Using IPM-CPR as a Management Program for Apple Orchards.

We have demonstrated how management of key orchard pests including the insect invasive species Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) can be accomplished using a systems-level approach termed IPM-CPR (Integrated Pest Management-Crop Perimeter Restructuring) in apple. We conducted on-farm comparisons of IPM-CPR to standard management program for managing H. halys, Cydia pomonella (L.) (Lepidoptera: Tortricidae), Grapholita molesta (Busck) (Lepidoptera: Tortricidae), and Lygus lineolaris Palisot de Beauvois (Hemiptera: Miridae) in commercial apple orchards in 2014, 2016, and 2017 in New Jersey, Maryland, and Virginia. The presence and abundance of key pests and fruit injury at harvest were used as a measure of success of the program. We compared the amount of insecticide applied for each management program. In majority of instances, there were no differences in the IPM-CPR and the standard management program in terms of H. halys numbers in baited pyramid traps and stink bug injury at harvest. Damage from C. pomonella and G. molesta in the IPM-CPR treatment was significantly lower than the standard management program in 2014 and 2017. Amount of active ingredient used was on average 62.1% lower in the IPM-CPR treatment compared with standard management program. Despite a reduction in insecticide use, there were minimal impacts on beneficial insects. Overall, IPM-CPR in apples successfully managed key orchard pests, including H. halys, and used significantly less insecticide than a standard insecticide-based management program and could be adopted as a systems-level approach for pest population reduction.

Long-term epidemiological dynamics of dengue in Barbados - one of the English-speaking Caribbean countries.

Using the dengue surveillance program, we prospectively collected data on all the suspected and confirmed cases of dengue in Barbados from 2006 to 2015. Data were analysed for demographic, seasonal and temporal dynamics of this disease in this country. The overall mean annual incidence rate of suspected and confirmed dengue over the study period was 0.49% (range 0.15%-0.99%) and 0.16% (range 0.05%-0.48%), respectively. There was a significant correlation between the mean monthly number of confirmed cases, the mean monthly rainfall and the mean monthly relative humidity percentage. Dengue in this population is predominantly an infection affecting children and young adults. The median age of the patients with both, suspected and confirmed dengue was 25 years and the highest proportion of cases was seen in the age group 0-15 years. The annual incidence rates of both the suspected and the confirmed cases showed an upward trend during the study period and this upward trend was more pronounced among children.

Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner.

BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies.

MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells.

Although many epidermal growth factor receptor (EGFR)-mutated lung cancer patients initially benefit from the EGFR-inhibitor erlotinib, all acquire resistance. So far, several mechanisms implicated in resistance have been identified, but the existence of multiple resistance mechanisms in parallel have only been sparsely investigated. In this study, we investigated parallel resistance mechanisms acquired by HCC827, an EGFR-mutated adenocarcinoma cell line dependent on EGFR activity and sensitive to erlotinib. The cell line was treated with erlotinib by stepwise escalation of the drug-concentration and erlotinib-resistant (HCC827ER) cells created. HCC827ER cells depicted a mixed epithelial and mesenchymal phenotype. To clarify potential parallel resistance mechanisms, 14 resistant subclones were established by limited dilution. Interestingly, all HCC827ER subclones harbored either a MET-amplification (6/14) or underwent EMT (8/14), mechanisms both found in previous studies, but not in co-occurrence. Both subclone-types were resistant to erlotinib, but only MET-subclones responded to the MET-inhibitors crizotinib and capmatinib. EMT-subclones on the other hand had markedly increased FGFR1 expression and responded to the FGFR-inhibitor AZD4547, whereas MET-subclones did not. Monitoring gene expression through the development of HCC827ER revealed upregulation of FGFR1 expression as an early response to erlotinib. In addition, FGFR1 expression increased upon short-term erlotinib treatment (48 h) identifying a physiological role immediately after erlotinib exposure. The high FGFR1 expression seen in EMT-subclones was stable even after five passages without erlotinib. Here we show, that parallel resistance mechanisms appear during erlotinib-resistance development in EGFR-mutated NSCLC cells and highlight a role for FGFR1 expression changes as an early response to erlotinib as well as a bypass-signaling mechanism.

CACNA1C hypermethylation is associated with bipolar disorder.

The CACNA1C gene, encoding a subunit of the L-type voltage-gated calcium channel is one of the best-supported susceptibility genes for bipolar disorder (BD). Genome-wide association studies have identified a cluster of non-coding single-nucleotide polymorphisms (SNPs) in intron 3 to be highly associated with BD and schizophrenia. The mechanism by which these SNPs confer risk of BD appears to be through an altered regulation of CACNA1C expression. The role of CACNA1C DNA methylation in BD has not yet been addressed. The aim of this study was to investigate if CACNA1C DNA methylation is altered in BD. First, the methylation status of five CpG islands (CGIs) across CACNA1C in blood from BD subjects (n=40) and healthy controls (n=38) was determined. Four islands were almost completely methylated or completely unmethylated, while one island (CGI 3) in intron 3 displayed intermediate methylation levels. In the main analysis, the methylation status of CGI 3 was analyzed in a larger sample of BD subjects (n=582) and control individuals (n=319). Out of six CpG sites that were investigated, five sites showed significant hypermethylation in cases (lowest P=1.16 × 10(-7) for CpG35). Nearby SNPs were found to influence the methylation level, and we identified rs2238056 in intron 3 as the strongest methylation quantitative trait locus (P=2.6 × 10(-7)) for CpG35. In addition, we found an increased methylation in females, and no difference between bipolar I and II. In conclusion, we find that CACNA1C methylation is associated with BD and suggest that the regulatory effect of the non-coding risk variants involves a shift in DNA methylation.

Epidemiological Trend and Clinical Observations among Children and Adults with Dengue in Barbados.

OBJECTIVE: To describe the epidemiological characteristics and the clinical manifestations of the confirmed dengue cases over a ten-year period in Barbados, one of the English-speaking Caribbean countries. METHODS: All the cases of confirmed dengue from 2000 to 2009 were retrospectively studied. Long-term trends in incidence rate, demographic characteristics such as age, gender and seasonal distribution; clinical manifestations, immunological characteristics, need for hospitalization and mortality were studied. RESULTS: There were 3413 confirmed cases of dengue including 778 (22.8%) children and 2635 (77.2%) adults. The mean annual incidence rate of dengue was 1.36/1000 population. The median age of the persons with confirmed dengue was 27 years. The largest number of cases was seen in the 11 to 16-year age group. Hospitalization was required in 13.1% of dengue cases; 72.5% and 84% of all dengue were secondary infections among the children and adults, respectively. Dengue haemorrhagic fever accounted for 2.2% and 6% of all confirmed dengue among children and adults, respectively. The overall case fatality rate in this study was 0.35%. CONCLUSIONS: Dengue is a significant health problem primarily in adolescents and young adults. It is characterized by less severe cases and lower mortality rate.

A 24-h a la carte food service as support for patients at nutritional risk: a pilot study.

BACKGROUND: Undernutrition and insufficient energy and protein intake is a common problem in hospitalised patients. The aim of this pilot study was to investigate whether a novel hospital menu would be an effective strategy for increasing nutritional intake in patients at nutritional risk. METHODS: A historically controlled intervention pilot study was conducted. Forty patients at nutritional risk were offered a novel hospital menu as a supplement to the ordinary hospital menu. The menu consisted of 36 naturally energy-enriched small dishes served on demand 24 h a day. Energy and protein intake were calculated as the mean over a period of 3 days. RESULTS: No significant difference in energy and protein intake was observed between the groups; however, a significant (P = 0.001) time gradient in total energy intake was observed in the intervention group. Moreover, a significant (P = 0.03) time gradient in energy intake received from the novel menu was observed. The dishes from the novel menu were mainly ordered from 11.00 h to 14.00 h and from 17.00 h to 18.00 h. CONCLUSIONS: No overall significant differences in energy and protein intake between the groups were found. However, the present pilot study revealed a significant time gradient in total energy intake (P = 0.001) and in energy intake from the novel menu (P = 0.03). This indicates the need to include a run-in period when investigating novel hospital menus as a support for patients at nutritional risk. Additionally, food service, available 24 h a day, appears to be unnecessary.

Function and expression of the proton-coupled amino acid transporter PAT1 along the rat gastrointestinal tract: implications for intestinal absorption of gaboxadol.

BACKGROUND AND PURPOSE: Intestinal absorption via membrane transporters may determine the pharmacokinetics of drug compounds. The hypothesis is that oral absorption of gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol) in rats occurs via the proton-coupled amino acid transporter, rPAT1 (encoded by the gene rSlc36a1). Consequently, we aimed to elucidate the in vivo role of rPAT1 in the absorption of gaboxadol from various intestinal segments obtained from Sprague-Dawley rats. EXPERIMENTAL APPROACH: The absorption of gaboxadol was investigated following its administration into four different intestinal segments. The intestinal expression of rSlc36a1 mRNA was measured by quantitative real-time PCR. Furthermore, the hPAT1-/rPAT1-mediated transport of gaboxadol or L-proline was studied in hPAT1-expressing Xenopus laevis oocytes, Caco-2 cell monolayers and excised segments of the rat intestine. KEY RESULTS: The absorption fraction of gaboxadol was high (81.3-91.3%) following its administration into the stomach, duodenum and jejunum, but low (4.2%) after administration into the colon. The pharmacokinetics of gaboxadol were modified by the co-administration of L-tryptophan (an hPAT1 inhibitor) and L-proline (an hPAT1 substrate). The in vitro carrier-mediated uptake rate of L-proline in the excised intestinal segments was highest in the mid jejunum and lowest in the colon. The in vitro uptake and the in vivo absorption correlated with the expression of rSlc36a1 mRNA along the rat intestine. CONCLUSIONS AND IMPLICATIONS: These results suggest that PAT1 mediates the intestinal absorption of gaboxadol and therefore determines its oral bioavailability. This has implications for the in vivo role of PAT1 and may have an influence on the design of pharmaceutical formulations of PAT1 substrates.

Self-assembling microparticles with controllable disruption properties based on cyclodextrin interactions.

In this paper, we present the formation of particles by self-assembly of cyclodextrin polymers and hydrophobically modified dextran followed by a controlled disruption of the particles by addition of a trigger molecule competing for the cyclodextrin cavities. The produced particles are formed from poly(vinylpyrrolidone)-co-beta-cyclodextrin and dextran-benzoate, both biocompatible polymers, and are all in the nano-/micrometer range and hence suitable for drug delivery purposes. The particle formation was studied in different ratios of poly(vinylpyrrolidone)-co-beta-cyclodextrin and dextran-benzoate by visual inspections, dynamic light scattering, isothermal titration calorimetry and SEM. The triggering of particle disruption was achieved by addition of hydroxyadamantane which has a very strong affinity towards the beta-cyclodextrin cavities. The stepwise addition of hydroxyadamantane was followed by dynamic light scattering and SEM measurements, revealing a disruption of the particles due to the addition of this competitor. These particles are believed to be promising candidates for controlled drug delivery systems, due to their unique ability to disrupt in a controlled manner.

The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes.

AIMS/HYPOTHESIS: Recent genome-wide association studies have suggested that a polymorphism in GCKR, the gene encoding the glucokinase regulatory protein, is involved in triacylglycerol regulation. Our aim was to examine in large-scale studies the common GCKR rs780094 polymorphism in relation to metabolic traits (mainly fasting hypertriacylglycerolaemia) and traits related to pancreatic beta cell function. METHODS: The polymorphism was genotyped in 16,853 Danes using Taqman allelic discrimination. Association was analysed in case-control studies and quantitative trait analyses. We also analysed the possible interactive effect between the GCK -30G>A polymorphism and the GCKR rs780094 variant on metabolic traits. RESULTS: The minor GCKR A-allele of rs780094 is associated with an increased level of fasting serum triacylglycerol (p = 6 x 10(-14)), impaired fasting (p = 0.001) and OGTT-related insulin release (p = 3 x 10(-6)), reduced homeostasis model assessment of insulin resistance (p = 0.0004), WHO-defined dyslipidaemia (p = 6 x 10(-9)) and a modestly decreased risk of type 2 diabetes (p = 0.01). Significantly increased fasting serum insulin concentrations were demonstrated when analysing the GCK -30A and GCKR rs780094 G-alleles in an additive model. CONCLUSIONS/INTERPRETATION: The GCKR rs780094 polymorphism, or another variant with which it is in tight linkage disequilibrium, is likely to increase glucokinase regulatory protein activity to induce improved glycaemic regulation at the expense of hypertriacylglycerolaemia as reflected in the present study of 16,853 Danes. We also suggest an additive effect of GCK and GCKR risk alleles on [corrected] serum insulin release.

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder.

Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of approximately 10% in the combined case group versus approximately 1% in controls (P-value 2.8 x 10(-7)). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

Drinking patterns among Hispanic adolescents: results from a national household survey.

OBJECTIVE: This is one of the first studies to examine and compare alcohol use for adolescent Cubans, Mexican Americans, Puerto Ricans and other Hispanics. METHOD: The data come from the 1993 National Household Survey on Drug Abuse (NHSDA), a national probability sample of the U.S. household population. The sample examined here (N = 1,865, 52% male) comprises 200 Cubans, 1,133 Mexican Americans, 255 Puerto Ricans and 277 Central/South Americans who were 12 to 17 years old. Drinking patterns are measured using a quantity-frequency index, and analyses are conducted using Stata. RESULTS: In the cross-tabulations, no ethnic differences in drinking patterns are found for males or females, nor is there evidence of gender differences within ethnic groups, although there are some age differences in alcohol use. In the logistic regression analyses, two ethnic differences emerge, although the factors most consistently associated with drinking behaviors in these analyses are age, Spanish language use and urban residence. Additional analyses using the 1998 NHSDA suggest that ethnic differences in alcohol use may emerge in late adolescence/early adulthood. CONCLUSIONS: Given the established findings of ethnic and gender differences in drinking among adult Hispanics, it is surprising that few differences are evidenced in adolescence. Future research should explore whether such differences emerge during the transition into adulthood and, if so, identify factors that produce them. In addition, to increase understanding of these ethnic groups' drinking patterns, future research should further investigate the factors associated with Hispanic adolescents' alcohol use, including both consideration of whether the predictors are the same across groups and of the role of sociocultural factors.

Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins.

Members of the heterochromatin protein 1 (HP1) family are silencing nonhistone proteins. Here, we show that in P19 embryonal carcinoma (EC) nuclei, HP1 alpha, beta, and gamma form homo- and heteromers associated with nucleosomal core histones. In vitro, all three HP1s bind to tailed and tailless nucleosomes and specifically interact with the histone-fold of histone H3. Furthermore, HP1alpha interacts with the linker histone H1. HP1alpha binds to H3 and H1 through its chromodomain (CD) and hinge region, respectively. Interestingly, the Polycomb (Pc1/M33) CD also interacts with H3, and HP1alpha and Pc1/M33 binding to H3 is severely impaired by CD mutations known to abrogate HP1 and Polycomb silencing in Drosophila. These results define a novel function for the conserved CD and suggest that HP1 self-association and histone binding may play a crucial role in HP1-mediated heterochromatin assembly.

Creutzfeldt-Jakob disease segregating in a three generation Danish family.

A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

Drinking in adulthood: similarities and differences in effects of adult roles for Hispanic ethnic groups and Anglos.

OBJECTIVE: This study examines whether the adult social roles perspective. an approach that explains drinking behaviors for Anglos, similarly affects alcohol use by Cubans, Mexican Americans, Puerto Ricans and Other Hispanics (Central and South Americans). METHOD: The 1993 National Household Survey on Drug Abuse, a national probability sample of the household population in the United States, is used. The sample utilized here (N= 13,822; 56.2% female) consisted of 9,388 Anglos, 611 Cubans, 2,459 Mexican Americans, 611 Puerto Ricans and 753 Central/South Americans age 18 and older. The outcome measures include past-year drinking, and for drinkers, heavy drinking and alcohol-related problems. Logistic regression analyses are conducted using Stata. RESULTS: The results show that there are some ethnic differences in the effects of the adult social roles. Of particular importance is the finding that being married has anomalous effects for Cubans (heavy drinking), Mexican Americans (problems) and Other Hispanics (problems) compared with Anglos and the other Hispanic ethnic groups. CONCLUSIONS: The adult social roles perspective has some utility for explaining Hispanic drinking patterns. Future research should consider not only traditional predictors of drinking but also such socio-cultural factors as acculturation and familism, to better understand adult alcohol use by members of Hispanic ethnic groups.

Examining drinking patterns and problems among hispanic groups: results from a national survey.

OBJECTIVE: This study examines and compares the drinking patterns and problems of members of four Hispanic groups (Cubans, Mexican Americans, Puerto Ricans and other Hispanics) in the United States, with information presented by gender and age. METHOD: The 1993 National Household Survey on Drug Abuse, a recent national probability sample of the household population aged 18 and over in the United States, is used. Data are obtained through in-person interviews. The sample includes 4,462 Hispanics of Cuban (n = 620), Mexican (n = 2,467), Puerto Rican (n = 619) and Central and South American (n = 756) origin. Analyses are conducted using SUDAAN. RESULTS: There are significant differences across the Hispanic groups in their drinking patterns and problems. Among men, Mexican Americans report the most frequent and heavy drinking, and the greatest prevalence of drunkenness and alcohol-related problems. Cubans report the lowest percentages of such respondents, and Puerto Ricans and other Hispanics are in between the other two groups. For women, fewer ethnic differences are evidenced than for men. In general, Puerto Ricans and Mexican Americans drink more often and heavily and experience more problems than the other groups. Even after controlling for predictors of adult alcohol use, some ethnic differences in drinking persist. CONCLUSIONS: The four Hispanic groups have different drinking patterns. More research is necessary to determine the factors associated with differences in drinking across Hispanic groups.

Serum tetranectin and CA125 in endometrial adenocarcinoma.

BACKGROUND: CA125 and tetranectin (TN) are prognostic markers in ovarian cancer. This study examines the values of these markers in endometrial cancer. MATERIALS AND METHODS: TN and CA125 were determined preoperatively in 99 patients with primary endometrioid adenocarcinoma and evaluated in relation to tumor grade, stage and cancer survival. RESULTS: The CA125 levels correlated significantly with tumor stage. Dichotomized according to a cut-off level of 35 U/ml, CA125 significantly correlated with cancer death. Multivariate regression analysis of cancer survival time showed that CA125 > 35 U/ml was not an independent factor when stage was introduced. TN levels were within the normal range in all patients and did not show any association with tumor grade, stage or survival. CONCLUSIONS: The study confirmed the role of CA125 as a prognostic factor in endometrial cancer and may be of aid in pointing out patients at high risk, whereas tetranectin did not show any prognostic effect.

Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family.

Mammalian TIF1alpha and TIF1beta (KAP-1/KRIP-1) are related transcriptional intermediary factors that possess intrinsic silencing activity. TIF1alpha is believed to be a euchromatic target for liganded nuclear receptors, while TIF1beta may serve as a co-repressor for the large family of KRAB domain-containing zinc finger proteins. Here, we report an association of TIF1beta with both heterochromatin and euchromatin in interphase nuclei. Co-immunoprecipitation of nuclear extracts shows that endogenous TIF1beta, but not TIF1alpha, is associated with members of the heterochromatin protein 1 (HP1) family. However, in vitro, both TIF1alpha and TIF1beta interact with and phosphorylate the HP1 proteins. This interaction involves a conserved amino acid motif, which is critical for the silencing activity of TIF1beta but not TIF1alpha. We further show that trichostatin A, an inhibitor of histone deacetylases, can interfere with both TIF1 and HP1 silencing. The silencing activity of TIF1alpha appears to result chiefly from histone deacetylation, whereas that of TIF1beta may be mediated via both HP1 binding and histone deacetylation.

Assessment of pH and oxygen status during hemodialysis using the arterial blood line in patients with an arteriovenous fistula.

BACKGROUND: In patients with arteriovenous fistulas, assessment of pH and oxygen status during hemodialysis (HD) using the extracorporeal dialysis arterial blood line is widely used both in daily routine and in most studies investigating hypoxia during HD. We designed this study to evaluate whether results of blood gas samples drawn from the extracorporeal arterial line were clinically acceptable in assessing oxygen status. METHODS: We compared samples drawn from the extracorporeal arterial line with conventionally arterial punctures during 18 routine HD sessions. The samples were drawn simultaneously and analyzed immediately for blood gases, pH and hemoximetry values. RESULTS: No significant difference was found between the values from the radial artery and the extracorporeal arterial blood line except for FMetHb. CONCLUSION: Thus, obtaining samples from the extracorporeal dialysis arterial blood line to evaluate the parameters of the oxygen status (pH, pO(2), pCO(2), ctHb, sO(2), FCOHb and ctO(2)) during routine HD is a clinically convenient and accurate sampling approach.