Xanthine phosphoribosyltransferase from Leishmania donovani. Molecular cloning, biochemical characterization, and genetic analysis.
Xanthine phosphoribosyltransferase (XPRT) from Leishmania donovani is a unique enzyme that lacks a mammalian counterpart and is, therefore, a potential target for antiparasitic therapy. To investigate the enzyme at the molecular and biochemical level, a cDNA encoding the L. donovani XPRT was isolated by functional complementation of a purine auxotroph of Escherichia coli that also harbors deficiencies in the prokaryotic phosphoribosyltransferase (PRT) activities. The cDNA was then used to isolate the XPRT genomic clone. XPRT encodes a 241-amino acid protein exhibiting approximately 33% amino acid identity with the L. donovani hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and significant homology with other HGPRT family members. Southern blot analysis revealed that XPRT was a single copy gene that co-localized with HGPRT within a 4.3-kilobase pair (kb) EcoRI fragment, implying that the two genes arose as a result of an ancestral duplication event. Sequencing of this EcoRI fragment confirmed that HGPRT and XPRT were organized in a head-to-tail arrangement separated by an approximately 2.2-kb intergenic region. Both the 3.2-kb XPRT mRNA and XPRT enzyme were significantly up-regulated in Deltahgprt and Deltahgprt/Deltaaprt L. donovani mutants. Genetic obliteration of the XPRT locus by targeted gene replacement indicated that XPRT was not an essential gene under most conditions and that the Deltaxprt null strain was competent of salvaging all purines except xanthine. XPRT was overexpressed in E. coli and the recombinant protein purified to homogeneity. Kinetic analysis revealed that the XPRT preferentially phosphoribosylated xanthine but could also recognize hypoxanthine and guanine. K(m) values of 7.1, 448.0, and >100 microM and k(cat) values of 3.5, 2.6, and approximately 0.003 s(-1) were calculated for xanthine, hypoxanthine, and guanine, respectively. The XPRT gene and XPRT protein provide the requisite molecular and biochemical reagents for subsequent studies to validate XPRT as a potential therapeutic target.


An epidemiological study of lung cancer: history and histological types in a general population in northern Finland.
A prospective epidemiological study was conducted to assess the incidence, diagnosis, histology and surgical treatment of lung cancer in northern Finland. The results were compared with those obtained in a similar survey 20 yrs earlier. Most of the patients with a suspected lung tumour were interviewed (72%) and the information was combined with that obtained from the national cancer registry. All pathological specimens were re-evaluated by a pathologist. A total of 602 new lung cancer cases (85% male, 15% female) were diagnosed during the years 1990-1992, the annual incidence per 100,000 being 63 for males and 9.5 for females. The number not reported to the Finnish Cancer Registry was low (<1%). Lung cancer was confirmed histologically in 381 cases (63%) and in addition cytologically in 135 cases (23%). Squamous cell carcinoma was the most common histological type (40%), the proportion of adenocarcinoma being 26%, small cell carcinoma 24% and large cell carcinoma 4%. The incidence of lung cancer had decreased significantly among males (from 87 to 63 per 100,000) compared with 20 yrs earlier but had increased among females (from 4.1 to 9.5), chiefly on account of adenocarcinoma. The findings of this prospective study show an increase in the incidence of lung adenocarcinoma among females, a histological type which is less closely related to smoking than the other cancers. This suggests that other risk factors may play an increasing role in the aetiology of lung cancer.


Rumination and anxiety mediate the effect of loneliness on depressed mood and sleep quality in college students.
We examined the mechanisms that underlie the observed relationships between loneliness and depressed mood and poor sleep quality in college students. This study was the first to investigate whether rumination and trait anxiety are psychological mechanisms that mediate this relationship. In Study 1 (n = 1,244), using factor analysis with cross-sectional data, we established that loneliness and rumination are distinct constructs. We then collected survey data in two cross-sectional samples (ns = 300 and 218) and one prospective (n = 334) sample to test whether rumination and anxiety were mediators of the relationship between loneliness and depressed mood and poor sleep quality. Structural equation modeling was used to test the proposed relationships. Participants completed self-report measures of loneliness, rumination, trait anxiety, depressed mood, and sleep quality. In addition, measures of hostility, neuroticism, negative affect, and tobacco use were also assessed and tested as mediators, while social support was assessed and tested as a moderator. Consistent across the three studies, we found that rumination and trait anxiety fully mediated the associations between loneliness and depressed mood as well as poor sleep quality; these relationships held after testing all other factors. This study helps explain how loneliness dynamics relate to poor health and suggests specific points of departure for the development of interventions.


Automated reading of MIC microdilution trays containing fluorogenic enzyme substrates with the Sensititre Autoreader.
The Sensititre Autoreader is a microcomputer-driven instrument capable of automatically reading antimicrobial susceptibility microdilution trays. The instrument measures the fluorescence liberated by bacterial enzymatic activity on fluorogenic substrates as an indicator of growth in each well. A mathematical algorithm converts the fluorescent signals from an antimicrobial dilution series to an MIC endpoint. A three-center study evaluated the performance of the Autoreader in comparison with MIC determined visually in a duplicate set of control plates lacking fluorogenic substrate. Among 828 isolates of gram-negative bacilli tested against 17 antimicrobial agents, Autoreader 18-h MIC were within +/- 1 twofold dilution of control MIC values (agreement) in 95.3% of instances. In 3.5% of the instances, Autoreader values occurred +/- 2 half-step dilutions from control values (minor discrepancy), and in only 1.2% of instances did Autoreader values deviate from control values by greater than +/- 2 dilution steps (major discrepancy). Agreement, minor discrepancies, and major discrepancies were noted among 148 gram-positive cocci tested against 11 antimicrobial agents in 93.5, 4.8, and 1.7% of the instances, respectively. Over half of the major discrepancies noted with gram-negative bacilli occurred with Proteus mirabilis-beta-lactam combinations, a problem that was resolved when a lower initial inoculum was used. Inter-and intralaboratory reproducibility was excellent. Standard Sensititre susceptibility trays may be instrument read at 18 h reproducibly and accurately with only slight modification of conventional procedures to include fluorogenic enzyme substrates in the incubation broth.


Outcome analysis of factors impacting the plastic surgery match.
Matching into an integrated plastic surgery program has become highly competitive. As a result it has become more difficult for both the applicants and the residency programs to determine which attributes are most important to match in plastic surgery and, more importantly, to make a surgeon who will contribute to the future of our specialty. This study was conducted to analyze potential associations between a successful match into plastic surgery and the number of interviews offered and attended, Alpha Omega Alpha (AOA) membership, and participation in away rotations. Increased competitiveness of the specialty also has required that the applicant spend significant time and money on the match process to improve his chances. Therefore, we looked at the financial impact of the interview process as well as at compliance with the new communication mandate by the Plastic Surgery Residency Review Committee designed to decrease some of the time and monetary costs associated with the match process. An anonymous 30-item survey was e-mailed to all the applicants to our institution last year. The survey consisted of questions addressing applicant profile with specific questions regarding the interview process. Descriptive statistics, including frequencies and proportions for each of the questions, were calculated. To assess the relationship between categorical outcomes, a Fisher exact test was used. Results with a P value less than 0.05 were considered to be statistically significant. Considering matching as the primary outcome measure, a statistically significant relationship was found with the number of plastic surgery interview invitations received and attended (P < 0.0001 for both), as well as with AOA membership (P = 0.018), with 89% (32/36) of the responders in AOA matching into plastic surgery. Although doing an away rotation did not have a significant association with match rate, one-third of responders matched where they did an away rotation. Gender was not found to influence match rate. This study supports with hard data the assumptions regarding matching into a competitive specialty: the more interview invitations received and interviews attended, and the more academically competitive the applicant, the more likely the applicant is to match. By applying this data, more precise guidelines may be developed to advise applicants concerning preparation for a successful match.


Mammal extinction facilitated biome shift and human population change during the last glacial termination in East-Central Europe.
The study of local extinction times, together with the associated environmental and human population changes in the last glacial termination, provides insights into the causes of mega- and microfauna extinctions. In East-Central (EC) Europe, groups of Palaeolithic humans were present throughout the last glacial maximum, but disappeared suddenly around 15,200 cal BP. In this study cave sediment profiles dated using radiocarbon techniques and a large set of mammal bones dated directly by AMS 14C were used to determine local extinction times. These were, in turn, compared to changes in the total megafauna population of EC Europe derived from coprophilous fungi, the Epigravettian population decline, quantitative climate models, pollen and plant macrofossil inferred climate, as well as to biome reconstructions. The results suggest that the population size of large herbivores decreased in the area after 17,700 cal BP, when temperate tree abundance and warm continental steppe cover both increased in the lowlands. Boreal forest expansion started around 16,200 cal BP. Cave sediments show the decline of narrow-headed vole and arctic lemming populations specifically associated with a tundra environment at the same time and the expansion of the common vole, an inhabitant of steppes. The last dated appearance of arctic lemming was at ~ 16,640 cal BP, while that of the narrow-headed vole at ~ 13,340, and the estimated extinction time of woolly mammoth was either at 13,830 (GRIWM) or 15,210 (PHASE), and reindeer at 11,860 (GRIWM) or 12,550 cal BP (PHASE). The population decline of the large herbivore fauna slightly preceded changes in terrestrial vegetation, and likely facilitated it via a reduction in the intensity of grazing and the concomitant accumulation of plant biomass. Furthermore, it is possible to conclude that the Late Epigravettian population had high degree of quarry-fidelity; they left the basin when these mammals vanished.


Comparison between transradial and transfemoral percutaneous coronary intervention in acute ST-elevation myocardial infarction.
Transradial (TR) access is increasingly being used in percutaneous coronary intervention (PCI). However, its role in PCI for ST-segment elevation myocardial infarction remains controversial because of concerns of procedural complexity adversely affecting the promptness of reperfusion. In this study, 150 consecutive patients who underwent PCI for acute ST-segment elevation myocardial infarction over a period of 24 months were prospectively evaluated; 46 had TR access (31%) and 104 (69%) had transfemoral (TF) access. All patients received thienopyridines, aspirin, and heparin per routine management. There were no significant differences between the TR access and TF access groups with respect to age (62.2 ± 11.6 vs 64.7 ± 14.1, p = 0.28), gender (76.1% vs 72.1% men, p = 0.69), or incidence of diabetes (23.9% vs 26.9%, p = 0.84). The TR and TF access groups were comparable with respect to door-to-balloon time (79.2 ± 32.3 vs 86.8 ± 51.8 minutes, p = 0.67) and amount of contrast used (190.5 ± 101.5 vs 172.2 ± 81.7 ml, p = 0.24). Total fluoroscopy time was longer in the TR access group compared to the TF access group (21.7 ± 12.7 vs 14.4 ± 10.4 minutes, p <0.0001). Postprocedural Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow was comparable for the 2 groups (87% for the TF group and 96% for the TR group, p = 0.15). There were no vascular complications in the TR access group compared to the TF access group (0% vs 5.8%, p = 0.18). In conclusion, this single-center observational study shows that TR access for PCI in STEMI is feasible and that it has fewer vascular complications and shorter length of hospital stay than the TF approach.


IV fosphenytoin in obese patients: Dosing strategies, safety, and efficacy.
Previous studies evaluated the disposition of IV phenytoin loading doses and found that obese patients had increased drug distribution into excess body weight, larger volumes of distribution, and longer half-lives when compared to their nonobese counterparts. We assess the safety and efficacy of fosphenytoin loading doses in patients with different body mass indices (BMIs). A retrospective chart review was conducted in 410 patients who received fosphenytoin. Patients were divided into 2 groups: BMI <30 (nonobese) and BMI ≥30 (obese). Patient demographics, fosphenytoin dose administered in mg/kg body weight, renal and liver function tests, fosphenytoin drug levels, and pre- and post-fosphenytoin administration vital signs were collected to assess for adverse events. Necessity of additional antiepileptic loading doses was used as a surrogate for clinical efficacy. The median dose of fosphenytoin administered was 19 mg/kg (interquartile range 15-20). The most frequently encountered adverse event was hypotension, which occurred in 39% of the cohort. Using a Bonferroni adjustment for multiple comparisons, there were no differences in adverse events between the 2 groups. The need for additional antiepileptic loading doses was not different between the 2 groups (p = 0.07). The incidence of adverse events and the need for repeat loading antiepileptic medications was similar between the 2 groups. From our findings, the patients in our study did not receive empiric loading dose adjustments and the current method of loading fosphenytoin achieves similar outcomes, regardless of the patient's BMI.


Rapid Detection of Total Viable Count in Intact Beef Dishes Based on NIR Hyperspectral Hybrid Model.
The total viable count (TVC) of bacteria is an important index to evaluate the freshness and safety of dishes. To improve the accuracy and robustness of spectroscopic detection of total viable bacteria count in a complex system, a new method based on a near-infrared (NIR) hyperspectral hybrid model and Support Vector Machine (SVM) algorithms was developed to directly determine the total viable count in intact beef dish samples in this study. Diffuse reflectance data of intact and crushed samples were tested by NIR hyperspectral and processed using Multiplicative Scattering Correction (MSC) and Competitive Adaptive Reweighted Sampling (CARS). Kennard-Stone (KS) and Samples Set Partitioning Based on Joint X-Y Distance (SPXY) algorithms were used to select the optimal number of standard samples transferred by the model combined with root mean square error. The crushed samples were transferred into the complete samples prediction model through the Direct Standardization (DS) algorithm. The spectral hybrid model of crushed samples and full samples was established. The results showed that the Determination Coefficient of Calibration (RP2) value of the total samples prediction set increased from 0.5088 to 0.8068, and the value of the Root Mean Square Error of Prediction (RMSEP) decreased from 0.2454 to 0.1691 log10 CFU/g. After establishing the hybrid model, the RMSEP value decreased by 9.23% more than before, and the values of Relative Percent Deviation (RPD) and Reaction Error Relation (RER) increased by 12.12% and 10.09, respectively. The results of this study showed that TVC instewed beef samples can be non-destructively determined based on the DS model transfer method combined with the hybrid model strategy. This study provided a reference for solving the problem of poor accuracy and reliability of prediction models in heterogeneous samples.


Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor.
Vascular endothelial growth factor (VEGF) is a leading candidate for an endogenous mediator of tumor angiogenesis. Recently, two endothelial cell surface receptors, flk-1 and flt-1, have been shown to mediate the angiogenic activities of VEGF. In this study, we have evaluated whether a soluble VEGF receptor could suppress tumor angiogenesis and thereby inhibit tumor growth. A soluble VEGF receptor was constructed by fusing the entire extracellular domain of murine flk-1 to a six-histidine tag at the COOH terminus (ExFlk.6His). In vitro, recombinant ExFlk.6His protein bound VEGF with high affinity (Kd, 16 nM) and blocked receptor activation in a dose-dependent manner and inhibited VEGF-induced endothelial cell proliferation and migration. ExFlk.6His bound to endothelial cells only in the presence of VEGF, and cell surface cross-linking yielded a high molecular weight complex consistent with the VEGF-mediated formation of a heterodimer between ExFlk.6His and the endogenous VEGF receptor. In vivo, ExFlk.6His potently inhibited corneal neovascularization induced by conditioned media from a rat mammary carcinoma cell line (R3230AC). Moreover, when ExFlk.6His protein was administered into a cutaneous tumor window chamber concomitantly with R3230AC carcinoma transplants, tumor growth was inhibited by 75% (P < 0.005) and vascular density was reduced by 50% (P < 0.002) compared with control-treated tumors. These results demonstrate the potential of ExFlk.6His to inhibit VEGF action by a potent "dominant-negative" mechanism and suggest that targeting VEGF action using a soluble receptor may be an effective antiangiogenic therapy for cancer and other "angiogenic" diseases.


Molecular analysis as an aid to assess the public health risk of non-O157 Shiga toxin-producing Escherichia coli strains.
Shiga toxin-producing Escherichia coli (STEC) strains are commensal bacteria in cattle with high potential for environmental and zoonotic transmission to humans. Although O157:H7 is the most common STEC serotype, there is growing concern over the emergence of more than 200 highly virulent non-O157 STEC serotypes that are globally distributed, several of which are associated with outbreaks and/or severe human illness such as hemolytic-uremic syndrome (HUS) and hemorrhagic colitis. At present, the underlying genetic basis of virulence potential in non-O157 STEC is unknown, although horizontal gene transfer and the acquisition of new pathogenicity islands are an expected origin. We used seropathotype classification as a framework to identify genetic elements that distinguish non-O157 STEC strains posing a serious risk to humans from STEC strains that are not associated with severe and epidemic disease. We report the identification of three genomic islands encoding non-LEE effector (nle) genes and 14 individual nle genes in non-O157 STEC strains that correlate independently with outbreak and HUS potential in humans. The implications for transmissible zoonotic spread and public health are discussed. These results and methods offer a molecular risk assessment strategy to rapidly recognize and respond to non-O157 STEC strains from environmental and animal sources that might pose serious public health risks to humans.


Differential reaction norms to ocean acidification in two oyster species from contrasting habitats.
Ocean acidification (OA), a consequence of the increase in anthropogenic emissions of carbon dioxide, causes major changes in the chemistry of carbonates in the ocean with deleterious effects on calcifying organisms. The pH/PCO2 range to which species are exposed in nature is important to consider when interpreting the response of coastal organisms to OA. In this context, emerging approaches, which assess the reaction norms of organisms to a wide pH gradient, are improving our understanding of tolerance thresholds and acclimation potential to OA. In this study, we deciphered the reaction norms of two oyster species living in contrasting habitats: the intertidal oyster Crassostrea gigas and the subtidal flat oyster Ostrea edulis, which are two economically and ecologically valuable species in temperate ecosystems. Six-month-old oysters of each species were exposed in common garden tanks for 48 days to a pH gradient ranging from 7.7 to 6.4 (total scale). Both species were tolerant down to a pH of 6.6 with high plasticity in fitness-related traits such as survival and growth. However, oysters underwent remodelling of membrane fatty acids to cope with decreasing pH along with shell bleaching impairing shell integrity and consequently animal fitness. Finally, our work revealed species-specific physiological responses and highlights that intertidal C. gigas seem to have a better acclimation potential to rapid and extreme OA changes than O. edulis. Overall, our study provides important data about the phenotypic plasticity and its limits in two oyster species, which is essential for assessing the challenges posed to marine organisms by OA.


Fungal colonization of the paranasal sinuses.
Fungal infection of the paranasal sinuses occur in four primary types: acute invasive (1), chronic invasive (2), chronic fungus ball (3) and allergic fungal sinusitis (4). The first and second form can be fatal and is often found in immunosuppressed patients. The present paper concerns a group of immunocompetent patients with non-invasive chronic sinusitis caused by moulds. Over the period from 1994 to 1998, 132 tissue samples from the paranasal sinuses obtained by endoscopic operation from 117 patients was examined for mycotic infections. The mycological examination was carried out if granulomatous and crumbly material was seen in the sinus by endoscopy (91 times maxillary sinus, 23 times ethmoid sinus, 11 times frontal sinus, 7 times sphenoid sinus). Out of 117 patients 29 were positive (24,9%). From 132 surgical specimens fungi were proved in 34 times (25,7%). The following fungal species were isolated: Aspergillus fumigatus 17 times, other Aspergillus spp 6 times, Alternaria alternate 2, Penicillium rugulosum 1, and moulds without differentiation 5 times. In the histological examination an invasive mycelial growth in the mucous membrane or in the bones was never observable. Our findings represented a commensal colonization of the paranasal sinuses, but not a mycosis. The colonization is evidently assisted by a chronic hyperthrophic sinusitis with increased mucus production which impedes the mucociliary clearance. For immunosuppressed patients, however, this situation causes a danger of invasion with fatal consequences.


Crystal structure of Schmallenberg orthobunyavirus nucleoprotein-RNA complex reveals a novel RNA sequestration mechanism.
Schmallenberg virus (SBV) is a newly emerged orthobunyavirus (family Bunyaviridae) that has caused severe disease in the offspring of farm animals across Europe. Like all orthobunyaviruses, SBV contains a tripartite negative-sense RNA genome that is encapsidated by the viral nucleocapsid (N) protein in the form of a ribonucleoprotein complex (RNP). We recently reported the three-dimensional structure of SBV N that revealed a novel fold. Here we report the crystal structure of the SBV N protein in complex with a 42-nt-long RNA to 2.16 Å resolution. The complex comprises a tetramer of N that encapsidates the RNA as a cross-shape inside the protein ring structure, with each protomer bound to 11 ribonucleotides. Eight bases are bound in the positively charged cleft between the N- and C-terminal domains of N, and three bases are shielded by the extended N-terminal arm. SBV N appears to sequester RNA using a different mechanism compared with the nucleoproteins of other negative-sense RNA viruses. Furthermore, the structure suggests that RNA binding results in conformational changes of some residues in the RNA-binding cleft and the N- and C-terminal arms. Our results provide new insights into the novel mechanism of RNA encapsidation by orthobunyaviruses.


Comparative transcriptome analysis of the necrotrophic fungus Ascochyta rabiei during oxidative stress: insight for fungal survival in the host plant.
Localized cell death, known as the hypersensitive response (HR), is an important defense mechanism for neutralizing phytopathogens. The hallmark of the HR is an oxidative burst produced by the host plant. We aimed to identify genes of the necrotrophic chickpea blight fungus Ascochyta rabiei that are involved in counteracting oxidative stress. A subtractive cDNA library was constructed after menadione treatment, which resulted in the isolation of 128 unigenes. A reverse northern blot was used to compare transcript profiles after H(2)O(2), menadione and sodium nitroprusside treatments. A total of 70 unigenes were found to be upregulated by more than two-fold following menadione treatment at different time intervals. A large number of genes not previously associated with oxidative stress were identified, along with many stress-responsive genes. Differential expression patterns of several genes were validated by quantitative real-time PCR (qRT-PCR) and northern blotting. In planta qRT-PCR of several selected genes also showed differential expression patterns during infection and disease progression. These data shed light on the molecular responses of the phytopathogen A. rabiei to overcome oxidative and nitrosative stresses and advance the understanding of necrotrophic fungal pathogen survival mechanisms.


Biomechanical considerations in the design of graft: the homeostasis hypothesis.
Since its inception in the 1960s, coronary artery bypass graft (CABG) evolved as one of the most common, best documented, and most effective of all major surgical treatments for ischemic heart disease. Despite its widespread use, however, the outcome is not always completely satisfactory. The objective of this review is to highlight the physical determinants of biomechanical design of CABG so that future procedures would have prolonged patency and better outcome. Our central axiom postulates the existence of a mechanical homeostatic state of the blood vessel, i.e., the variation in vessel wall stresses and strains are relatively small under physiological conditions. Any perturbation of mechanical homeostasis leads to growth and remodeling. In this sense, stenosis and failure of a graft may be viewed as an adaptation process gone awry. We outline the principles of engineering design and discuss the biofluid and biosolid mechanics principles that may have the greatest bearing on mechanical homeostasis and the long-term outcome of CABG.


Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa.
In cystic fibrosis (CF), defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells and submucosal glands results in chronic pulmonary infection with Pseudomonas aeruginosa. The pulmonary infection incites an intense host inflammatory response, causing progressive suppurative pulmonary disease. Mouse models of CF, however, fail to develop pulmonary disease spontaneously. We examined the effects of bronchopulmonary infection on mice homozygous for the S489X mutation of the CFTR gene using an animal model of chronic Pseudomonas endobronchial infection. Slurries of sterile agarose beads or beads containing a clinical isolate of mucoid P. aeruginosa were instilled in the right lung of normal or CF mice. The mortality of CF mice inoculated with Pseudomonas-laden beads was significantly higher than that of normal animals: 82% of infected CF mice, but only 23% of normal mice, died within 10 d of infection (P = 0.023). The concentration of inflammatory mediators, including TNF-alpha, murine macrophage inflammatory protein-2, and KC/N51, in bronchoalveolar lavage fluid in CF mice 3 d after infection and before any mortality, was markedly elevated compared with normal mice. This inflammatory response also correlated with weight loss observed in both CF and normal littermates after inoculation. Thus, this model may permit examination of the relationship of bacterial infections, inflammation, and the cellular and genetic defects in CF.


Dapagliflozin: a new sodium-glucose cotransporter 2 inhibitor for treatment of type 2 diabetes.
The pharmacologic properties and clinical efficacy of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes, are reviewed. Dapagliflozin (Farxiga, AstraZeneca) is a selective SGLT2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Dapagliflozin lowers blood glucose independent of insulin secretion and action by inhibiting renal reabsorption of glucose, thus promoting increased urinary excretion of glucose. Dapagliflozin has been shown to improve glycemic parameters in patients with type 2 diabetes when used as monotherapy or in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin. Dapagliflozin treatment is associated with weight reduction, it has a low intrinsic propensity to cause hypoglycemia, and it may offer the advantage of a complementary mechanism of action when added to other therapies. During Phase III clinical trials, dapagliflozin was generally well tolerated, with an overall frequency of adverse events similar to that reported with placebo use. However, increased rates of genital and, in some trials, urinary tract infections have been reported in dapagliflozin-treated groups relative to placebo groups. Pooled data from clinical trials indicated an imbalance in bladder cancer cases between dapagliflozin-treated and placebo groups; however, most cases were diagnosed within one year of exposure. Ongoing research is expected to further delineate the effects of dapagliflozin on bladder cancer risk and cardiovascular safety measures. Dapagliflozin, an SGLT2 inhibitor, offers a novel treatment option for type 2 diabetes that is independent of insulin secretion or action.


Direct Parametric Reconstruction With Joint Motion Estimation/Correction for Dynamic Brain PET Data.
Direct reconstruction of parametric images from raw photon counts has been shown to improve the quantitative analysis of dynamic positron emission tomography (PET) data. However it suffers from subject motion which is inevitable during the typical acquisition time of 1-2 hours. In this work we propose a framework to jointly estimate subject head motion and reconstruct the motion-corrected parametric images directly from raw PET data, so that the effects of distorted tissue-to-voxel mapping due to subject motion can be reduced in reconstructing the parametric images with motion-compensated attenuation correction and spatially aligned temporal PET data. The proposed approach is formulated within the maximum likelihood framework, and efficient solutions are derived for estimating subject motion and kinetic parameters from raw PET photon count data. Results from evaluations on simulated [11C]raclopride data using the Zubal brain phantom and real clinical [18F]florbetapir data of a patient with Alzheimer's disease show that the proposed joint direct parametric reconstruction motion correction approach can improve the accuracy of quantifying dynamic PET data with large subject motion.


[Rs17042171 at chromosome 4q25 is associated with atrial fibrillation in the Chinese Han population from the central plains].
To determine the correlations of single nucleotide polymorphisms (SNPs) with atrial fibrillation (AF) in the Chinese Han population from the central plains. Methods: A total of 168 hospitalized patients, including 56 AF and 112 controls, were recruited in this case-control study. The clinical data were obtained from the medical records. All 5 SNPs, rs337711 in KCNN2, rs11264280 near KCNN3, rs17042171 near PITX2, rs6771157 and rs6795970 in SCN10A, were genotyped using amplification refractory mutation system-polymerase chain reaction or direct sequencing. The χ2 test was used to compare categorical variables and preliminarily examine correlations between the genotype frequencies and AF. Subsequently, a logistic regression model was constructed to determine the associations between the SNPs and AF based on the above screened results. Odds ratios (ORs) and 95% confidence interval (CI) were calculated to assess the strength of the correlations. Moreover, we downloaded the genotype data from the HapMap Project for linkage disequilibrium analysis of rs17042171. Results: AF patients were likely to be of older age and longer left atrial diameter and had more coronary artery disease and higher hypertension compared with the control group (P<0.05). Among the 5 SNPs, the frequency distribution of genotype AA for rs17042171 was significantly different between the AF and control groups (P<0.05). After adjusting for several covariates, there was still a high risk ratio in patients with the AA genotype compared with the AC+CC genotype (OR: 5.591, 95%CI 2.176 to 14.365, P-B<0.008). Similarly, stratification analysis on the AA genotype demonstrated significant differences between rs17042171 and persistent AF. However, there were not significant correlations between AF and the control groups for the other 4 SNPs (P<0.05). Conclusion: Rs17042171, near PITX2 on chromosome 4q25, is associated with AF susceptibility in the Chinese Han population from the central plains, suggesting that this SNP can provide a new strategy for clinical diagnosis in AF patients.


Experimental demonstration of an inertial collimation mechanism in nested outflows.
Interaction between a central outflow and a surrounding wind is common in astrophysical sources powered by accretion. Understanding how the interaction might help to collimate the inner central outflow is of interest for assessing astrophysical jet formation paradigms. In this context, we studied the interaction between two nested supersonic plasma flows generated by focusing a long-pulse high-energy laser beam onto a solid target. A nested geometry was created by shaping the energy distribution at the focal spot with a dedicated phase plate. Optical and x-ray diagnostics were used to study the interacting flows. Experimental results and numerical hydrodynamic simulations indeed show the formation of strongly collimated jets. Our work experimentally confirms the "shock-focused inertial confinement" mechanism proposed in previous theoretical astrophysics investigations.


Optimizing exercise for fat loss.
From the standpoint of promoting fat loss, the chief benefits of aerobic exercise are attributable to fat oxidation during exercise and a post-exercise reduction of respiratory quotient. The ability of exercise to selectively promote fat oxidation should be optimized if exercise is done post-absorptively (preferably during morning fasting metabolism), if caffeine and possibly hydroxycitrate/carnitine are administered prior to exercise, if the exercise regimen is of moderate intensity and prolonged duration, and if no calories are ingested for several hours following exercise. A simple mathematical model is presented which delineates the factors that determine daily fat balance during exercise training. This model clarifies the crucial importance of low-fat eating if exercise is to have an optimal impact on fat stores. As a complement to aerobics, resistance exercise can benefit dieters by helping to preserve lean mass and metabolic rate in the face of a persistently negative caloric balance.


Three-Way DNA Junction as an End Label for DNA in Atomic Force Microscopy Studies.
Atomic Force Microscopy (AFM) is widely used for topographic imaging of DNA and protein-DNA complexes in ambient conditions with nanometer resolution. In AFM studies of protein-DNA complexes, identifying the protein's location on the DNA substrate is one of the major goals. Such studies require distinguishing between the DNA ends, which can be accomplished by end-specific labeling of the DNA substrate. We selected as labels three-way DNA junctions (3WJ) assembled from synthetic DNA oligonucleotides with two arms of 39-40 bp each. The third arm has a three-nucleotide overhang, GCT, which is paired with the sticky end of the DNA substrate generated by the SapI enzyme. Ligation of the 3WJ results in the formation of a Y-type structure at the end of the linear DNA mole cule, which is routinely identified in the AFM images. The yield of labeling is 69%. The relative orientation of arms in the Y-end varies, such dynamics were directly visualized with time-lapse AFM studies using high-speed AFM (HS-AFM). This labeling approach was applied to the characterization of the nucleosome arrays assembled on different DNA templates. HS-AFM experiments revealed a high dynamic of nucleosomes resulting in a spontaneous unraveling followed by disassembly of nucleosomes.


Text Messaging Interventions for Improvement in Physical Activity and Sedentary Behavior in Youth: Systematic Review.
The use of text messages (short message service, SMS) to change physical activity and sedentary behavior in youth is of interest due to the need for novel, more effective intervention approaches. Previous reviews have examined a variety of technology-based interventions and their impact on different health behaviors, but evidence regarding the impact of just SMS on physical activity and sedentary behavior is lacking. The aim of this study was to assess the effectiveness and use of theory of SMS interventions for improving physical activity and sedentary behavior in youth. Authors systematically searched electronic databases from March to November 2017. Citations were sifted using additional reviewers, and a qualitative synthesis of eligible studies was conducted using piloted data extraction forms. To be eligible for inclusion, studies had to be of a randomized controlled or quasi-experimental design, incorporate SMS, involve adolescents between the ages of 10 and 19 years, and assess at least one physical activity or sedentary behavior outcome. Risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool. A total of 13 studies reporting 11 interventions were included in the qualitative analysis. Studies included interventions that were conducted in schools, online, or face-to-face. Studies were of high heterogeneity with regard to study duration, participant characteristics, intervention content, and outcome measures. Findings were equivocal with regard to intervention effectiveness for physical activity and sedentary behavior. Overall, 7 interventions resulted in an improvement for physical activity and 6 for sedentary behavior. All studies were judged to be of high risk of bias for at least 1 item. Some studies in this review showed promising results for using SMS to improve physical activity and sedentary behavior in youth. High heterogeneity of design and outcome measures precluded data pooling and conclusions as to which specific intervention elements are linked to increased effectiveness cannot be drawn. The authors propose incorporating the following elements in future studies: specific focus on desired health behavior; mixed-methods design; include long-term follow-up; include self-monitoring, goal setting, and feedback; combine SMS with a mobile app; and send 3 or more SMS text messages per week. More rigorous studies are needed to explore the relationship between intervention effectiveness and specific intervention components such as content and delivery.


IAP proteins as targets for drug development in oncology.
The inhibitors of apoptosis (IAPs) constitute a family of proteins involved in the regulation of various cellular processes, including cell death, immune and inflammatory responses, cell proliferation, cell differentiation, and cell motility. There is accumulating evidence supporting IAP-targeting in tumors: IAPs regulate various cellular processes that contribute to tumor development, such as cell death, cell proliferation, and cell migration; their expression is increased in a number of human tumor samples, and IAP overexpression has been correlated with tumor growth, and poor prognosis or low response to treatment; and IAP expression can be rapidly induced in response to chemotherapy or radiotherapy because of the presence of an internal ribosome entry site (IRES)-dependent mechanism of translation initiation, which could contribute to resistance to antitumor therapy. The development of IAP antagonists is an important challenge and was subject to intense research over the past decade. Six molecules are currently in clinical trials. This review focuses on the role of IAPs in tumors and the development of IAP-targeting molecules for anticancer therapy.


A highly conductive, pliable and foldable Cu/cellulose paper electrode enabled by controlled deposition of copper nanoparticles.
There is great interest in extending cellulosic platforms to applications in flexible, lightweight, low-cost and sustainable electronics. The critical need is the development of methods to confer electronic properties to these materials platforms (i.e., paper and fabrics). Here we report a highly conductive, pliable and foldable Cu/cellulose paper electrode enabled by a simple low-cost and scalable wet-processing method to coat a Cu nanoparticle (NP) layer on common cellulose paper, where polydopamine adhesion and electroless deposition were used to yield highly conductive paper with a sheet resistance as low as 0.01 Ω sq-1. This Cu/cellulose paper has excellent stability because of the strong adhesion between Cu NPs and cellulose, and because the methods are sufficiently mild to prevent damage to the paper substrate. This fabrication method results in the controlled deposition of Cu NPs and yields Cu/cellulose paper with highly hydrophobic and self-cleaning properties, high photothermal conversion efficiency, and excellent electromagnetic interface (EMI) shielding effectiveness. This high-performance Cu/cellulose paper could have promising application potential for a range of emerging applications in flexible electronics and packaging.


Ternary monolayers as DNA recognition interfaces for direct and sensitive electrochemical detection in untreated clinical samples.
Detection of specific DNA sequences in clinical samples is a key goal of studies on DNA biosensors and gene chips. Herein we present a highly sensitive electrochemical genosensor for direct measurements of specific DNA sequences in undiluted and untreated human serum and urine samples. Such genosensing relies on a new ternary interface involving hexanedithiol (HDT) co-immobilized with the thiolated capture probe (SHCP) on gold surfaces, followed by the incorporation of 6-mercapto-1-hexanol (MCH) as diluent. The performance of ternary monolayers prepared with linear dithiols of different lengths was systematically examined, compared and characterized by cyclic voltammetry and electrochemical impedance spectroscopy, with HDT exhibiting the most favorable analytical performance. The new SHCP/HDT+MCH monolayer led to a 80-fold improvement in the signal-to-noise ratio (S/N) for 1 nM target DNA in undiluted human serum over the common SHCP+MCH binary alkanethiol interface, and allowed the direct quantification of the target DNA down to 7 pM (28 amol) and 17 pM (68 amol) in undiluted/untreated serum and urine, respectively. It also displayed attractive antifouling properties, as indicated from the favorable S/N obtained after a prolonged exposure (24h) to untreated biological matrices. These attractive features of the SHCP/HDT+MCH sensor interface indicate considerable promise for a wide range of clinical applications.


Differential Susceptibility and Vulnerability of Brain Cells in C57BL/6 Mouse to Mitochondrial Dysfunction Induced by Short-Term Cuprizone Exposure.
Cuprizone (CPZ) is a chemical chelator toxic to mitochondria of cells. While inducing oligodendrocyte (OL) loss and demyelination, CPZ caused no fatal damage to the other brain cells (neurons, astrocytes, and microglia) in previous studies, suggesting differential susceptibility and vulnerability of brain cells to the CPZ intoxication. To demonstrate this interpretation, C57BL/6 mice were fed rodent chow without or with CPZ (0.2%, w/w) for 7 days. One day later, mitochondrial function of brain cells was assessed by proton magnetic resonance spectroscopy (1H-MRS) and biochemical analysis. Another batch of mice were processed to localize the CPZ-induced damage to mitochondrial DNA, label brain cells, and identify apoptotic cells. Compared to controls, CPZ-exposed mice showed significantly lower levels of N-acetyl-L-aspartate, phosphocreatine, and ATP detected by 1H-MRS, indicating mitochondrial dysfunction in brain cells. Susceptibility analysis showed an order of OLs, microglia, and astrocytes from high to low, in terms of the proportion of 8-OHdG labeled cells in each type of these cells in corpus callosum. Vulnerability analysis showed the highest proportion of caspase-3 positive cells in labeled OLs in cerebral cortex and hippocampus, where neurons showed no caspase-3 labeling, but the highest proportion of 8-OHdG labeling, indicating a lowest vulnerability but highest susceptibility to CPZ-induced mitochondrial dysfunction. Immature OLs, microglia, and astrocytes showed adaptive changes in proliferation and activation in response to CPZ-exposure. These data for the first time demonstrated the CPZ-induced mitochondria dysfunction in brain cells of living mouse and specified the differential susceptibility and vulnerability of brain cells to the CPZ intoxication.


Prospects and challenges for intestinal microbiome therapy in pediatric gastrointestinal disorders.
Fecal microbiome (microbiota) transplantation is an emerging treatment not only for refractory/recurrent Clostridium difficile infections and chronic gastrointestinal diseases, but also for metabolic syndrome, and even possibly for neurological disorders. This non-conventional therapy has been perhaps more appropriately designated as fecal bacteriotherapy (FB) as well. The employment of FB is spreading into pediatric gastroenterology. This focused review highlights the pediatric applications of FB and discusses hypotheses for its mechanism of action. We propose that intestinal microbiome therapy may be a more appropriate term for FB, which integrates its potential future applications.


Expression profiles of miRNAs in Gossypium raimondii.
miRNAs are a class of conserved, small, endogenous, and non-protein-coding RNA molecules with 20-24 nucleotides (nt) in length that function as post-transcriptional modulators of gene expression in eukaryotic cells. Functional studies have demonstrated that plant miRNAs are involved in the regulation of a wide range of plant developmental processes. To date, however, no research has been carried out to study the expression profiles of miRNAs in Gossypium raimondii, a model cotton species. We selected 16 miRNAs to profile their tissue-specific expression patterns in G. raimondii four different tissues, and these miRNAs are reported to play important roles in plant growth and development. Our results showed that the expression levels of these miRNAs varied significantly from one to another in a tissue-dependent manner. Eight miRNAs, including miR-159, miR-162, miR-164, miR-172, miR-390, miR-395, miR-397, and miR-398, exhibited exclusively high expression levels in flower buds, suggesting that these miRNAs may play significant roles in floral development. The expression level of miR-164 was relatively high in shoots beside flower buds, implying that the function of miR-164 is not only limited to floral development but it may also play an important role in shoot development. Certain miRNAs such as miR-166 and miR-160 were extremely highly expressed in all of the four tissues tested compared with other miRNAs investigated, suggesting that they may play regulatory roles at multiple development stages. This study will contribute to future studies on the functional characterization of miRNAs in cotton.


The beta 1-adrenergic receptor of the turkey erythrocyte. Molecular heterogeneity revealed by purification and photoaffinity labeling.
The beta 1-adrenergic receptor of turkey erythrocytes has been purified by a combination of affinity and high performance steric exclusion chromatography. These procedures provide preparations with specific activities of greater than 15,000 pmol/mg of protein with an overall recovery of approximately 30% of the receptor activity solubilized from membrane preparations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radioiodinated purified receptor reveals two bands of labeled protein with apparent Mr = 40,000 +/- 2,000 and 45,000 +/- 3,000 in a 3-4:1 ratio. These same two peptides can also be labeled specifically and in approximately the same ration in both membranes and purified preparations using the photoaffinity probe 125I-labeled p-azidobenzylcarazolol. When the two purified polypeptides are completely separated by high performance liquid chromatography and subjected to detailed ligand binding studies, identical beta 1-adrenergic specificities are found for the two receptor forms. Preliminary characterization of these two proteins by partial protease digestion suggests a large degree of similarity between them, albeit with some significant differences. These results demonstrate that both purification and photoaffinity labeling identify two polypeptides in turkey erythrocyte membranes as containing a beta 1-adrenergic receptor binding site. The functional and structural relationships of these two forms of the receptor remain to be elucidated.


The molecular mechanism of actinomycin D in preventing neointimal formation in rat carotid arteries after balloon injury.
The pathological mechanism of restenosis is primarily attributed to excessive proliferation of vascular smooth muscle cells (SMC). Actinomycin D has been regarded as a potential candidate to prevent balloon injury-induced neointimal formation. To explore its molecular mechanism in regulating cell proliferation, we first showed that actinomycin D markedly reduced the SMC proliferation via the inhibition of BrdU incorporation at 80 nM. This was further supported by the G1-phase arrest using a flowcytometric analysis. Actinomycin D was extremely potent with an inhibitory concentration IC50 at 0.4 nM, whereas the lethal dose LD50 was at 260 microM. In an in vivo study, the pluronic gel containing 80 nM and 80 microM actinomycin D was applied topically to surround the rat carotid adventitia; the thickness of neointima was substantially reduced (45 and 55%, respectively). The protein expression levels of proliferating cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and Raf were all suppressed by actinomycin D. Extracellular signal-regulated kinases (Erk) involved in cell-cycle arrest were found to increase by actinomycin D. These observations provide a detailed mechanism of actinomycin D in preventing cell proliferation thus as a potential intervention for restenosis.


Tetrahydrouridine specifically facilitates deoxycytidine incorporation into herpes simplex virus DNA.
As reported by Jamieson and Subak-Sharpe (J. Gen. Virol. 31:303-313, 1976), exogenous deoxycytidine is very poorly incorporated into herpes simplex virus DNA. Here it is shown that this incorporation was dramatically increased in the presence of tetrahydrouridine (THU), a specific inhibitor of cytidine-deoxycytidine deaminase. Thus, the exclusion of deoxycytidine from herpes simplex virus DNA probably results from massive degradation by the deaminase, which is consistent with the observation that in the absence of THU, most of the nucleotides formed from exogenous deoxycytidine are dUMP. The effect of tHU upon deoxycytidine incorporation was specific for herpes simplex virus-infected cells; THU did not increase deoxycytidine incorporation into DNA of uninfected cells. Therefore, one might expect THU to enhance the antiviral activity of 1-beta-D-arabinofuranasylcytosine since this analog is also readily deaminated. However, THU increased both the antiviral activity and the cell toxicity only slightly and to about the same extent. Therefore, the metabolism of 1-beta-D-arabnofuranosylcytosine is different from that of deoxycytidine in herpes simplex virus-infected cells.


In-silico selection of cancer blood plasma proteins by integrating genomic and proteomic databases.
Blood protein markers have been studied for the clinical management of cancer. Due to the large number of the proteins existing in blood, it is often necessary to pre-select potential protein markers before experimental studies. However, to date there is a lack of automated method for in-silico selection of cancer blood proteins that integrates the information from both genetic and proteomic studies in a cancer-specific manner. In this work, we synthesized both genomic and proteomic information from several open access databases and established a bioinformatic pipeline for in-silico selection of blood plasma proteins overexpressed in specific type of cancer. We demonstrated the workflow of this pipeline with an example of breast cancer, while the methodology was applicable for other cancer types. With this pipeline we obtained 10 candidate biomarkers for breast cancer. The proposed pipeline provides a useful and convenient tool for in-silico selection of candidate blood protein biomarkers for a variety of cancer research.


Effect of 3,3'-iminodipropionitrile on experimental intravitreal proliferation in albino rabbits.
The effect of 3,3'-iminodipropionitrile (IDPN) on experimental intravitreal proliferation in albino rabbits was studied by light and electron microscopy. About 2.5 x 10(5) tissue cultured fibroblasts were injected into the vitreous cavity of albino rabbits. Immediately after the injection, phosphate-buffered solution (PBS) or IDPN was injected into the vitreous cavity. Four weeks later, traction retinal detachment was seen in 12 of 18 control eyes (67%), 6 of 10 eyes treated with 20 mg IDPN (60%), 5 of 10 eyes treated with 40 mg IDPN (50%), and 3 of 20 eyes treated with 80 mg IDPN (15%). The intravitreal injection of 80 mg of IDPN inhibited traction detachment significantly. In eyes treated with 80 mg of IDPN, fibroblasts in the proliferative tissue were slender, irregularly arranged, and mostly degenerated. Collagen fibers were slender and fragmented. These results indicate that the intravitreal injection of IDPN might be helpful in the therapy for proliferative vitreoretinopathy.


Two related viroids cause grapevine yellow speckle disease independently.
We have confirmed that two closely related circular RNA molecules previously named grapevine yellow speckel viroid (GYSV) and grapevine viroid 1B (GV1B) are indeed viroids. Electron microscopy after spreading under non-denaturing conditions revealed that GYSV has a rod-like structure typical of viroids. Purified GYSV and GV1B replicated independently in inoculated grapevine seedlings and some of the infected plants developed yellow speckle symptoms indicating that both viroids can cause grapevine yellow speckle disease. Plus-sense RNA transcripts derived from a dimeric GYSV cDNA clone induced yellow speckle symptoms in a grapevine seedling confirming the role of GYSV in the yellow speckle disease. Two oligonucleotide probes were synthesized for the detection of the two related viroids. The probes which could detect each viroid individually were used to assess correlations between the occurrence of these viroids and the incidence of the disease.


Association Between Statin Use and Sex Hormone in the Multi-Ethnic Study of Atherosclerosis Cohort.
Based on the 2018 American College of Cardiology/American Heart Association cholesterol guidelines, the number of individuals eligible for statin therapy to reduce atherosclerotic cardiovascular disease risk has greatly expanded. Statins inhibit cholesterol biosynthesis, which can impair gonadal steroidogenesis. We evaluated the effect of statins on endogenous sex hormones in a large epidemiological study. A total of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants underwent the baseline examination. Of these, 6171 had measurements of serum sex hormones available: dehydroepiandrosterone (DHEA), SHBG, estradiol, and total and bioavailable testosterone. Multivariable linear regression models were used to assess the relationship of statin use with each sex hormone. A total of 345 women (17.4%) and 464 men (14.7%) were statin users (mean age, 67 years; 41% white, 29% black, 11% Chinese, and 19% Hispanic). Among the users vs nonusers of statins, the mean SHBG was 3.54 nmol/L (P < 0.01) lower in women and 3.37 nmol/L (P < 0.001) lower in men; the mean DHEA was 1.06 nmol/L (P < 0.05) lower in women and 0.70 nmol/L (P < 0.01) lower in men, after adjustment for potential confounders. With further propensity score adjustment, the mean DHEA and SHBG levels were 0.67 nmol/L (P < 0.05) and 3.49 nmol/L (P < 0.001) lower, respectively, for statin users vs nonusers. No statistically significant association was noted between estradiol, total testosterone, and bioavailable testosterone and statin use. Statin users have lower levels of SHBG and DHEA. This is especially relevant owing to the increasing use of statin therapy.


Fetus, fasting, and festival: the persistent effects of in utero social shocks.
The Fetal Origins Hypothesis (FOH), put forward in the epidemiological literature and later flourished in the economics literature, suggests that the time in utero is a critical period for human development. However, much attention has been paid to the consequences of fetal exposures to more extreme natural shocks, while less is known about fetal exposures to milder but more commonly experienced social shocks. Using two examples of under-nutrition due to mild social shocks, i.e. Ramadan fasting and festival overspending, this paper summarizes our current knowledge, especially the contribution from economics, and key challenges in exploring fetal exposures to milder social shocks. I also discuss the salient added value of identifying milder versus more extreme fetal shocks. Finally, implications are drawn on individual decisions and public policy to improve children's well-being before they are born or even before their mothers realize that they are pregnant.


Cervical stitch (cerclage) in combination with other treatments for preventing spontaneous preterm birth in singleton pregnancies.
Preterm birth (PTB) remains the foremost global cause of perinatal morbidity and mortality. Thus, the prevention of spontaneous PTB still remains of critical importance. In an attempt to prevent PTB in singleton pregnancies, cervical cerclage, in combination with other treatments, has been advocated. This is because, cervical cerclage is an intervention that is commonly recommended in women with a short cervix at high risk of preterm birth but, despite this, many women still deliver prematurely, as the biological mechanism is incompletely understood. Additionally, previous Cochrane Reviews have been published on the effectiveness of cervical cerclage in singleton and multiple pregnancies, however, none has evaluated the effectiveness of using cervical cerclage in combination with other treatments. To assess whether antibiotics administration, vaginal pessary, reinforcing or second cerclage placement, tocolytic, progesterone, or other interventions at the time of cervical cerclage placement prolong singleton gestation in women at high risk of pregnancy loss based on prior history and/or ultrasound finding of 'short cervix' and/or physical examination. History-indicated cerclage is defined as a cerclage placed usually between 12 and 15 weeks gestation based solely on poor prior obstetrical history, e.g. multiple second trimester losses due to painless dilatation. Ultrasound-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation for transvaginal ultrasound cervical length < 20 mm in a woman without cervical dilatation. Physical exam-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation because of cervical dilatation of one or more centimetres detected on physical (manual) examination. We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (26 September 2019), and reference lists of retrieved studies. We included published, unpublished or ongoing randomised controlled trial (RCTs). Studies using a cluster-RCT design were also eligible for inclusion in this review but none were identified. We excluded quasi-RCTs (e.g. those randomised by date of birth or hospital number) and studies using a cross-over design. We also excluded studies that specified addition of the combination therapy after cervical cerclage because the woman subsequently became symptomatic. We included studies comparing cervical cerclage in combination with one, two or more interventions with cervical cerclage alone in singleton pregnancies. Two review authors independently screened titles and abstracts of all retrieved articles, selected studies for inclusion, extracted data, assessed risk of bias, and evaluated the certainty of the evidence for this review's main outcomes. Data were checked for accuracy. Standard Cochrane review methods were used throughout. We identified two studies (involving a total of 73 women) comparing cervical cerclage alone to a different comparator. We also identified three ongoing studies (one investigating vaginal progesterone after cerclage, and two investigating cerclage plus pessary). One study (20 women), conducted in the UK, comparing cervical cerclage in combination with a tocolytic (salbutamol) with cervical cerclage alone in women with singleton pregnancy did not provide any useable data for this review. The other study (involving 53 women, with data from 50 women) took place in the USA and compared cervical cerclage in combination with a tocolytic (indomethacin) and antibiotics (cefazolin or clindamycin) versus cervical cerclage alone - this study did provide useable data for this review (and the study authors also provided additional data on request) but meta-analyses were not possible. This study was generally at a low risk of bias, apart from issues relating to blinding. We downgraded the certainty of evidence for serious risk of bias and imprecision (few participants, few events and wide 95% confidence intervals). Cervical cerclage in combination with an antibiotic and tocolytic versus cervical cerclage alone (one study, 50 women/babies) We are unclear about the effect of cervical cerclage in combination with antibiotics and a tocolytic compared with cervical cerclage alone on the risk of serious neonatal morbidity (RR 0.62, 95% CI 0.31 to 1.24; very low-certainty evidence); perinatal loss (data for miscarriage and stillbirth only - data not available for neonatal death) (RR 0.46, 95% CI 0.13 to 1.64; very low-certainty evidence) or preterm birth < 34 completed weeks of pregnancy (RR 0.78, 95% CI 0.44 to 1.40; very low-certainty evidence). There were no stillbirths (intrauterine death at 24 or more weeks). The trial authors did not report on the numbers of babies discharged home healthy (without obvious pathology) or on the risk of neonatal death. Currently, there is insufficient evidence to evaluate the effect of combining a tocolytic (indomethacin) and antibiotics (cefazolin/clindamycin) with cervical cerclage compared with cervical cerclage alone for preventing spontaneous PTB in women with singleton pregnancies. Future studies should recruit sufficient numbers of women to provide meaningful results and should measure neonatal death and numbers of babies discharged home healthy, as well as other important outcomes listed in this review. We did not identify any studies looking at other treatments in combination with cervical cerclage. Future research needs to focus on the role of other interventions such as vaginal support pessary, reinforcing or second cervical cerclage placement, 17-alpha-hydroxyprogesterone caproate or dydrogesterone or vaginal micronised progesterone, omega-3 long chain polyunsaturated fatty acid supplementation and bed rest.


Is pertussis in infants a potential cause of retinal haemorrhages?
To determine the prevalence of retinal haemorrhages in infants with pertussis infection with the purpose of clarifying the differential diagnosis of the cases of abusive head trauma. Prospective study of children aged 15 days to 2 years admitted to our hospital with a diagnosis of pertussis over a period of 4 years (May 2004-May 2008). All children underwent one detailed ophthalmological examination within 72 h of admission. If retinal haemorrhages were detected, further investigation was undertaken to rule out systemic disorder or maltreatment. 35 children with pertussis infection were examined. None was found to have retinal haemorrhages. Therefore, applying Wilson's method, the data suggest with 95% confidence that the true effect estimate for retinal haemorrhage occurring due to symptomatic pertussis infection requiring admission to hospital is no higher than 9.9%. Pertussis infections are unlikely to cause retinal haemorrhages in children under 2 years of age.


Push-off forces in elite short-track speed skating.
This study performed an analysis of the push-off forces of elite-short-track speed skaters using a new designed instrumented short-track speed skate with the aim to improve short-track skating performance. Four different skating strokes were distinguished for short-track speed skaters at speed. The strokes differed in stroke time, force level in both normal and lateral directions, and the centre of pressure (COP) on the blade. Within the homogeneous group of male elite speed skaters (N = 6), diversity of execution of the force patterns in the four phases of skating was evident, while skating at the same velocities. The male participants (N = 6) with a better personal record (PR) kept the COP more to the rear of their blades while hanging into the curve (r = 0.82, p < 0.05), leaving the curve (r = 0.86, p < 0.05), and entering the straight (r = 0.76, p < 0.10). Furthermore, the male skaters with a better PR showed a trend of a lower lateral peak force while entering the curve (r = 0.74, p < 0.10). Females showed a trend towards applying higher body weight normalised lateral forces than the males, while skating at imposed lower velocities.


Influence of socioeconomic position and gender on current cigarette smoking among people living with HIV in sub-Saharan Africa: disentangling context from composition.
Smoking is still gaining ground in Sub-Saharan Africa, especially among socially disadvantaged groups. People living with HIV represent a subgroup with a significantly elevated prevalence of cigarette smoking. The objective of the study was to examine the influence of individual-, neighbourhood- and country-level socioeconomic position on current cigarette smoking among people living with HIV in Sub-Saharan Africa. We applied multivariable multilevel logistic regression analysis on Demographic and Health Survey data collected between 2003 and 2012 in sub-Saharan Africa. We identified 31,270 individual living with HIV (Level 1) nested within 7,054 neighbourhoods (Level 2) from 19 countries (Level 3). After adjustment for individual-, neighbourhood- and country-level factors, respondents, the following significant independent risk factors for increasing odds of being a current cigarette smokers among people living with HIV: male gender (odds ratio [OR] = 62.49; 95 % credible interval [CrI] 45.93 to 78.28), from the poorer households (OR = 1.62, 95 % CrI 1.38 to 1.90); living in urban areas (OR = 1.24, 95 % CrI 1.09 to 1.41), from neighbourhoods with low poverty rate (OR = 1.25, 95 % CrI 1.09 to 1.43), illiteracy rate (OR = 1.28, 95 % CrI 1.14 to 1.42), low unemployment rate (OR = 1.11, 95 % crI 1.01 to 1.43); and from countries with low socio-economic deprivation (OR = 1.53, 95 CrI 1.08 to 1.96). About 3.4 % and 39.4 % variation in cigarette smoking behaviour among people living with HIV is conditioned by differences between neighbourhoods and countries. Gender, education and socioeconomic context are independently associated with current cigarette smoking among people living with HIV in sub-Saharan Africa.


Tissue responses of the monkey retina: tuning and dependence on inner layer integrity.
Recent technical and conceptual advances have made it possible to experiment with models of local human inner retinal disease and changes in very small, tissue-specific signals. Local retrograde degeneration of the ganglion cells was induced in four rhesus monkeys by 160 degrees microdiathermy fiber layer burns at the nasal or temporal edges of the optic disc. There were no abnormalities of the classical electroretinograms (ERGs) during the following 210 days. With nasal lesions, pattern-evoked retinal (PERR) and cortical responses over a range of grating contrasts and spatial frequencies were largely normal. The authors found a cortical spatial tuning peak near 0.5 cycles/deg (cpd) and a retinal peak at 0.25-0.3 cpd. With temporal lesions, the retinal signals to high frequency stimuli (greater than 1.0 cpd) approached zero between 20-60 days. The cortical evoked signal declined with a course similar to the retinal components. Histological evidence was found for extensive loss of ganglion cells and fibers in a central 30-40 degrees temporal area, including the macula, 210 days after the temporal lesions. This is strong evidence that local ganglion cell-dependent electrical potentials, bearing little relation to the ERG, can be measured in response to selected stimuli.


Latent classes of smartphone dependency trajectories and predictors of classes among middle school students in South Korea.
With widespread use of smartphones, side effects of smartphone dependency among adolescents are emerging as a social problem. Screening high-risk groups is important for appropriate interventions to prevent smartphone dependency in early adolescence. This study thus aimed to identify latent classes of smartphone dependency trajectories and predictors of classes among South Korea's middle school students. We used data from 2164 middle school students from the Korean Children and Youth Panel Survey (2018-2020). Latent growth curve modeling (LGCM) was performed to confirm the longitudinal trajectory, and latent class growth modeling (LCGM) was performed to identify latent classes of middle school students' smartphone dependency. Then, multinomial logistic regression analysis was conducted to explore predictors of the classes. The LGCM showed that the trajectory of all middle school students' smartphone dependency increased (intercept 30.65, slope = 1.09). However, the LCGM identified three latent classes: (1) low-stable (intercept 23.01, nonsignificant slope), (2) medium-increasing (intercept 30.37, significant increasing slope), and (3) high-increasing (intercept 37.79, significant increasing slope). Predictors of each latent class included gender, aggressive behavior, self-esteem, parental smartphone dependency, parenting attitude, and negative peer relationships. The results indicate that the smartphone dependency trajectory of all adolescents is not the same, and there are latent classes with different trajectory patterns. These findings may contribute to the development of nursing interventions for the smartphone dependency of adolescents. Such interventions should encourage positive factors and eliminate negative factors and, especially, involve parents.


Recent advances in engineered chitosan-based nanogels for biomedical applications.
In the last few decades, chitosan-based nanostructured materials have attracted significant attention and have been applied in different biomedical fields. Chitosan-based nanogels with appealing physical and biological characteristics have been developed for various biomedical applications due to their excellent properties related to biocompatibility, biodegradability, antibacterial activity, low immunogenicity, large surface area, and stimuli responsiveness. Numerous approaches, such as physical gelation, self-assembly, polymerization, ionic gelation and microemulsion, have been employed to fabricate chitosan-based nanogels with multiple functionalities. These nanogels are promising as effective vehicles for drug delivery, cell culture, bioimaging and therapy. This paper reviews recent progress in the preparation and application of engineered chitosan-based nanogels in biomedical fields.


[Electron transport in hemoproteins. VIII. The effect of chemical modification of ferricytochrome C on the rate of its reduction by oxymyoglobin].
The influence of chemical modification of separate amino acid residues in ferricytochrome c (Cyt c) on the rate of the redox reaction with MbO2 has been studied at various pH and ionic strength values. It is shown that alkylation of His-33 and Met-65 by bromacetate does not affect the reaction rate. On the contrary, acylation of Tyr-74 or one of the neighbouring lysines, Lys-72 or Lys-73, by the spin-label N-(2,2',5,5'-tetramethyl-3-carboxypyrrolin-1-oxy)-imidazol diminishes sharply the efficiency of electron transfer in the redox system studied. Besides, unlike the reaction between native proteins, the rate of electron transfer in this case does not depend on ionic strength. The modification of Tyr-74 or Lys 72/43 does not alter the midpoint potential and the entire conformation of Cyt c. The observed effects can therefore be explained by essential disturbance of interactions, first of all, the electrostatic ones in the active complex, which is induced by the attachment of the bulky reagent to the site of "active contact" of Cyt c. Based on the obtained findings and the atomic coordinates of Cyt c, the positions of all charge and some uncharged groups on the surface of Cyt c interacting with myoglobin during electron transfer are presented.


[Chemical composition of calcium channels of characean algal cells].
The present study was performed to determine the chemical composition and molecular weight of channel-forming complex by fractioning the cell homogenate supernatant by different means (chromatography, gel-electrophoresis, using dissociating and denaturating agents). Availability of the channel-forming complexes in individual fractions is judged from reconstruction of channels in BLM. The Ca-channels reconstructed in BLM are formed by molecules of a protein nature (presumably, peptides). Their molecular weight is no more than 20000 (presumably, 5000). A high stability of spacial organization of channel forming molecules was observed. The channels--subunits aggregate without any change in properties of the selective filter. The thermodynamically preferred agagregates have conductivity of 200 pmho in 0.1 M KCl and seem to consist of 80 channels--subunits which are switched off and on all together.


Quantitative Genetic Variation in, and Environmental Effects on, Pathogen Resistance and Temperature-Dependent Disease Severity in a Wild Trout.
Health after pathogen contact varies among individuals because of differences in pathogen load (which is limited by resistance) and disease severity in response to pathogen load (which is limited by tolerance). To understand pathogen-induced host evolution, it is critical to know not only the relative contributions of nongenetic and genetic variation to resistance and tolerance but also how they change environmentally. We quantified nongenetic and genetic variation in parasite load and the associated temperature-dependent disease among trout siblings from two rivers. We detected a genetic variance for parasite load 6.6 times as large in the colder river. By contrast, genetic variance for disease traits tended to be larger in the warmer river, where the disease was manifested more severely. The relationships between disease severity and pathogen load (tolerance) exhibited plateaus at low pathogen load and stronger steepening slopes at high pathogen load in the warmer river. Our study demonstrates the environmental influence on disease severity, nongenetic and genetic variance for health-damage-limiting host abilities, and the shape of tolerance curves. Environmental variability is predicted to govern the presence and intensity of selection, change the relative contributions of nongenetic and genetic variance, and therefore hamper evolution toward more resistant and tolerant hosts.


Making Dopamine Connections in Adolescence.
A dramatic maturational process ongoing in adolescence is prefrontal cortex development, including its dopamine innervation. Dopamine axons grow from the striatum to the prefrontal cortex, the only known case of long-distance axon growth during adolescence. This is coordinated by the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer), which in turn controls the intrinsic development of the prefrontal cortex itself. Stimulant drugs in adolescence alter DCC in dopamine neurons and, in turn prefrontal cortex maturation, impacting cognitive abilities. Variations in DCC expression are linked to psychiatric conditions of prefrontal cortex dysfunction, and microRNA regulation of DCC may be key to determining adolescent vulnerability or resilience. Since early interventions are proving to effectively ameliorate disease outcome, the Netrin-1 system is a promising therapeutic target.


[Morphologic studies of the pathogenesis of ligneous conjunctivitis].
The cases of ligneous conjunctivitis published since 1964 are presented in a review of the literature. A total of 84 cases have been described. The predominance of this disease in women is lower than was previously thought. Ligneous conjunctivitis tends to occur more frequently in children. However, it is not a "disease of little girls". Two cases are described in the present paper, including pathomorphological studies. In both cases, neutrophilic granulocytes were studied by electron microscopy. The results are compared with a control case and with corresponding reports in the literature. The number of granules in the neutrophilic granulocytes was significantly reduced in both cases. In one of the cases studied the granules were increased in size. These findings support the hypothesis that ligneous conjunctivitis could be the result of a lowered resistance associated with a disturbance of wound healing.


Long-term retention of adalimumab treatment and associated prognostic factors for 1189 patients with Crohn's disease.
There are few studies on the long-term efficacy of adalimumab treatment for patients with Crohn's disease. We have conducted a large, multicenter, retrospective cohort study to evaluate the long-term retention rate and prognostic factors associated with the discontinuation of adalimumab treatment in patients with Crohn's disease. Data were collected from all patients with Crohn's disease who had received at least one induction dose of 160 mg of adalimumab between October 2010 and December 2013 at 41 institutions. The cumulative retention rates of adalimumab treatment following the first administration were estimated using the Kaplan-Meier method. Prognostic factors related to the cumulative retention rates were evaluated by log-rank tests and multivariate Cox regression analysis. A total of 1189 patients were included in the study. The 1-, 2-, 3-, and 4-year cumulative retention rates of adalimumab were 81%, 72%, 65%, and 62%, respectively. The multivariate Cox regression analysis confirmed female sex, previous infliximab use, perianal disease, concomitant treatment with prednisolone at baseline, higher C-reactive protein levels, and lower albumin levels as significant independent predictors of poor retention rate of adalimumab treatment. Significantly, more female patients than male patients discontinued adalimumab because of adverse events, especially skin reactions, infections, and arthralgia. Our data demonstrated a good retention rate of adalimumab in patients with Crohn's disease over a 4-year period. Female sex, perianal disease, concomitant treatment with prednisolone at baseline, previous infliximab use, higher C-reactive protein levels, and lower albumin levels were associated with poor retention of adalimumab treatment.


Selection and Insertion of Vascular Access Devices in Pediatrics: A Systematic Review.
To critically review the evidence for the selection and insertion of pediatric vascular access devices (VADs). Data were sourced from the US National Library of Medicine, Cumulative Index to Nursing and Allied Health, the Cochrane Library databases, Embase, and international clinical trial databases. Clinical practice guidelines, systematic reviews, cohort designs, randomized control trials (RCTs), quasi RCTs, before-after trials, or case-control studies that reported on complications and/or risk as well as reliability of VADs in patients aged 0 to 18 years were included. Articles were independently reviewed to extract and summarize details on the number of patients and catheters, population, age of participants, VAD type, study method, indication, comparators, and the frequency of VAD failure or complications. VAD selection and insertion decision-making in general hospitalized and some specialized patient populations were well evidenced. The use of single-lumen devices and ultrasound-guided techniques was also broadly supported. There was a lack of RCTs, and for neonates, cardiac patients, patients with difficult venous access, midline catheters, catheter-to-vein ratio, and near-infrared devices, the lack of evidence necessitated broadening the review scope. Limitations include the lack of formal assessment of the quality of evidence and the lack of RCTs and systematic reviews. Consequently, clinical decision-making in certain pediatric populations is not guided by strong, evidence-based recommendations. This is the first synthesis of available evidence for the selection and insertion of VADs in pediatric patients and is important for determining the appropriateness of VADs in pediatric patients.


Calcium-siRNA nanocomplexes: what reversibility is all about.
Gene silencing using small interfering RNA (siRNA) relies on the critical need for a safe and effective carrier, capable of strong but reversible complexation, siRNA protection, cellular uptake, and cytoplasmatic unloading of its cargo. We hypothesized that a delivery platform based on the eletrostatic interactions of siRNA with calcium ions in solution would fulfill these needs, ultimately leading to effective gene silencing. Physical characterization of the calcium-siRNA complexes, using high resolution microscopy and dynamic light scattering (DLS), showed the formation of stable nanosized complexes ~80nm in diameter, bearing mild (~-7mV) negative surface charge. The complexes were extremely stable in the presence of serum proteins or high concentrations of heparin; they maintained their nanosized features in suspension for days; and effectively protected the siRNA from enzymatic degradation. The Ca-siRNA complexes were disintegrated in the presence of Ca-chelating ion exchange resin, thus proving their reversibility. Excellent cytocompatibility of calcium-siRNA complexes was achieved using physiological calcium ion concentrations. The calcium-siRNA complexes successfully induced a very high (~80%) level of gene silencing in several cell types, at both mRNA and protein levels, associated with efficient cellular uptake. Collectively, our results show that the developed delivery platform based on reversible calcium-siRNA interactions offers a simple and versatile method for enhancing the therapeutic efficiency of siRNA.


Advanced drug delivery systems that target the vascular endothelium.
Targeted drug delivery to endothelial cells lining the vascular lumen will provide effective, precise and safe therapeutic interventions for treatment of diverse disease conditions. Rational design of such drug delivery systems (DDS) includes the following intertwined tasks: 1) selection of proper target determinants on endothelial surfaces, such as cell adhesion molecules, ectopeptidases, or caveolar antigens; 2) production of affinity ligands useful for targeting, such as affinity peptides, antibodies, or their fragments; 3) selection and adopting of suitable delivery vehicles (such as liposomes or polymer nanocarriers); and 4) formulation of DDS with optimal targeting and therapeutic features. Important therapeutic features of DDS include: 1) sufficient targeting effectiveness, circulation time, and safety (i.e., lack of systemic and local adverse effects); 2) precise subcellular localization of drugs targeted to endothelial cells; and 3) adequate amplitude, kinetics, and duration of effects. This review utilizes examples of DDS-mediated interventions in vascular inflammation, oxidative stress, and thrombosis and analyzes them in an attempt to create design parameters that best regulate the pharmacological and therapeutic features of DDS that target endothelial cells.


The impact of multi-morbidity on disability among older adults in South Africa: do hypertension and socio-demographic characteristics matter?
Alongside the global population ageing phenomenon, there has been a rise in the number of individuals who suffer from multiple chronic conditions. Taking the case of South Africa, this study aims, first, to investigate the association between multi-morbidity and disability among older adults; and second, to examine whether hypertension (both diagnosed and undiagnosed) mediates this relationship. Lastly, we consider whether the impact of the multi-morbidity on disability varies by socio-demographic characteristics. Data were drawn from Wave 1 (2007-08) of the South African Study on Global Ageing and Adult Health. Disability was measured using the 12-item World Health Organisation Disability Assessment Schedule (WHODAS) 2.0. Scores were transformed into a binary variable whereby those over the 90th percentile were classified as having a severe disability. The measure of multi-morbidity was based on a simple count of self-reported diagnosis of selected chronic conditions. Self-reports of diagnosed hypertension, in addition to blood pressure measurements at the time of interview, were used to create a three category hypertension variable: no hypertension (diagnosed or measured), diagnosed hypertension, hypertension not diagnosed but hypertensive measured blood pressure. Interactions between the number of chronic diseases with sex, ethnicity and wealth were tested. Logistic regression was used to analyze the relationships. 25.4% of the final sample had one and 13.2% two or more chronic diseases. Nearly half of the respondents had a hypertensive blood pressure when measured during the interview, but had not been previously diagnosed. A further third self-reported they had been told by a health professional they had hypertension. The logistic regression showed in comparison to those with no chronic conditions, those with one or two or more had significantly higher odds of severe disability. Hypertension was insignificant and did not change the direction or size of the effect of the multi-morbidity measure substantially. The interactions between number of chronic conditions with wealth were significant at the 5% level. The diagnosis of multiple chronic conditions, can be used to identify those most at risk of severe disability. Limited resources should be prioritized for such individuals in terms of preventative, rehabilitative and palliative care.


Intrinsic photoaffinity labeling probes for cholecystokinin (CCK)-gastrin family receptors. D-Tyr-Gly-[Nle28,31,pNO2-Phe33)CCK-26-33).
Attempts to biochemically characterize the pancreatic cholecystokinin (CCK) receptor by affinity labeling have utilized either 125I-Bolton-Hunter-CCK-33 ("long" probes) or decapeptide analogues of the carboxyl terminus of CCK ("short" probes), and covalent attachment via the amino-terminal regions of these probes. The long probe has identified a protein of Mr = 80,000 while "shorter" probes, which have their site of cross-linking closer to the receptor binding region of the probes, have labeled a distinct protein of Mr = 85,000-95,000. To extend and complement these observations, we have designed and synthesized a new probe for the CCK receptor which incorporates a photolabile p-nitrophenylalanine moiety within the theoretical receptor-binding region of the hormone, as its carboxyl-terminal residue. This "intrinsic" photoaffinity labeling probe has been shown to possess full biological activity, with potency and efficacy in stimulating amylase secretion by dispersed rat pancreatic acini similar to that of CCK-8 (CCK-26-33). When iodinated oxidatively, this probe binds rapidly, in a temperature-dependent, reversible, saturable, specific, high affinity manner to enriched pancreatic plasma membranes. In this work, we have used this probe to specifically label the CCK binding site on rat pancreatic plasma membranes. The Mr = 85,000-95,000 protein previously identified with amino-terminal cross-linking of short probes appears to be the protein labeled with this reagent as well. This provides strong evidence that this pancreatic plasma membrane protein contains the CCK-binding domain of the CCK receptor. This intrinsic photoaffinity labeling probe should be quite useful for the characterization of the active site of this receptor and for other CCK and gastrin receptors in many species.


Zona glomerulosa cell responses to atrial natriuretic factor in genetically hypertensive rats.
We examined whether abnormalities in target cell responsiveness to atrial natriuretic factor (ANF), similar to those previously found in the kidney, could also be present in the zona glomerulosa cells of spontaneously hypertensive rats (SHR) and salt-sensitive Dahl rats (S rats). We found an attenuated aldosterone (Aldo) response to angiotensin II (ANG II) in zona glomerulosa cell suspensions isolated from hypertensive SHR compared with those from Wistar-Kyoto (WKY) rats, whereas cells derived from hypertensive S rats showed a significantly higher Aldo response to the maximum stimulatory dose of ANG II than those from salt-resistant Dahl rats (R rats). The maximum observed Aldo responses to ACTH stimulation were not different in SHR or S rats compared with their respective controls. ANF exerted a potent inhibitory action on both ANG II- and ACTH-stimulated secretions of glomerulosa cell suspensions, without any difference in its potency between hypertensive and control rats. The equipotent inhibitory action of ANF on the ANG II- and ACTH-stimulated secretion of Aldo in those cell suspensions suggests that the previously observed alterations in the target cell responsiveness to ANF do not exist in the adrenal zona glomerulosa cells of SHR and Dahl S rats.


[Effects of melatonin in the brain of the senescence-accelerated mice-prone 8 (SAMP8) model].
Senescence-accelerated mice (SAM) represent an aging model establish by selective inbreeding of the AKR/J strain. SAMP8 is a suitable model to study the genetics or proteics fundamental mechanisms of aging, in physiological or pathological conditions, because SAMP8 develop neuropathological markers also found in neurodegenerative diseases like Alzheimer. Melatonin is known as sleep hormone because its action controlling the sleep/awake circadian rhythm. Moreover, melatonin has antioxidant properties and may have an important anti-aging role. The chronic treatment with melatonin in the SAMP8 model was able to reduce oxidative stress and the neurodegenerative calpain/Cdk5 pathway and primed phosphorylation of GSK3beta and tau hiperphosphorylation markers of cerebral aging and neurodegeneration in SAMP8 brains, indicating the neuroprotective and anti-aging effect of melatonin.


[Interaction of morphine and non-steroid anti-inflammatory agents].
A study was made of the analgesic action of combined morphine and nonsteroidal anti-inflammatory agents (NAIA)--voltaren, ibuprophen and metindol. It was established that injection of morphine prior to NAIA gives rise to a reduction in the analgesic effect, whereas the combined use of the drugs or administration of NAIA following morphine entails the retention of the effect. Pretreatment with prostaglandin E produces opposite changes in the effect of the analgesics--potentiation of analgesia upon morphine injection and its reduction after NAIA. The data obtained present indirect evidence for the importance of prostaglandins in the antagonism of morphine and NAIA.


A Lifestyle Modification Program for Secondary Prevention of Atrial Fibrillation: A Pilot Study.
Lifestyle modification programs, such as cardiac rehabilitation, may reduce atrial fibrillation (AF) burden and improve quality of life (QOL), but remain unproven. The objective of this pilot study was to assess feasibility, acceptability, and preliminary effectiveness of an exercise and nutrition-based cardiac rehabilitation-like program for AF patients. We enrolled overweight adults aged ≥ 30 years with symptomatic AF in a 12-week cardiac lifestyle group program, including 6 virtual and 6 in-person visits. All visits included discussion and education about nutrition, exercise, and behavior modification. In-person visits included supervised aerobic exercise and strength training. Outcomes at baseline and 12 weeks included feasibility of participation, acceptability, change in weight and BMI, and changes in survey-based AF burden, symptoms, and QOL. From 84 invitees, 11 (13.1%) were enrolled (mean age 64; baseline BMI 38 kg/m2); 9 (82%) completed the program. Patients attended an average of 9.7 (81%) visits (Range: 6-11). Mean weight loss was 9.1 pounds (Range: 0-16); mean BMI decrease was 1.4 kg/m2 (Range: 0-2.6). Patients found the program helpful overall: all reported making diet and exercise changes during the program. Compared to baseline, patients reported decreased AF burden (12.9 vs. 11.7, p = 0.03) and symptom (10.1 vs. 5.6, p = 0.003) scores at the conclusion of the program. Patients also reported increased QOL overall (68.9 vs. 86.4, p = 0.001). Participation in a cardiac rehab-like program was feasible and acceptable for overweight patients with symptomatic AF. Results suggest preliminary effectiveness of the program for reducing AF burden and symptoms and increasing QOL.


Schistosomiasis Seroprevalence among Children Aged 0-14 Years in Nigeria, 2018.
The first nationally representative, population-based study of schistosomiasis seroprevalence in Nigeria was conducted using blood samples and risk-factor data collected during the 2018 Nigeria HIV/AIDS Indicator and Impact Survey (NAIIS). Schistosomiasis seroprevalence was estimated by analyzing samples for reactivity to schistosome soluble egg antigen (SEA) in a multiplex bead assay; NAIIS survey data were assessed to identify potential risk factors for seropositivity. The SEA antibody data were available for 31,459 children aged 0 to 14 years. Overall seroprevalence was 17.2% (95% CI: 16.3-18.1%). Seropositive children were identified in every age group, including children < 5 years, and seroprevalence increased with increasing age (P < 0.0001). Several factors were associated with increased odds of seropositivity, including being a boy (odds ratio [OR] = 1.34, 95% CI: 1.24-1.45), living in a rural area (OR = 2.2, 95% CI: 1.9-2.5), and animal ownership (OR = 1.67, 95% CI: 1.52-1.85). Access to improved sanitation and drinking water sources were associated with decreased odds of seropositivity (OR = 0.52, 95% CI: 0.47-0.58 and OR = 0.53, 95% CI: 0.47-0.60, respectively) regardless of whether the child lived in a rural (sanitation: adjusted odds ratio [aOR] = 0.7, 95% CI: 0.6-0.8; drinking water: aOR = 0.7, 95% CI: 0.6-0.8) or urban area (sanitation: aOR = 0.6, 95% CI: 0.5-0.7; drinking water: aOR = 0.5, 95% CI: 0.4-0.6), highlighting the importance of these factors for schistosomiasis prevention and control. These results identified additional risk populations (children < 5 years) and a new risk factor (animal ownership) and could be used to monitor the impact of control programs.


Highly-integrated programs for the prevention of obesity and overweight in children and adolescents: results from a systematic review and meta-analysis.
Since overweight and obesity has become epidemic in children and adolescents, the aim of this study was to determine the role of highly-integrated programs in preventing and reducing prevalence of children and adolescent obesity and overweight, even evaluating if this approach has properly been effective in communities with different determinants as in the Pacific Area. According to PRISMA guidelines, a systematic review of literature was conducted and a meta-analysis was performed to compare obese/overweight prevalence between the intervention and the control group. We identified 23 studies describing 14 programs. For 11 out of 14 programs, obese/overweight prevalence changing from baseline were definable and meta-analysis of them showed a significant change of obese/overweight prevalence (-0.03; 95% CI = -0.04 to -0.01; P < 0.0001). Secondary outcomes as dietary (such as vegetable intake, carbonated beverages, fruit juice, drinks, healthful food consumption), physical activity and TV-time-spent was analyzed in many of the studies to define community readiness and behavioral changes. Macro-interventions, based on what was observed in our systematic review have a high potential to reach the entire population. Adoption of coordinated cross-sectoral, multi-component and multi-stakeholder initiatives to oppose obesity remains a challenge, but it is also desirable as one of the possible solutions to this major public health issue.