There are several important issues to consider in evaluating current treatment practices for acute coronary syndromes, including limitations of clinical trial databases, a trend toward progressive shortening of length of hospital stay, and variations in the availability of resources among treatment centers. In response to the need for a broader database that would address the global impact of clinical management practices in acute coronary syndromes, the Global Registry of Acute Coronary Events (GRACE) Registry has been established. The GRACE Registry will initially collect data on patient care from a variety of treatment centers in 14 countries, the plan being to eventually enroll 10,000 patients per year. This international observational database will obtain information on the complete spectrum of acute coronary syndromes, with the specific goals of describing diagnostic and treatment strategies, determining hospital outcomes, improving quality of care, and developing hypotheses for future clinical research.


Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction.
Serum and glucocorticoid inducible kinase 1 (SGK1) plays a pivotal role in early angiogenesis during embryonic development. In this study, we sought to define the SGK1 downstream signalling pathways in the adult heart and to elucidate their role in cardiac neo-angiogenesis and wound healing after myocardial ischemia. To this end, we employed a viable SGK1 knockout mouse model generated in a 129/SvJ background. Ablation of SGK1 in these mice caused a significant decrease in phosphorylation of SGK1 target protein NDRG1, which correlated with alterations in NF-κB signalling and expression of its downstream target protein, VEGF-A. Disruption of these signalling pathways was accompanied by smaller heart and body size. Moreover, the lack of SGK1 led to defective endothelial cell (ECs) migration and tube formation in vitro, and increased scarring with decreased angiogenesis in vivo after myocardial infarct. This study underscores the importance of SGK1 signalling in cardiac neo-angiogenesis and wound healing after an ischemic insult in vivo.


[Biphasic action of caffeine on contractile activity of frog myocardium].
Action of caffeine on the isometric contractions and intracellular potentials of the frog heart muscle involved the positive inotropic effect only at high concentrations (0.1-20 mM). The "dose-action" curve for the twitch responses reached plateau at caffeine concentration higher than 4 mM. Two phases of the caffeine effect on the frog myocardium contractility were identified: transient increase of the contraction amplitude (the 1st phase) was followed by the inhibition of contractions and shortening of the APs (the 3nd phase). The magnitude of the contractile changes and the duration of each phase depended on the caffeine concentration.


Immediate effects of 2 types of braces on pain and grip strength in people with lateral epicondylalgia: a randomized controlled trial.
Repeated-measures, crossover, double-blinded randomized controlled trial. To compare the immediate effectiveness of 2 types of counterforce braces in improving pain-free grip strength, pressure pain threshold, and wrist angle during a gripping task in individuals with lateral epicondylalgia. Sports medicine management of lateral epicondylalgia often includes application of a counterforce brace, but the comparative effectiveness of different braces is unclear. The most common brace design consists of a single strap wrapped around the proximal forearm. A variation of this brace is the use of an additional strap that wraps above the elbow, which aims to provide further unloading to the injured tissue. Pain-free grip strength, pressure pain threshold, and wrist angle during a gripping task were measured on 34 participants with a clinical diagnosis of lateral epicondylalgia (mean ± SD age, 47.8 ± 8.5 years). Measurements were made without a brace, as well as immediately before and after the application of 2 types of counterforce braces. Each condition was tested during a separate session, with a minimum of 48 hours between sessions. Analysis-of-variance models were used to test the differences within and between conditions. Pain-free grip strength (17.2 N; 95% confidence interval: 7.5, 26.8) and pressure pain threshold (42.2 kPa; 95% confidence interval: 16.5, 68.0) significantly improved on the affected side immediately following the intervention conditions as well as the control condition. There was no significant difference between braces or the control condition for any outcome. Both types of counterforce braces had an immediate positive effect in participants with lateral epicondylalgia, without differences between interventions and similar to a no-brace control condition. Therefore, while the use of a brace may be helpful in managing immediate symptoms related to lateral epicondylalgia, the choice of which brace to use may be more a function of patient preference, comfort, and cost. Further research is required to investigate the comparative longer-term and clinical effects of the 2 braces. ACTRN12609000354280 ( www.anzctr.org.au).


Biosynthesis of the defensive alkaloid cicindeloine in Stenus solutus beetles.
To protect themselves from predation and microorganismic infestation, rove beetles of the genus Stenus produce and store bioactive alkaloids like stenusine, 3-(2-methyl-1-butenyl)pyridine, and cicindeloine in their pygidial glands. The biosynthesis of stenusine and 3-(2-methyl-1-butenyl)pyridine was previously investigated in Stenus bimaculatus and Stenus similis, respectively. Both molecules follow the same biosynthetic pathway, where the N-heterocyclic ring is derived from L-lysine and the side chain from L-isoleucine. The different alkaloids are finally obtained by slight modifications of shared precursor molecules. The piperideine alkaloid cicindeloine occurs as a main compound additionally to (E)-3-(2-methyl-1-butenyl)pyridine and traces of stenusine in the pygidial gland secretion of Stenus cicindeloides and Stenus solutus. Feeding of S. solutus beetles with [D,(15)N]-labeled amino acids followed by GC/MS analysis techniques showed that cicindeloine is synthesized via the identical pathway and precursor molecules as the other two defensive alkaloids.


Effectiveness of Implanted Cardiac Rhythm Recorders With Electrocardiographic Monitoring for Detecting Arrhythmias in Pregnant Women With Symptomatic Arrhythmia and/or Structural Heart Disease: A Randomized Clinical Trial.
Arrhythmias are an important cause of maternal morbidity and mortality but remain difficult to diagnose. To compare implantable loop recorder (ILR) plus 24-hour Holter electrocardiographic (ECG) monitoring with standard 24-hour Holter ECG monitoring alone in terms of acceptability, ability to identify significant arrythmias, and effect on management and pregnancy outcome in women who were symptomatic or at high risk of arrythmia because of underlying structural heart disease. This single-center, prospective randomized clinical trial recruited 40 consecutive patients from the Cardiac Disease and Maternity Clinic at Groote Schuur Hospital in Cape Town, South Africa. Pregnant patients with symptoms of arrhythmia and/or structural heart disease at risk of arrhythmia were included. Patients were randomized to standard care (SC; 24-hour Holter ECG monitoring [n = 20]) or standard care plus ILR (SC-ILR; 24-hour Holter ECG monitoring plus ILR [n = 20]). Only 17 consented to ILR insertion, and the 3 who declined ILR were allocated to the SC group. Arrhythmias considered included atrial fibrillation, atrial flutter, premature ventricular complexes, supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation. Among the 40 women in this trial, the mean (SD) age was 28.4 (5.5) years. Holter monitoring detected arrhythmias in 3 of 23 patients (13%) in the SC group and 4 of 17 patients (24%) in the SC-ILR group compared with 9 of 17 patients (53%) patients who had arrhythmias detected by ILR. Seven patients (4 with supraventricular tachycardia, 1 with premature ventricular complexes, and 2 with paroxysmal atrial fibrillation recorded by ILR) did not have arrhythmias detected by 24-hour Holter monitoring. Three of these 7 patients (43%) had a change in management as a result of their ILR recordings. There were no maternal deaths. However, the SC group had a significantly lower mean (SD) gestational stage at delivery (35 [5] weeks vs 38 [2], P = .04). The ILR was better than 24-hour Holter monitoring in detecting arrhythmias, which led to a change in management for a significant proportion of patients. Our findings suggest that ILR may be beneficial for pregnant women at risk of arrhythmia. ClinicalTrials.gov Identifier: NCT02249195.


Natural Herbal Remedy Wumei Decoction Ameliorates Intestinal Mucosal Inflammation by Inhibiting Th1/Th17 Cell Differentiation and Maintaining Microbial Homeostasis.
Evidence has shown that the traditional Chinese herbal medicine Wumei decoction (WMD) has a protective effect on ulcerative colitis. Here, we studied the anti-inflammatory effects and potential mechanisms of WMD on chronic colitis in mice. A dextran sulfate sodium (DSS)-induced chronic colitis model and CD45RBhighCD4+ T cell transfer model were established in mice. Body weight, Disease Activity Index, and colon length were assessed, and histopathology was confirmed by hematoxylin and eosin staining. Colon tissue samples were collected to detect the frequencies of various immune cells, expression of cytokines, and tight junction-related proteins using flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. 16S ribosomal DNA sequencing was performed to distinguish differential microbiota of fecal samples. Severe chronic colitis was observed in mice after DSS exposure and in Rag1-/- mice reconstituted with CD45RBhighCD4+ T cells, as manifested by weight loss, hematochezia, and shortening and thickening of the colon, which were reversed by WMD treatment. WMD markedly suppressed intestinal mucosal CD4+ T cell differentiation and the secretion of proinflammatory cytokines (eg, tumor necrosis factor α, interleukin-1β, interferon γ, and IL-17A) by flow cytometry, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Moreover, WMD promoted the expression of occludin, zonula occludens-1, and E-cadherin, thereby maintaining the epithelial barrier function. Additionally, 16S ribosomal DNA sequencing revealed that WMD regulated the dysbiosis of gut microbiota in CD45RBhighCD4+ T cell-reconstituted Rag1-/- mice, evidenced by an increase of Allobaculum and Bacteroides and a decrease of Ileibacterium. WMD ameliorates chronic colitis in mice induced by DSS or reconstituted with CD45RBhighCD4+ T cells through suppressing Th1/Th17 cell differentiation and the secretion of proinflammatory cytokines, maintaining epithelial barrier function, and improving the dysbiosis.


Cigar and pipe smoking and cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).
The carcinogenicity of cigar and pipe smoking is established but the effect of detailed smoking characteristics is less well defined. We examined the effects on cancer incidence of exclusive cigar and pipe smoking, and in combination with cigarettes, among 102,395 men from Denmark, Germany, Spain, Sweden and the United Kingdom in the EPIC cohort. Hazard ratios (HR) and their 95% confidence intervals (CI) for cancer during a median 9-year follow-up from ages 35 to 70 years were estimated using proportional hazards models. Compared to never smokers, HR of cancers of lung, upper aerodigestive tract and bladder combined was 2.2 (95% CI: 1.3, 3.8) for exclusive cigar smokers (16 cases), 3.0 (2.1, 4.5) for exclusive pipe smokers (33 cases) and 5.3 (4.4, 6.4) for exclusive cigarette smokers (1,069 cases). For each smoking type, effects were stronger in current smokers than in ex-smokers and in inhalers than in non-inhalers. Ever smokers of both cigarettes and cigars [HR 5.7 (4.4, 7.3), 120 cases] and cigarettes and pipes [5.1 (4.1, 6.4), 247 cases] had as high a raised risk as had exclusive cigarette smokers. In these smokers, the magnitude of the raised risk was smaller if they had switched to cigars or pipes only (i.e., quit cigarettes) and had not compensated with greater smoking intensity. Cigar and pipe smoking is not a safe alternative to cigarette smoking. The lower cancer risk of cigar and pipe smokers as compared to cigarette smokers is explained by lesser degree of inhalation and lower smoking intensity.


Nonlinear Moderation Effect of Vagal Regulation on the Link between Childhood Trauma and Adolescent Internalizing and Externalizing Symptoms.
Childhood trauma is a leading early adverse environment that increases psychopathological symptoms. Respiratory sinus arrhythmia (RSA) suppression to challenges as a marker of self-regulation is found to linearly moderate the link between early adverse experiences and psychopathological symptoms, but yielding mixed findings. The present study examined the relationships between childhood trauma and internalizing and externalizing symptoms via a 1.5-year longitudinal design and the quadratic moderation effect of RSA suppression on these relationships among adolescents. In November 2021 (T1), the final sample of 275 Chinese adolescents (Mage = 12.94, SDage = 0.79; 49.82% females) completed the short form of Childhood Trauma Questionnaire and the Achenbach Youth Self-Report-2001 and underwent a speech task during which their baseline RSA and stress exposure RSA were obtained. In June 2023 (T2), 251 adolescents completed the Achenbach Youth Self-Report-2001. Results showed that childhood trauma at T1 was positively correlated with internalizing and externalizing symptoms at T1 and T2. RSA suppression to stress quadratically moderated these associations, such that adolescents with moderate rather than higher or lower RSA suppression had the least internalizing and externalizing symptoms at T1 and T2 when exposed to childhood trauma. The findings suggest that moderate RSA suppression to stress as a marker of optimal vagal regulation buffers the risk of developmental psychopathology from early adverse experiences.


[Total hip arthroplasty in patients under 40 years of age and, if indicated, reconstruction of acetabular defects with bone impaction grafting].
To determine the long-term results of primary cemented total hip arthroplasty in patients under the age of 40. In cases of acetabular defects, initial reconstruction with bone impaction grafting was performed. Cohort analysis. Details of patients under the age of 40 who underwent primary cemented total hip arthroplasty between 1 January 1988 and 30 June 2004 were analysed. The primary goal of this study was to determine the time until revision surgery. Kaplan Meier analysis was used to calculate prosthesis survival. A total of 175 total hip arthroplasties in 130 patients were included in the study. Acetabular reconstruction using bone impaction grafting was performed on 84 hips (48%). The average age at surgery was 31 years. Six patients (8 hips) died during follow-up; none of these had undergone revision surgery. Average follow-up was 8.1 years (range: 2.0-18.5). In total, 24 hips (14%) were revised. Reasons for revision were: septic loosening (n = 8), recurrent dislocations (n = 4), traumatic loosening (n = 1) and aseptic loosening (n = 11). The 10-year prosthesis survival was 83% (95% CI: 76-90) with the endpoint 'revision for any reason' and 92% (95% CI: 86-98) with the endpoint 'revision for aseptic loosening'. Aseptic survival of the cups with and without bone impaction grafting was 95% (95% CI: 89-100) and 90% (95% CI: 81-99) (p = 0.73), respectively. Hip replacement with cemented total hip arthroplasty in patients under the age of 40 produced good long-term results. Acetabular deficiencies reconstructed with bone impaction grafting also produced good results in this group of patients.


Distribution of Clostridium difficile variant toxinotypes and strains with binary toxin genes among clinical isolates in an American hospital.
Genetic variants of Clostridium difficile have been reported with increasing frequency, but their true incidence is unknown. C. difficile strains have been classified into variant toxinotypes according to variations in the pathogenicity locus encoding the major virulence factors, toxins A and B. Some strains produce an additional toxin, binary toxin CDT. This survey of clinical isolates (153) from patients in a single hospital set out to ascertain the distribution of variant toxinotypes and strains possessing binary toxin genes. A PCR-RFLP-based method of toxinotyping identified 123 (80.4 %) isolates as toxinotype 0, 13 (8.5 %) strains as non-toxigenic and 17 (11.1 %) as belonging to variant toxinotypes. Binary toxin genes were amplified by PCR in nine strains (5.8 %), all of which were variant toxinotypes. Toxin variants of C. difficile are pathogenic and commonly isolated and need to be considered when evaluating new diagnostic testing strategies for C. difficile disease.


Long-term mouse cytomegalovirus infection of tracheal organ culture: relation to host cell replication.
Tracheal organ cultures infected with mouse cytomegalovirus (MCMV) were shown to produce virus for up to 180 days with virus replication primarily in epithelial cells. Persistent virus infections were established in tracheal organ cultures from both MCMV-susceptible and MCMV-resistant strains of mice. In acutely infected tracheal organ cultures, cellular DNA synthesis appeared to precede the production of significant amounts of virus antigens and the release of virus into culture fluids. Since persistently infected tracheal organ cultures continued to synthesize cellular DNA, the results suggest that host cell turnover may continually renew the population of MCMV-susceptible cells. The results suggest a possible mechanism for virus persistence in tracheal organ culture based on continuing serial infection of newly susceptible cells combined with prolonged release of virus infected cells.


Endoscopic argon-ion laser phototherapy of bleeding gastric lesions.
An argon-ion laser, coupled to a flexible fiberoptic endoscope, was used to photocoagulate experimentally produced bleeding gastric ulcers in dogs. Argon-ion laser phototherapy rapidly and effectively achieved hemostasis in all bleeding ulcers. Bleeding arteries up to 2 mm in diameter were photocoagulated. Intact normal gastric mucosa was exposed to laser energy for varying periods of time to determine if transmural photothermal injury occurred. Exposure for greater than 15 seconds at 1.0 w of throughput power caused microscopical evidence of transmural injury. Healed, laser-treated ulcers could not be differentiated from nontreated control ulcers or normal stomach one month after injury. The Beer law and the heattransfer factors relating to soft tissues are discussed. The coupled argon-ion laser-endoscope may be a safe tool to treat self-limited superficial bleeding gastric lesions.


Genetic characteristics and pathogenicity of the first bluetongue virus serotype 20 strain isolated in China.
Bluetongue virus (BTV), a member of the genus Orbivirus in the family Reoviridae, is transmitted by biting midges and causes severe disease in domestic and wild ruminants. In the present study, a BTV strain, BTV-20/GX015/China/2013 (GX015), was isolated from sentinel cattle in Guangxi, China. Virus neutralization tests and phylogenetic analyses based on genomic segments 2 (S2) and 6 (S6) indicated that GX015 belongs to BTV serotype 20 (BTV-20) and represents a new topotype within BTV-20 strains, which makes GX015 the first BTV-20 strain isolated in China. Genomic analyses suggested that the 10 genomic segments of GX015 originated from a reassortment event, in which S2 and S6 are derived from exotic BTV-20 strains (South Africa or Australia), whereas the remaining eight genomic segments are apparently of Chinese origin and most likely share the same ancestor with a Taiwanese BTV-12 strain. Importantly, we evaluated the infectivity and pathogenicity of the BTV-20 strain in mice lacking the interferon receptor (IFNAR-/- mice, a good animal model for studying the pathogenesis, virulence and transmission of BTVs) and sheep for the first time, and found that GX015 causes severe disease and death in IFNAR-/- mice and clinical signs and viraemia in the natural host sheep. These results improve our understanding of the genetic characteristics, diversity and pathogenicity of BTVs, which is important for developing diagnostic methods and vaccines for the surveillance and prevention of bluetongue disease.


Role of diet in the development of immune tolerance in the context of allergic disease.
Diet is arguably one of the most significant environmental exposures during early development. Here, we explore the effects of key perinatal dietary exposures on immune development and susceptibility to allergic disease. Dietary changes are at the centre of the emerging epigenetic paradigms that underpin the rise in many modern diseases. There is growing evidence that exposures in pregnancy and the early postnatal period can modify gene expression and disease susceptibility. Specific nutrients, including antioxidants, oligosaccharides, polyunsaturated fatty acids, folate and other vitamins, have documented effects on immune function. Some have also been implicated in modified risk of allergic disease in observational studies. Intervention studies are largely limited to trials with polyunsaturated fatty acids and oligosaccharides, showing preliminary but yet unconfirmed benefits in allergy prevention. Avoidance of food allergens in pregnancy, lactation or infancy has provided no clear evidence in allergy prevention and is no longer recommended. Rather there is focus on their role in tolerance induction. Modern dietary changes are clearly implicated in the rising propensity for inflammatory immune responses. These dietary changes, which appear to be providing less tolerogenic conditions during early immune programming, may provide important avenues for preventing disease.


Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial.
Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. Astellas Pharma Global Development and Seagen.


Factors associated with radiographic lesions in early axial spondyloarthritis. Results from the DESIR cohort.
To assess whether factors such as inflammation by laboratory tests and MRI differ between early axial SpA with and without radiographic lesions. Cross-sectional analysis of baseline data from Devenir des Spondylarthropathies Indifferenciées Récentes (DESIR) cohort patients having recent-onset inflammatory back pain and meeting Assessment of SpondyloArthritis international Society criteria. The baseline evaluation included radiographs and MRI of the SI joints (SIJs) and spine. Patients were classified as having radiographic lesions if they had at least one obvious sacroiliitis, grade 2 for at least one vertebral corner or grade 1 for at least two vertebral corners (at the cervical or lumbar level, according to the modified Stoke Ankylosing Spondylitis Spine Score). Associations between baseline characteristics and the presence of radiographic lesions were evaluated by estimating multi-adjusted odd ratios (aORs) and their 95% CIs using a logistic regression model. Of 475 patients, 180 (37.9%) had radiographic lesions. Factors positively associated with radiographic lesions were alcohol use (aOR 2.42; 95% CI 1.31, 4.44; P = 0.005), CRP level (aOR 1.44; 95% CI 1.13, 1.84; P = 0.003) and SIJ inflammation by MRI (aOR 2.25; 95% CI 1.40, 3.60; P = 0.001); negative associations occurred with good NSAID responsiveness (aOR 0.44; 95% CI 0.24, 0.81; P = 0.008); spinal MRI inflammation was associated with radiographic lesions only in smokers (aOR 1.99; 95% CI 1.01, 3.92; P = 0.048). Alcohol use, poor responsiveness to NSAIDs, CRP elevation, SIJ MRI inflammation and spinal MRI inflammation in smokers were independently associated with radiographic lesions in early axial SpA.


Effect of C-Reactive Protein-Guided Antibiotic Treatment Duration, 7-Day Treatment, or 14-Day Treatment on 30-Day Clinical Failure Rate in Patients With Uncomplicated Gram-Negative Bacteremia: A Randomized Clinical Trial.
Antibiotic overuse drives antibiotic resistance. Gram-negative bacteremia is a common infection that results in substantial antibiotic use. To compare the clinical effectiveness of C-reactive protein (CRP)-guided, 7-day, and 14-day antibiotic durations 30, 60, and 90 days after treatment initiation. Multicenter, noninferiority, point-of-care randomized clinical trial including adults hospitalized with gram-negative bacteremia conducted in 3 Swiss tertiary care hospitals between April 2017 and May 2019, with follow-up until August 2019. Patients and physicians were blinded between randomization and antibiotic discontinuation. Adults (aged ≥18 years) were eligible for randomization on day 5 (±1 d) of microbiologically efficacious therapy for fermenting, gram-negative bacteria in blood culture(s) if they were afebrile for 24 hours without evidence for complicated infection (eg, abscess) or severe immunosuppression. Randomization in a 1:1:1 ratio to an individualized CRP-guided antibiotic treatment duration (discontinuation once CRP declined by 75% from peak; n = 170), fixed 7-day treatment duration (n = 169), or fixed 14-day treatment duration (n = 165). The primary outcome was the clinical failure rate at day 30, defined as the presence of at least 1 of the following, with a non-inferiority margin of 10%: recurrent bacteremia, local suppurative complication, distant complication (growth of the same organism causing the initial bacteremia), restarting gram-negative-directed antibiotic therapy due to clinical worsening suspected to be due to the initial organism, or death due to any cause. Secondary outcomes included the clinical failure rate on day 90 of follow-up. Among 504 patients randomized (median [interquartile range] age, 79 [68-86] years; 306 of 503 [61%] were women), 493 (98%) completed 30-day follow-up and 448 (89%) completed 90-day follow-up. Median antibiotic duration in the CRP group was 7 (interquartile range, 6-10; range, 5-28) days; 34 of the 164 patients (21%) who completed the 30-day follow-up had protocol violations related to treatment assignment. The primary outcome occurred in 4 of 164 (2.4%) patients in the CRP group, 11 of 166 (6.6%) in the 7-day group, and 9 of 163 (5.5%) in the 14-day group (difference in CRP vs 14-day group, -3.1% [1-sided 97.5% CI, -∞ to 1.1]; P < .001; difference in 7-day vs 14-day group, 1.1% [1-sided 97.5% CI, -∞ to 6.3]; P < .001). By day 90, clinical failure occurred in 10 of 143 patients (7.0%) in the CRP group, 16 of 151 (10.6%) in the 7-day group, and 16 of 153 (10.5%) in the 14-day group. Among adults with uncomplicated gram-negative bacteremia, 30-day rates of clinical failure for CRP-guided antibiotic treatment duration and fixed 7-day treatment were noninferior to fixed 14-day treatment. However, interpretation is limited by the large noninferiority margin compared with the low observed event rate, as well as low adherence and wide range of treatment durations in the CRP-guided group. ClinicalTrials.gov Identifier: NCT03101072.


An Unusual Case of Sudden Death: Is There a Relationship Between Thyroid Disorders and Fatal Pulmonary Thromboembolism? A Case Report and Review of Literature.
In adults, the most common cause of sudden death is coronary heart disease or defects in the cardiac conduction system; however, there are many cases of sudden death occurring from other causes such as fatal pulmonary thromboembolism. Several risk factors are recognized, including hospitalization, surgery, obesity, pregnancy, the use of oral contraceptives, traumatic fractures, and genetic conditions, which cause hypercoagulable states such as factor V Leiden mutations. Although many risk factors have been identified, the mortality rate is still high. An association between thyroid disease and coagulation disorders has previously been demonstrated. However, scientific literature does not yet agree on the association between thyroid diseases and pulmonary thromboembolism. Excessive thyroid hormones can determine an alteration in the hemostatic system through different mechanisms, which lead to a hypercoagulable state. In forensic literature, there are no reports of fatal thromboembolism in patients with thyroid disorders. We reported a case of a 41-year-old woman who died during sexual activity. The autopsy findings highlighted the presence of massive pulmonary embolism. Histopathological analysis showed structural anomalies of the thyroid gland. A retrospective analysis of her medical history and possible genetic alterations were performed.


[A statistical analysis of liver diseases (based on the autopsy data from the clinics of the I. M. Sechenov Moscow Medical Academy for 1978-1987)].
6170 autopsy protocols have been analysed and the conclusion is made that alcoholic liver cirrhosis is predominating in the structure of liver diseases. Viral liver cirrhosis is less important by its incidence than alcoholic one. Liver tumors are of importance against the background of alcoholic and viral cirrhosis. Primary liver tumors, autoimmune and metabolic diseases occur rarely. The material confirms the fact that alcohol is a principal etiological factor in development of liver diseases.


Age differences in WISC-III subtests of children experiencing academic difficulties.
WISC-III subtest scores of 180 children referred because of academic difficulties were analyzed for differences based on age (M = 9.6, SD = 2.7) and IQ. Rank-orders of all subtests indicated no significant correlations across the six age-IQ groups, suggesting that interpretation of changes in subtest rankings may require consideration of age and IQ, especially for such children. When data were organized into Acquired Knowledge, Spatial Ability, and speed-related task categories, analyses of variance showed a main effect for IQ. Furthermore, scores on Acquired Knowledge were associated with age at the lower category of IQ, whereas Spatial Ability and speed-related tasks were not related to age.


The burden and undertreatment of fragility fractures among senior women.
Using a large population database, we showed that fragility fractures were highly prevalent in senior women and were associated with significant physical disability. However, treatment rates were low because osteoporosis treatment was not prescribed or not agreed to by the majority of women with prevalent fragility fractures. The purpose of the study is to estimate prevalence of fragility fractures (FF), risk factors, and treatment rates in senior women and to assess impact of FF on physical function and quality of life. Women aged 65 years and older from the EpiReumaPt study (2011-2013) were evaluated. Rheumatologists collected data regarding FF, clinical risk factors for fractures, and osteoporosis (OP) treatment. Health-related quality of life (EQ5D) and physical function (HAQ) were analyzed. Peripheral dual-energy X-ray absorptiometry was performed. FF was defined as any self-reported low-impact fracture that occurred after 40 years of age. Prevalence estimates of FF were calculated. Among 3877 subjects evaluated in EpiReumaPt, 884 were senior women. The estimated prevalence of FF was 20.7%. Lower leg was the most frequent fracture site reported (37.8%) followed by wrist (18.6%). Only 7.1% of the senior women reporting a prevalent FF were under treatment for OP, and 13.9% never had treatment. OP treatment was not prescribed in 47.7% of FF women, and 23.4% refused treatment. Age (OR = 2.46, 95% CI 1.11-5.47), obesity (OR = 2.05, 95% CI 1.14-3.70), and low wrist BMD (OR = 2.29; 95% CI 1.20, 4.35; p = 0.012) were positively associated with prevalent FF. A significantly higher proportion of women in the lowest quintile of wrist bone mineral density reported FF (OR = 2.29, 95% CI 1.20-4.35). FF were associated with greater physical disability (β = 0.33, 95% CI 0.13-0.51) independent of other comorbidities. FF was frequently reported among senior women as an important cause of physical disability. However, the prevalence of OP treatment was low, which constitutes a public health problem in this vulnerable group.


Dielectric elastomer actuators based on stretchable and self-healable hydrogel electrodes.
Dielectric elastomer actuator (DEA) based on dielectric elastomer holds promising applications in soft robotics. Compliant electrodes with large stretchability and high electrical conductivity are the vital components for the DEAs. In this study, a type of DEA was developed using carbon nanotube/polyvinyl alcohol (CNT/PVA) hydrogel electrodes. The CNT/PVA hydrogel electrodes demonstrate a stretchability up to 200% with a small relative resistance change of approximately 1.2, and a self-healing capability. The areal strain of the DEA based on the CNT/PVA hydrogel electrodes is more than 40%, much higher than the ones based on pure PVA electrodes.


Vapor Nanobubbles around Heated Nanoparticles: Wetting Dependence of the Local Fluid Thermodynamics and Kinetics of Nucleation.
Plasmonic nanobubbles are composite objects resulting from the interaction between light and metallic nanoparticles immersed in a fluid. Plasmonic nanobubbles have applications in photothermal therapies, drug delivery, microfluidic manipulations, and solar energy conversion. Their early formation is, however, barely characterized due to the short time and length scales relevant to the process. Here, we investigate, using molecular dynamics (MD) simulations, the effect of nanoparticle wettability on both the local fluid thermodynamics and the kinetics of nanobubble generation in water. We first show that the local onset temperature of vapor nucleation decreases with the nanoparticle/water interfacial energy and may be 100 K below the water spinodal temperature in the case of weak nanoparticle/water interactions. Second, we demonstrate that vapor nucleation may be slower in the case of weak water/nanoparticle interactions. This result, which is qualitatively at odds with the predictions of isothermal classical nucleation theory, may be explained by the competition between two antagonist effects: while, classically, hydrophobicity increases the vapor nucleation rate, it also penalizes interfacial thermal transfer, slowing down kinetics. The kinetics of heat transfer from the nanoparticle to water is controlled by the interfacial thermal conductance. This quantity turns out not only to decrease with the nanoparticle hydrophobicity but also drops down prior to phase change, yielding even longer nucleation times. Such conclusions were reached by considering the comparison between MD and continuous heat transfer models. These results put forward the role of nanoparticle wettability in the generation of plasmonic nanobubbles observed experimentally and open the path to the control of boiling using nanopatterned surfaces.


A SELDI-TOF-MS study in Lacunar Stroke with Subsequent Haptoglobin Phenotyping.
Using Surface-Enhanced Laser Desorption / Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS), we aimed to detect differences in protein profile in serum samples of two lacunar stroke subtypes. SELDI-TOF-MS, followed by protein identification, was performed in samples of 8 first-ever lacunar stroke patients with MR imaging showing a single symptomatic lacunar lesion (type 1), and 8 with multiple additional "silent" lacunar lesions and extensive white matter lesions (type 2). A 16 kDa protein, identified as alpha-2-chain of haptoglobin (Hp), was found to be overrepresented in type 1 compared to type 2 (peak intensity 12.5 vs. 5.0; p=0.02). As a polymorphism with two alleles, Hp-1 and Hp 2, determines the presence of alpha-1 and/or alpha-2-chains in the Hp-molecule, Hp phenotypic analysis was performed. Hp 1 : Hp-2 allele frequency was 0.562 : 0.438 in type 1 and 0.812 : 0.188 in type 2 (population reference approximately 0.4 : 0.6). We conclude that the overrepresentation of the alpha-2-chain in lacunar stroke type 1 compared to type 2 relates to a higher Hp-2 allele frequency in the former. Yet, compared to population reference, the phenotype distribution in both patient groups deviates towards a high Hp-1 allele frequency. Our findings suggest a role for the Hp gene in the etiology of cerebral small vessel disease. Larger studies are now needed to explore this new candidate gene.


New Cytotoxic Secondary Metabolites from Marine Bryozoan Cryptosula pallasiana.
A new sterol, (23R)-methoxycholest-5,24-dien-3β-ol (1), two new ceramides, (2S,3R,4E,8E)-2-(tetradecanoylamino)-4,8-octadecadien-l,3-diol (6) and (2S,3R,2'R,4E,8E)-2-(tetradecanoylamino)-4,8-octadecadien-l,3,2'-triol (7), together with three known sterols (2-4), a lactone (5) and two ceramides (8,9), were isolated from the marine bryozoan Cryptosula pallasiana, collected at Huang Island of China. The structures of the new compounds were elucidated by extensive spectroscopic analyses, chemical methods and quantum electronic circular dichroism (ECD) calculations. Among the isolated compounds, sterol 1 possessed a rare side chain with a methoxy group at C-23, and a double bond between C-24 and C-25. Ceramides 6 and 7 possessed 14 carbons in their long-chain fatty acid base (FAB), which were different from the normal ceramides with 16 carbons in the FAB. Moreover, compounds 5 and 8 were isolated for the first time from marine bryozoans. Compounds 1-9 were evaluated for their cytotoxicity against human tumor cell lines HL-60, Hep-G2 and SGC-7901. The results showed that lactone 5 appears to have strong cytotoxicity against the test tumor cell lines, with IC50 values from 4.12 μM to 7.32 μM, and sterol 1 displayed moderate cytotoxicity with IC50 values between 12.34 μM and 18.37 μM, while ceramides 6-9 showed weak cytotoxicity with IC50 ranging from 21.13 μM to 58.15 μM.


Lactase and sucrase-isomaltase gene expression during Caco-2 cell differentiation.
The Caco-2 cell line is derived from a human colon adenocarcinoma and differentiates in vitro into small-intestinal enterocyte-like cells, expressing the hydrolases lactase and sucrase-isomaltase. We cultured Caco-2 cells on permeable supports from 0 to 37 days after plating to study endogenous lactase and sucrase-isomaltase gene expression in relation to cell differentiation. Profiles of lactase and sucrase-isomaltase mRNA, protein and enzyme activity were analysed on a per-cell basis, using immunocytochemistry, RNase protection assays, metabolic polypeptide labelling and enzyme activity assays. Tight-junction formation was complete 6 days after plating. Immunocytochemistry of Caco-2 cross-sections showed lactase and sucrase-isomaltase predominantly in the microvillar membrane of polarized cells. mRNA, protein and enzyme activity of lactase appeared consecutively, reaching maximum levels 8-11 days after plating. Whereas lactase mRNA and protein biosynthesis showed a sharp decline after peak levels, lactase activity remained high until 37 days after plating. In contrast, mRNA and protein biosynthesis and activity of sucrase-isomaltase peaked successively 11-21 days after plating, and exhibited comparable levels throughout the entire experiment. The following conclusions were reached. (1) In Caco-2 cells, biosynthesis of lactase and sucrase-isomaltase is regulated by the amount of their mRNAs, indicating transcriptional control. (2) Sucrase-isomaltase activity is most probably transcriptionally controlled at all time points. (3) In contrast, lactase activity is initially regulated by its level of biosynthesis. After its peak at 8 days, the slow decline in activity compared with its biosynthesis indicates high stability. (4) Different mRNA profiles for lactase and sucrase-isomaltase indicate different mechanisms of transcriptional regulation of these genes.


Economic costs of obesity: a systematic review.
Obesity is a growing public health problem leading to substantial economic impact. This study aimed to summarize the economic impact of obesity and to critically analyze the methods used in the cost-of-illness (COI) studies on obesity. We conducted systematic search in PubMed and Scopus from September 1, 2016, to July 22, 2022. Original COI studies estimating the economic cost of obesity and/or overweight in at least one country, published in English were included. To facilitate the comparison of estimates across countries, we converted the cost estimates of different years to 2022 purchasing power parity (PPP) values using each country's consumer price index (CPI) and PPP conversion rate. Nineteen studies were included. All studies employed a prevalence-based approach using Population Attributable Fraction (PAF) methodology. About half of the included studies (53%) were conducted in high-income countries while the others (47%) were conducted in middle-income countries. The economic burden of obesity ranged between PPP 15 million in Brazil to PPP 126 billion in the USA, in the year 2022. Direct medical costs accounted for 0.7% to 17.8% of the health system expenditure. Furthermore, the total costs of obesity ranged from 0.05% to 2.42% of the country's gross domestic product (GDP). Of the seven studies that estimated both direct and indirect costs, indirect costs accounted for the largest portion of five studies. Nevertheless, a variety in methodology across studies was identified. The number of co-morbidities included in the analysis varied across studies. Although there was a variety of methodologies across studies, consistent evidence indicated that the economic burden of obesity was substantial. Obesity prevention and control should be a public health priority, especially among countries with high prevalence of obesity.


Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective.
To inform an operationalised definition of recovery from myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) for research and practice. Without a consensus on defining and measuring recovery, there will continue to be controversy amongst researchers, clinicians, and patients when interpreting treatment outcomes. This study explores physicians' views on recovery from ME and CFS. We conducted semi-structured interviews with 10 physician participants who are experts in the ME and CFS field. Our deductive thematic analysis, using a realist perspective, provided a framework for differentiating recovery and significant improvement. Physicians conceptualised recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age), whereas they viewed significant improvement as a substantial reduction in symptoms with considerable functional gains, where patients may operate in daily life but still must cope or be treated. Our findings provide recommendations and approaches for measuring: daily functioning, symptomatology, quality of life, and physical functioning. Implications for rehabilitation Physicians viewed recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age). Recovery from myalgic encephalomyelitis and chronic fatigue syndrome should be viewed as multidimensional, considering patients' daily life, psychosocial functioning, and overall physical functioning. These findings can improve practitioner-client interactions, as they provide recommendations for measuring recovery in research and practice.


A prospective single-center registry for the use of intracoronary gamma radiation in patients with diffuse in-stent restenosis.
Based on single-center prospective registry data, the study evaluates short- and long-term results of intracoronary gamma radiation in patients with diffuse in-stent restenosis in the reality of routine clinical practice. Percutaneous coronary intervention and subsequent catheter-based irradiation with iridium-192 was performed in 84 vessels (81 patients) with diffuse in-stent restenosis. Repeat coronary angiography was performed in 35 patients with clinical restenosis. With a mean follow-up of 12.0 +/- 0.5 months, major adverse cardiac events were observed in 29 (34.5%) patients, including 2 cases of cardiac death, 3 myocardial infarctions, 21 target lesion revascularizations, and 4 target vessel revascularizations. Five of six patients with total occlusion of the target vessel at baseline developed target lesion restenosis. Late total occlusion of the target vessel was observed in four patients. The 1-year event-free survival rate was 69.8%. Total occlusion of the target vessel at baseline was the single independent predictor of cardiac events at 1-year follow-up (P < 0.001). In patients with a target lesion in the left anterior descending artery, predictors of cardiac events also included female sex (P = 0.014), current smoking (P = 0.014), stenting during brachytherapy session (P = 0.02), and smaller reference vessel diameter at baseline (P = 0.01). The results of our registry are similar to those of randomized trials. As applied in routine clinical practice, intracoronary gamma radiation is a feasible, safe, and effective tool in the treatment of diffuse in-stent restenosis. Late events in the entire group were predicted by total occlusion at baseline.


A microscopy-compatible temperature regulation system for single-cell phenotype analysis - demonstrated by thermoresponse mapping of microalgae.
This work describes a programmable heat-stage compatible with in situ microscopy for the accurate provision of spatiotemporally defined temperatures to different microfluidic devices. The heat-stage comprises an array of integrated thin-film Joule heaters and resistance temperature detectors (RTDs). External programming of the heat-stage is provided by a custom software program connected to temperature controllers and heater-sensor pairs. Biologically relevant (20-40 °C) temperature profiles can be supplied to cells within microfluidic devices as spatial gradients (0.5-1.5 °C mm-1) or in a time-varying approach via e.g. step-wise or sinusoidally varying profiles with negligible temperature over-shoot. Demonstration of the device is achieved by exposing two strains of the coral symbiont Symbiodinium to different temperature profiles while monitoring their single-cell photophysiology via chlorophyll fluorometry. This revealed that photophysiological responses to temperature depended on the exposure duration, exposure magnitude and strain background. Moreover, thermal dose analysis suggested that cell acclimatisation occurs under longer temperature (6 h) exposures but not under shorter temperature exposures (15 min). As the thermal sensitivity of Symbiodinium mediates the thermal tolerance in corals, our versatile technology now provides unique possibilities to research this interdependency at single cell resolution. Our results also show the potential of this heat-stage for further applications in fields such as biotechnology and ecotoxicology.


Possible role of streptomycin released from spore cell wall of Streptomyces griseus.
Vegetative mycelia and spores of the investigated high- and low-producer strains of Streptomyces griseus bound significant amounts (4%) of streptomycin, which could be removed by increasing ionic strength. The release of antibiotic from the spores was easier when the spores were germinating. This phenomenon is considered to play an ecological role. We suppose that the streptomycin released during the germination process may protect the young hyphae from the different bacteria growing in the microenvironment of the Streptomyces spores.


Calcium-independent phospholipase A2 beta is dispensable in inflammasome activation and its inhibition by bromoenol lactone.
Calcium-independent phospholipase A2 (iPLA2) has been suggested to play an important role in the activation of caspase-1 induced by lipopolysaccharides (LPS). Here, we used pharmacological and genetic approaches to study the role of iPLA 2 in the activation of caspase-1. Bromoenol lactone (BEL), an inhibitor that was originally used to support a role for iPLA2 in the secretion of IL-1 beta, prevented caspase-1 activation induced by LPS and ATP as described, and also activation triggered by Salmonella infection and cytosolic flagellin, which rely on the Nlrc4 inflammasome. Analysis of BEL enantiomers showed that the S-BEL form was more effective than R-BEL in inhibiting the inflammasome, suggesting a role for iPLA2 . However, caspase-1 activation and IL-1 beta secretion and their inhibition by BEL were unimpaired in macrophages deficient in iPLA2 beta. BEL was originally identified as an inhibitor of serine proteases. Consistent with the latter, the serine proteases inhibitors TPCK, TLCK and AAF-cmk prevented the activation of the Nlrc4 and Nlrp3 inflammasomes while pan-cathepsin inhibitors were ineffective. These results indicate that iPLA2 beta is not critical for caspase-1 activation as currently proposed. Instead, the results suggest that serine protease(s) targeted by BEL may play a critical role in the activation of the inflammasome triggered by microbial stimuli.


Oncolytic viruses.
Viruses capable of inducing lysis of malignant cells through their replication process are known as "oncolytic" viruses. Clinical trials in oncology have been performed with oncolytic viruses for nearly fifty years. Both systemic and intratumoral routes of administration have been explored. Toxicity has generally been limited to injection site pain, transient fever and tumor necrosis. Responses with early crude materials were usually short in duration; however, recent trials with gene attenuated viruses suggest more prolonged duration to responses observed.


Sin Nombre virus infection in field workers, Colorado, USA.
We report 2 cases of Sin Nombre virus (SNV) infection in field workers, possibly contracted through rodent bites. Screening for antibodies to SNV in rodents trapped in 2 seasons showed that 9.77% were seropositive. Quantitative real-time PCR showed that 2 of 79 deer mice had detectable titers of SNV RNA.


Ecological Momentary Assessment of Youth Anxiety: Evaluation of Psychometrics for Use in Clinical Trials.
Background: Ecological momentary assessment (EMA) captures naturalistic experience in real time and holds promise to improve our understanding and treatment of youth psychopathology. While psychometric evaluation of EMA methods is crucial, particularly for use as a tool in clinical trials, research examining the reliability and validity of EMA items in youth is lacking. Method: This study evaluates EMA responses from 204 child and adolescent participants (M age = 12.54, 60.8% female), including 131 participants with an anxiety disorder and 73 participants with no psychiatric diagnosis. We assessed the within- and between-person variability, internal consistency, test-retest reliability, and convergent and discriminant validity of two EMA items probing anxiety symptoms; one positive affect item served as a comparison. Results: All psychometric properties of the anxiety items were at least satisfactory in youth with anxiety disorders. However, there was restricted variability and poor test-retest reliability in youth with no diagnosis. Discussion: These results might facilitate future clinical trials using EMA to investigate pediatric anxiety. Results also suggest that unique EMA items might be needed to reliably track anxiety in healthy youth. Future work should continue to examine the psychometric properties of EMA protocols before implementation in clinical trials. ClinicalTrials.gov identifier: NCT00018057.


No evidence for an open vessel effect in centrifuge-based vulnerability curves of a long-vesselled liana (Vitis vinifera).
Vulnerability to cavitation curves are used to estimate xylem cavitation resistance and can be constructed using multiple techniques. It was recently suggested that a technique that relies on centrifugal force to generate negative xylem pressures may be susceptible to an open vessel artifact in long-vesselled species. Here, we used custom centrifuge rotors to measure different sample lengths of 1-yr-old stems of grapevine to examine the influence of open vessels on vulnerability curves, thus testing the hypothesized open vessel artifact. These curves were compared with a dehydration-based vulnerability curve. Although samples differed significantly in the number of open vessels, there was no difference in the vulnerability to cavitation measured on 0.14- and 0.271-m-long samples of Vitis vinifera. Dehydration and centrifuge-based curves showed a similar pattern of declining xylem-specific hydraulic conductivity (K(s)) with declining water potential. The percentage loss in hydraulic conductivity (PLC) differed between dehydration and centrifuge curves and it was determined that grapevine is susceptible to errors in estimating maximum K(s) during dehydration because of the development of vessel blockages. Our results from a long-vesselled liana do not support the open vessel artifact hypothesis.


Desirability or feasibility: self-other decision-making differences.
Making decisions for the self and providing advice to others are common in daily life. The current research examines the differences in weight that people attach to desirability and feasibility when deciding for themselves versus others. Based on construal level theory, we propose that in a decision-making process, individuals who decide for others tend to focus more on desirability than on feasibility compared with those who decide for themselves. Across five experiments, the predicted self-other differences were observed in preference in the decision stage (Experiments 1a and 1b), information seeking in the predecision stage (Experiment 2), and information recall in the postdecision stage (Experiments 3a and 3b). These findings show that decision behaviors are determined by the decision target (i.e., for whom such decisions are made).


Psychological Distress and Drug Use Patterns of Young Adult Ecstasy Users: A Complementary Analysis of Australian Datasets.
We examine psychological distress (PD) in young adult Ecstasy users in relation to age of initiation and frequency of use of Ecstasy, cannabis, alcohol, and tobacco. Using two Australian community samples, we assess whether different sampling methods produce comparable estimates of these associations. The Natural History Study of Drug Use (NHSDU; N = 339) in 2009 used population sampling and the 2009 Ecstasy and Related Drug Reporting System (EDRS; N = 359) used purposive sampling. Participants, aged 19-23 years, were recurrent Ecstasy users. PD was assessed using Kessler 10 in the EDRS and Hospital Anxiety Depression Scale in the NHSDU. In both samples, PD was associated with daily tobacco use and early drug initiation, but not frequent Ecstasy use. One-third smoke tobacco daily. Study limitations and implications are noted.


Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: systematic review and meta-analysis.
To conduct a comprehensive, systematic review and meta-analysis of the efficacy and tolerability of mirtazapine over other antidepressants in the acute-phase treatment of major depression. Studies were initially identified through electronic searches of the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register up to June 2006. The following search terms were used: depress*, dysthymi*, adjustment disorder*, mood disorder*, affective disorder, affective symptoms, and mirtazapine. No language restriction was imposed. The reference lists of the included studies, previous relevant systematic reviews, and trial registers were also hand searched. Pharmaceutical companies and experts in the field were contacted for more studies. Twenty-five randomized controlled trials were included. Two independent assessors examined the quality of the trials and extracted data on an intention-to-treat basis. The primary outcome measure was the relative risk (RR) of response (99% CIs) at the conclusion of acute-phase treatment. In relation to the early phase of treatment (at 2 weeks), there were no statistically significant differences between mirtazapine and the tricyclics in terms of the response (RR = 0.90, 99% CI = 0.69 to 1.18, p = .30 [8 trials contributed to this outcome]) or remission (RR = 0.87, 99% CI = 0.52 to 1.47, p = .50 [8 trials]) outcomes, but mirtazapine was superior to the selective serotonin reuptake inhibitors (SSRIs) in terms of both the response (RR = 1.36, 99% CI = 1.13 to 1.64, p < .0001 [12 trials]) and remission (RR = 1.68, 99% CI = 1.20 to 2.36, p < .0001 [12 trials]). In the subgroup analyses, mirtazapine significantly produced more response than paroxetine (RR = 2.02, 99% CI = 1.09 to 3.75, p = .003 [3 trials]) and venlafaxine (RR = 1.77, 99% CI = 1.08 to 2.89, p = .003 [2 trials]). At the end of acute-phase treatment (6-12 weeks, all trials), no significant differences were observed in the efficacy outcomes. No significant differences were observed between mirtazapine and the other antidepressants in terms of either the total number of dropouts due to any reason (21 trials) or the total number of dropouts due to the development of side effect (23 trials) during the trials. Although mirtazapine is likely to have a faster onset of action than SSRIs, no significant differences were observed at the end of 6 to 12 weeks' treatment. Clinicians should focus on other practically relevant considerations to tailor treatment to best fit the needs of individual patients.


Retinoic acid stimulates the differentiation of PC12 cells that are deficient in cAMP-dependent protein kinase.
Retinoic acid (RA) induced neuronal differentiation in A126-1B2 cells and 123.7 cells, two mutant lines of PC12 that are deficient in cAMP-dependent protein kinase, but not in the parental PC12 cell line. A single exposure to RA was sufficient to cause neurite formation and inhibit cell division for a period of greater than 3 wk, suggesting that RA may cause a long-term, stable change in the state of these cells. In A126-1B2 cells, RA also induced the expression of other markers of differentiation including acetylcholinesterase and the mRNAs for neurofilament (NF-M) and GAP-43 as effectively as nerve growth factor (NGF). Neither NGF nor RA stimulated an increase in the expression of smg-25A in A126-1B2 cells, suggesting that the cAMP-dependent protein kinases may be required for an increase in the expression of this marker. RA also caused a rapid increase in the expression of the early response gene, c-fos, but did not effect the expression of egr-1. RA equivalently inhibited the division of A126-1B2 cells, 123.7 cells and parental PC12 cells, so RA induced differentiation is not an indirect response to growth arrest. In contrast, the levels of retinoic acid receptors (RAR alpha and RAR beta), and retinoic acid binding protein (CRABP) mRNA were strikingly higher in both A126-1B2 cells and 123.7 cells than in the parental PC12 cells. The deficiencies in cAMP-dependent protein kinase may increase the expression of CRABP and the RARs; and, thus, cAMP may indirectly regulate the ability of RA to control neurite formation and neural differentiation. Thus, RA appears to regulate division and differentiation of PC12 cells by a biochemical mechanism that is quite distinct from those used by peptide growth factors.


Recent developments in analytical chromatography.
Capillary gas chromatography (GC) is rapidly reaching a state of maturity. Recent advances in GC include new highly selective and stable open-tubular columns, capillary sampling techniques, and element-sensitive (plasma) detectors. An impressive growth of modern liquid chromatography continues with an emphasis on the separations of biopolymers, new silica-based and stable polymeric packings, microcolumn techniques, electroosmotically driven separations, and ultrasensitive detection. Supercritical fluid chromatography has gained considerable attention primarily because of its distinctive detection capabilities. Novel combinations of chromatographic techniques with each other, or with spectroscopic methods, continue to be explored.


[Systematics of somatoform disorders in children and adolescents].
Somatoform disorders in children and adolescents are common and can cause significantly reduced wellbeing and quality of life. Considerable subjective impairment leads to a high number of doctors' visits, which along with a reoccurrence of negative findings, often results in a sense of helplessness in the patient and a lack of trust towards the physician. The criteria for somatoform disorders are illustrated based on the classification scheme ICD-10 and in consideration of the DSM-V. Referring to Noeker (2008) the special role of the parents for the development of somatoform disorders is explained. The typical clinical profile of somatoform disorders in children and adolescents is described. As a diagnostic instrument the newly developed Screening for Somatoform Disorders in Children and Adolescents (SOMS-CA) (Winter, Pfeiffer, Köberle, Lenz, Lehmkuhl, 2008) is introduced. Furthermore it is demonstrated that patients with somatoform disorders are seen predominantly within consulting and liaison services of the paediatric clinic. The importance of interdisciplinary cooperation between paediatrics and child and adolescent psychiatry and -psychotherapy in early diagnosis and introduction of appropriate treatment is highlighted.


Reducing False-Positive Screening MRI Rate in Women with Extremely Dense Breasts Using Prediction Models Based on Data from the DENSE Trial.
Background High breast density increases breast cancer risk and lowers mammographic sensitivity. Supplemental MRI screening improves cancer detection but increases the number of false-positive screenings. Thus, methods to distinguish true-positive MRI screening results from false-positive ones are needed. Purpose To build prediction models based on clinical characteristics and MRI findings to reduce the rate of false-positive screening MRI findings in women with extremely dense breasts. Materials and Methods Clinical characteristics and MRI findings in Dutch breast cancer screening participants (age range, 50-75 years) with positive first-round MRI screening results (Breast Imaging Reporting and Data System 3, 4, or 5) after a normal screening mammography with extremely dense breasts (Volpara density category 4) were prospectively collected within the randomized controlled Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial from December 2011 through November 2015. In this secondary analysis, prediction models were built using multivariable logistic regression analysis to distinguish true-positive MRI screening findings from false-positive ones. Results Among 454 women (median age, 52 years; interquartile range, 50-57 years) with a positive MRI result in a first supplemental MRI screening round, 79 were diagnosed with breast cancer (true-positive findings), and 375 had false-positive MRI results. The full prediction model (area under the receiver operating characteristics curve [AUC], 0.88; 95% CI: 0.84, 0.92), based on all collected clinical characteristics and MRI findings, could have prevented 45.5% (95% CI: 39.6, 51.5) of false-positive recalls and 21.3% (95% CI: 15.7, 28.3) of benign biopsies without missing any cancers. The model solely based on readily available MRI findings and age had a comparable performance (AUC, 0.84; 95% CI: 0.79, 0.88; P = .15) and could have prevented 35.5% (95% CI: 30.4, 41.1) of false-positive MRI screening results and 13.0% (95% CI: 8.8, 18.6) of benign biopsies. Conclusion Prediction models based on clinical characteristics and MRI findings may be useful to reduce the false-positive first-round screening MRI rate and benign biopsy rate in women with extremely dense breasts. Clinical trial registration no. NCT01315015 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Imbriaco in this issue.


Comparing the efficacy of tamsulosin and silodosin in the medical expulsion therapy for ureteral calculi.
Urolithiasis is a chronic disease of mankind, which has enormous public health importance and it accounts for a substantial economic burden on our society. Hence, it becomes all the more important to formulate cheaper and easier means for treating this condition. The past few years have seen a number of drugs being introduced and successfully used in the medical expulsion therapy of small, uncomplicated ureteral calculi, with each drug claiming to provide better results than the others. Ours is perhaps the first study which has compared the efficacy of tamsulosin and silodosin in the medical expulsion therapy for ureteral calculi. To compare the efficacy of tamsulosin (0.4mg) vs silodosin (8mg), both in terms of the stone expulsion rate and the time to stone expulsion. A prospective and a randomized controlled study was conducted in the Department of Urology, Regional Institute of Medical Sciences (RIMS), Imphal, Manipur, India. From February to August 2012, 100 patients who were between the age group of 18-50 years, who had unilateral, uncomplicated middle or lower ureteral stones </= 1cm were enrolled and they were divided into two groups. Group 1 received tamsulosin (0.4mg) daily, whereas Group 2 received silodosin (8mg) daily for a maximum period of 4 weeks. The patients were followed up weekly or biweekly with imaging studies. The primary endpoint was the stone expulsion rate and the secondary endpoints were the stone expulsion time, the rate of the interventions and the side effects. The statistical analysis was performed by using the Student's t-test and the Chi-squared test. A p value of < 0.05 was considered to be statistically significant. The SPSS-16 software was used for the statistical analysis of the data. A spontaneous stone expulsion was observed in 58% of the patients in group 1 and in 82% of the patients in Group 2, which was statistically significant. There was also a significant difference between the groups with regards to the mean stone expulsion time. A lower analgesic use was found in Group 2. In our study, silodosin was found to be clinically superior to tamsulosin, both in terms of the stone expulsion rate and the stone expulsion time.


Effects of amiloride and ouabain on contractile state, Ca and Na fluxes, and Na content in cultured chick heart cells.
Amiloride has been reported to reduce the positive inotropic and toxic actions of cardiac glycosides in patients as well as in experimental animals. To investigate the mechanism by which amiloride interacts with glycosides at the cellular level, we examined the effect of amiloride and ouabain on cellular Na content and uptake, Ca flux via Na-Ca exchange, and contractile state. Amiloride (1 mM) reduced cellular Na content by 16% (p less than 0.05) under normal conditions and by 45% in the presence of 1 mM ouabain compared to respective control values observed in the absence of amiloride. Amiloride (1 mM) reduced the initial rate of 45Ca uptake by 40% in ouabain (1 mM)-treated cells. This reduction of 45Ca uptake could be mimicked by lowering cellular Na content by 42%. Amiloride (1 mM) did not alter significantly the initial rate of 24Na uptake under normal conditions but reduced it by 32% in the presence of 3 microM ouabain. Amiloride (1 mM) produced a transient increase followed by a gradual decrease in the amplitude of cell motion over 60 min to 10% of control level. At other concentrations between 0.1 and 3 mM, amiloride produced negative inotropic effects only. Amiloride increased the concentration of ouabain needed to produce rhythm disturbances and contracture, and reduced Na-free contracture amplitude by 18%. These results are consistent with the view that amiloride antagonizes the arrhythmogenic effects of ouabain by inhibiting the glycoside-induced elevation in cellular Na content and, consequently, the increases in [Ca]i that occur via Na-dependent pathways. The reduced cellular Na content appears to be due to decreased Na influx via Na-H exchange.


Defensive glands in the adult and larval stages of the darkling beetle, Luprops tristis.
Invasion by large populations of the litter-dwelling darkling beetle Luprops tristis Fabricius (Coleoptera: Tenebrionidae) following the short spell of summer rains during April, and their extended state of dormancy is a regular event in rubber plantation habitats in south-western India. Strong smelling secretions of the beetle cause blisters on skin of human beings. Such secretions appear defensive because they appear to facilitate their avoidance by other predatory organisms. Defensive glands in the larvae and adults of L. tristis are described, as well as the mode of eversion of the glands. The glands in larvae consist of two pairs of noneversible glands in a conical depression on the 2(nd) and 3(rd) sternites, whereas in adults only one pair occurs between 7(th) and 8(th) sternal segments. These glands may be a major reason for avoidance of larvae and adults by their natural enemies and their very high numbers in the litter of rubber plantations.