Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder.
Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.


Relationship between obstructive lung disease and non-alcoholic fatty liver disease in the Korean population: Korea National Health and Nutrition Examination Survey, 2007-2010.
Previous studies have shown that progressive forms of non-alcoholic fatty liver disease (NAFLD) occur frequently in patients with obstructive lung disease (OLD). However, few studies have written about this relationship. This study aimed to investigate the relationship between OLD and NAFLD. The Korea National Health and Nutrition Examination Survey is a national population-based, cross-sectional surveillance program that was initiated to assess the health and nutritional status of the Korean population. From 2007 to 2010, 11,738 subjects were enrolled. The subjects were defined as having NAFLD when they had scores higher than -0.640 in a NAFLD liver fat score prediction model, which was a previously validated prediction score. Individuals with forced expiratory volume in one second/forced vital capacity <0.7 were considered to have OLD. The subjects were divided into non-OLD and OLD groups and non-NAFLD and NAFLD groups. All analyses were performed using sample weighting using the complex samples plan. The prevalences of NAFLD and OLD were 30.2% and 8.9%, respectively. Although not statistically significant, subjects in the NAFLD group involved a higher tendency of having OLD than did those in the non-NAFLD group (8.5% vs 10.0%, respectively, P=0.060). Subjects with OLD showed a higher tendency to have NAFLD than non-OLD subjects (30.0% vs 33.7%, respectively, P=0.060). NAFLD subjects were at higher odds of OLD (odds ratio=1.334; 95% confidence interval=1.108-1.607, P=0.002) than non-NAFLD subjects, after adjusting for age, sex, and smoking history. OLD subjects were at higher odds of NAFLD (odds ratio=1.556; 95% confidence interval=1.288-1.879, P<0.001) than non-OLD subjects, after adjusting for age, sex, and smoking history. This study showed that NAFLD is related to OLD. Clinicians should be aware of possible liver comorbidities in OLD patients and that extrahepatic disease in NAFLD patients may vary more than previously thought.


Impact of obstructive sleep apnea on long-term blood pressure variability in Japanese men: a cross-sectional study of a work-site population.
Blood pressure variability (BPV) has been shown to be associated with cardiovascular diseases. The effects on long-term BPV of obstructive sleep apnea (OSA) are not yet known. We evaluated a total of 1653 Japanese male workers (18-69 years) at a work site to diagnose OSA, and we divided them into three groups: non-OSA (apnea-hypopnea index (AHI): < 5, n = 1414), mild-to-moderate OSA (5 ≤ AHI < 30: n = 131) and severe OSA (AHI ≥ 30: n = 108). The standard deviation and coefficient of variation of the subjects' BPV were calculated by using their annual blood pressure measurements at routine physical examinations from 2012 to 2015 (four measurements). The multivariable-adjusted BPV of systolic blood pressure (SBP) was significantly higher in the severe-OSA group compared to the non-OSA group. A multiple regression analysis also revealed that OSA was positively associated with BPV of SBP. We focused on the mild-to-moderate OSA group to evaluate the association of OSA treatment with BPV, because most of the severe-OSA subjects were being treated with continuous positive airway pressure or an oral appliance. The BPV of both systolic and diastolic blood pressure was significantly decreased in the treated subjects. These findings suggest that OSA is associated with increases in long-term BPV which was improved by the treatment of OSA in Japanese men of a work-site population.


Localization of epidermal growth factor (EGF) receptor in the rat corpus luteum, and EGF and transforming growth factor-alpha stimulation of luteal cell steroidogenesis in vitro.
Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) have potent mitogenic effects on granulosa and theca cells. However, their effects on steroidogenesis by these cells is controversial, and there is limited information regarding their effects on luteal cell steroidogenesis. The present study investigated the cellular distribution of the EGF receptor (EGF-R) in the rat corpus luteum (CL) by immunocytochemical staining, and the effects of EGF and TGF-alpha on progesterone and 20 alpha-dihydroprogesterone (20 alpha-OH-P) production in cultures of luteal cells. Using a primary antibody directed against the human EGF-R peptide, specific EGF-R staining was obtained in the CL. Both small and large luteal cells had EGF-R staining. In initial cell culture experiments, treatment of freshly isolated luteal cells with EGF or TGF-alpha (0.5-50 ng/ml) for 24 h had no effect on progesterone and 20 alpha-OH-P accumulation. Addition of LH (250 ng/ml) alone caused a 3.5-fold increase in both progestins, but co-treatment with EGF or TGF-alpha produced no further enhancement of progestin accumulation. However, when cells were seeded overnight and the attached cells were washed prior to growth factor treatment for 3 days with media change every 24 h, both EGF and TGF-alpha caused dose-dependent increases in progesterone accumulation/24 h period (up to 2-fold at 50 ng/ml growth factor) on days 1 and 2 but not day 3 of treatment. 20 alpha-OH-P accumulation was similarly stimulated (up to 2.5-fold) by EGF and TGF-alpha under these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)


Vaccination with recombinant adhesins from the RgpA-Kgp proteinase-adhesin complex protects against Porphyromonas gingivalis infection.
Porphyromonas gingivalis is a pathogen associated with chronic periodontitis, an inflammatory disease of the supporting tissues of the teeth. A major virulence factor for P. gingivalis is the RgpA-Kgp proteinase-adhesin complex. We have prepared the following recombinant proteins corresponding to domains/regions of the RgpA-Kgp complex; rRgpA(cat), rRgpA(A1), rRgpA(A2), rRgpA(A4), rRgpA(A1)(784-1009), rRgpA(A1)(911-1009), rKgp(A1) and rKgp(A1)(759-989). The ability of each recombinant protein to attenuate P. gingivalis infection, when used as a vaccine, in the murine lesion model was determined. All of the recombinant adhesin domains were found to significantly attenuate P. gingivalis infection with the most effective being rKgp(A1) and rKgp(A1)(759-989) followed by rRgpA(A1), rRgpA(A1)(784-1009) and rRgpA(A1)(911-1009). The predominant antibody isotype was IgG1. The A1 adhesins, which gave the best protection, contain specific motifs implicated in binding to host tissue. Immunisation with rRgpA(cat) had no effect on P. gingivalis infection. As well as detecting the Kgp(A1) adhesin in a Western blot, the rKgp(A1) and rKgp(A1)(759-989) antisera were also immunoreactive with the A1 and A3 adhesins of RgpA and HagA. Flow cytometric analysis indicated that rKgp(A1) and rRgpA(A1) antisera recognised native antigen on P. gingivalis whole cells. Furthermore, the rKgp(A1) and rKgp(A1)(759-989) antisera exhibited a similar immunoreactive profile with outer membrane preparations of all P. gingivalis serotypes and clinical isolates tested. The recombinant A1 adhesin therefore has potential in the development of a P. gingivalis vaccine.


Racial Socialization, Racial Identity, and Academic Attitudes Among African American Adolescents: Examining the Moderating Influence of Parent-Adolescent Communication.
A significant gap remains in our understanding of the conditions under which parents' racial socialization has consequences for adolescents' functioning. The present study used longitudinal data to examine whether the frequency of communication between African American parents and adolescents (N = 504; 49 % female) moderates the association between parent reports of racial socialization (i.e., cultural socialization and preparation for bias) at 8th grade and adolescent reports of racial identity (perceived structural discrimination, negative public regard, success-oriented centrality) at 11th grade, and in turn, academic attitudes and perceptions. Parents' racial socialization practices were significant predictors of multiple aspects of adolescents' racial identity in families with high levels of communication, but they did not predict any aspects of adolescents' racial identity in families with low levels of communication. Results highlight the importance of including family processes when examining the relations between parents' racial socialization and adolescents' racial identity and academic attitudes and perceptions.


Immunological properties of trehalose dimycolate (cord factor) and other mycolic acid-containing glycolipids--a review.
Mycolic acids are characteristic fatty acids of Mycobacteria and are responsible for the wax-like consistence of these microorganisms. Decades of research revealed that mycolic acid-containing glycolipids, in particular trehalose-6,6'-dimycolate (TDM, cord factor) as their best-studied representative, exert a number of immunomodifying effects. They are able to stimulate innate, early adaptive and both humoral and cellular adaptive immunity. Most functions can be associated with their ability to induce a wide range of chemokines (MCP-1, MIP-1alpha, IL-8) and cytokines (e.g., IL-12, IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10). This review tries to link well-known properties of mycolic acid-containing glycolipids, e.g., stimulation of cellular and humoral immunity, granuloma formation and anti-tumor activity, with recent findings in molecular immunology and to give an outlook on potential practical applications.


Molecular identification of Echinococcus species from eastern and southern Qinghai, China, based on the mitochondrial cox1 gene.
The Qinghai-Tibetan Plateau (QTP, in western China), which is the largest and highest plateau on Earth, is a highly epidemic region for Echinococcus spp. We collected 70 Echinococcus samples from humans, dogs, sheep, yaks, plateau pikas, and voles in eastern and southern Qinghai and genotyped them using the mitochondrial DNA marker cytochrome oxidase subunit I gene and maximum parsimony and Bayesian reconstruction methods. Based on the 792-bp sequence matrix, we recorded 124 variable sites, of which, 115 were parsimony-informative. Thirty-four haplotypes (H1-H34) were detected, of which H1-H15, H16-H17, and H18-H34 belonged to Echinococcus shiquicus, Echinococcus multilocularis, and Echinococcus granulosus, respectively. Within 26 human isolates, three were identified as E. multilocularis and 23 were E. granulosus. We also detected a dual infection case in a dog with E. multilocularis and E. granulosus. The intraspecific haplotype (Hd ± SD) and nucleotide (Nd ± SD) diversity of E. shiquicus (0.947 ± 0.021; 0.00441 ± 0.00062) was higher than that for E. granulosus (0.896 ± 0.038; 0.00221 ± 0.00031) and E. multilocularis (0.286 ± 0.196; 0.00036 ± 0.00025). Moreover, the haplotype network of E. shiquicus showed a radial feature rather than a divergent feature in a previous study, indicating this species in the QTP has also evolved with bottleneck effects.


Trends and sub-national disparities in TB notifications in India: Insights from HMIS data.
Tuberculosis (TB) is a public health crisis across the globe, especially in the developing world including India. Around 27% of 10 million TB cases and 33% of 1.2 million TB deaths were contributed from India alone during 2018. Present study aims to estimate TB notification rates at national and sub-national levels up to District administrative blocks, which is very important with policy perspective. The study mainly uses data from India's Health Management Information System (HMIS) for three consecutive years, 2017-18, 2018-19 and 2019-20. TB notification rates were calculated for India up to the lowest administrative level of health Districts. GIS maps were being used for mapping District-wise TB notification rates for 2017-18 and 2019-20. Results show that TB notification rates have increased from 152/lakh population in 2017-18 to 197 in 2019-20, an increase of 30%. Similarly, the increasing trends in TB notification rates were also observed at State as well as District level. However, wide rural-urban and public-private differences were observed in TB notification rates. Further, results illustrated huge inter-State and inter-District variations; and half of the TB cases in India were contributed only by six larger States. The findings of the study shows the increasing notification in India since 2017-18, which is a clear indication of the efforts put in the TB program to achieve targets and goals committed to end TB by 2025. In this regard present estimates based on HMIS data significantly contributes to the policy formulation even at the lowest administrative level of health Districts.


Hypercholesterolemia induces leukocyte entrapment in the retinal microcirculation of rats.
To evaluate leukocyte dynamics in the retinal microcirculation of hypercholesterolemic rats in vivo using acridine orange digital fluorography. 18 male pigmented rats were divided into 3 groups according to their diet; (A) control diet (0.1% cholesterol) for 8 weeks, (B) control diet for an initial 4 weeks followed by a high-cholesterol (HC) diet (5% cholesterol) for another 4 weeks and (C) HC diet for 8 weeks. Leukocyte dynamics were observed with acridine orange digital fluorography. The diameter of major retinal vessels and the number of leukocytes trapped in the retina were evaluated quantitatively. Both groups B and C showed approximately 4-fold higher serum cholesterol levels than in group A. The diameters of retinal arteries and veins were not significantly different among the three groups. Also, no rolling leukocytes were observed in any of the groups. In the retinal microcirculation at 30 minutes after acridine orange injection, the density of trapped leukocytes in both groups B and C was significantly greater than in group A (23.19 +/- 2.13, 28.56 +/- 1.96 and 13.67 +/- 1.45 cells/mm(2), respectively, p < 0.01). Furthermore, group C exhibited a significantly greater number of trapped leukocytes than in group B (p < 0.01). Enhanced leukocyte entrapment in the retinal microcirculation was induced in the early stage of hypercholesterolemia. Entrapment was increased as the period of hypercholesterolemia was prolonged. Leukocyte accumulation in the retina may be an early vascular dysfunction leading to arteriosclerosis in hypercholesterolemia.


Meal timing across the day modulates daily energy intake in adult patients with type 2 diabetes.
We assessed the association between the timing of meals across the day with diet composition and metabolic parameters in patients with type-2 diabetes (T2D). Eighty adults (55.2 ± 6.8 years, 45% males) patients with T2D (without insulin therapy) were included. Three non-consecutive dietary records assessed food intake. The onset time of each consumed meal/beverage was identified and assigned to one of three periods of the day: Period 1 (P1, 06:00-11:59 h), Period 2 (P2, 12:00-17:59 h), and Period 3 (P3, 18:00-00:30 h). Energy intake in P1 was lower compared to P2 and P3 (22.8 ± 7.9%, 37.5 ± 9.6%, and 39.7 ± 9.9%, respectively, P < 0.001). The same pattern was found for both total protein and fat intake, but carbohydrate intake was similar among periods. Patients with greater daily energy intake (as % of total energy) in P3 showed increased total food consumption, total energy, protein, and fat intake (all P < 0.05). The opposite pattern was observed in patients with greater daily energy intake in P1 (all P < 0.05). Regression analysis showed that daily energy intake was significantly reduced when a higher proportion of carbohydrates was eaten in P1 (vs. P3, P < 0.04). Increased energy intake late during the day is related to increased total food and daily energy intake in patients with T2D. A greater proportion of total carbohydrates eaten early during the day relates to lower total energy intake. Our results suggest that earlier food intake may be a nutritional tool for dietary and metabolic control in these patients.


Prognostic factors for actual long-term survival in the era of multidisciplinary treatment for pancreatic ductal adenocarcinoma.
Recent advances in multidisciplinary treatments are improving the postoperative prognosis of pancreatic ductal adenocarcinoma (PDAC). However, the prognosis even after potentially curative resection remains poor. The aim of this study was to identify the clinical and pathological features of actual 5-year survivors under current circumstances. A total of 128 patients who underwent pancreatectomy for PDAC at our institution between January 2006 and December 2011 were retrospectively analyzed. The actual 5-year overall survival rate for all patients was 30.9%, with a median survival time of 33.1 months. Of 128 patients, 25 (19.5%) survived for 5 years after surgery without disease recurrence. A univariate analysis showed that the pretreatment serum CA19-9 value, tumor depth, lymph node metastasis, and UICC stage at resection were significant predictive factors for the actual long-term survival. A multivariate analysis showed that a pretreatment serum CA19-9 value ≥ 110 U/mL was a significant unfavorable prognostic indicator. In addition, all subjects in the 5-year survival group completed adjuvant chemotherapy. The recurrence rate in the liver was significantly lower and that in the lung significantly higher in the long-term survival group than in the short-term survival group. The factors contributing to the long-term survival of PDAC were the pretreatment CA19-9 value and the completion of adjuvant chemotherapy. To achieve the actual long-term survival and cure after pancreatectomy for pancreatic cancer, further treatment strategies enhancing the completion rate of adjuvant chemotherapy are required.


An investigation into noninvasive follicular thyroid neoplasms with papillary-like nuclear features: does the initial proposal on noninvasive follicular thyroid neoplasms with papillary-like nuclear features behavior hold true?
Current management of patients with noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) is lobectomy with close clinical follow-up. Because this entity is still young, we present our 5-year institutional experience with NIFTP since that time. Cases of NIFTP diagnosed from 2017 to 2022 were identified. Data points including patient demographics, radiology, cytologic and pathologic diagnoses, molecular profiles, and clinical follow-up were documented. A literature review of NIFTP case series was performed. A total of 379 cases were included (mean age: 52 years, female:male ratio 3.3:1). Ultrasound findings were available for 260 patients, and 247 underwent fine-needle aspiration (FNA). The FNA diagnoses per the Bethesda System for Reporting Thyroid Cytology were nondiagnostic (n = 2), benign (n = 16), atypia of undetermined significance/follicular lesion of undetermined significance (n = 119), follicular neoplasm/suspicious for follicular neoplasm (n = 68), suspicious for malignancy (n = 31), and malignant (n = 11). Molecular testing was performed in 179 cases. Lobectomy was performed for 183, total thyroidectomy for 192, and nodulectomy for 4 cases. The average size of NIFTP was 2.3 cm, and 232 cases had additional nodules (including benign and malignant neoplasms). Multifocal NIFTP occurred in 32 patients. Lymph nodes were evaluated in 196 cases with metastatic carcinoma in 29 cases (all with concurrent diagnoses of carcinoma). Most patients were alive at follow-up, 100 were lost to follow-up, and three died from other causes. Literature review revealed 2870 NIFTP cases with similar patient demographics and pathologic findings. We confirm that NIFTP is a low-risk neoplasm with indolent clinical behavior, which can be managed conservatively.


Deletion of macrophage migration inhibitory factor gene induces down regulation of sex hormones and ultrastructural abnormalities in mouse testes.
Macrophage migration inhibitory factor (MIF) is a multifunctional protein that acts as a pro-inflammatory cytokine, pituitary hormone, immunoregulator and mitogen. The MIF gene knockout (MIFKO) mouse has been used to study the MIF response in many tissues, such as with skin injury and spinal cord injury; however, there is little information about the MIFKO mouse testis. This study reports the levels of serum and intratesticular estradiol and testosterone, the ultrastructure of the testis, and preliminary findings from in vitro fertilization. Our results revealed a decrease in estradiol and testosterone levels and deformation in spermiogenesis, in the MIFKO mouse. These initial findings study may lead to a better understanding of the role that MIF plays in the mouse testis.


Magnesium deficiency in patients on home enteral nutrition.
Home enteral nutrition (HEN) is an established method of long term nutritional support. Many patients receiving HEN have Crohn's disease complicated by intestinal failure and malnutrition, including magnesium deficiency. It is unknown if HEN can correct magnesium deficiency or if patients on HEN can become magnesium deficient. We measured total magnesium intake in nine patients receiving HEN, and assessed their magnesium status. Two patients had magnesium intakes below the recommended dietary allowance of 15 mmol/day. Four patients (44%) had biochemical evidence of magnesium deficiency, although no patient had clinical signs of magnesium deficiency. Several magnesium deficient patients used a liquid feed which had a low magnesium content. Patients on HEN should have their magnesium status checked regularly and may require magnesium supplements.


How is muscle phenotype controlled by nerve activity?
Motor neurons are known to affect muscle growth and fiber type profile (fast/slow, oxidative/glycolytic) by regulating muscle gene expression. However, the mechanism by which the information contained in specific action potential patterns is decoded by the transcriptional machinery of muscle fiber nuclei remains to be established. This is a basic issue in nerve/muscle biology, which has major implications in neurology, sport medicine and aging. We describe here a general strategy aimed at identifying the signal transduction pathways mediating the effects of nerve activity. This approach is based on the overexpression of constitutively active or dominant negative transduction factors in regenerating skeletal muscle.


HLA antigens and haplotypes associated with idiopathic haemochromatosis in Veneto: peculiar association with HLA-A3,B35.
HLA-A and HLA-B antigens were determined in 16 unrelated subjects orginating from Veneto affected by idiopathic haemochromatosis (IH). HLA-A3 was found in 13/16 patients vs. 300/1,348 controls (p less than 0.00005). Prevalences of A3,B35 haplotype were 0.4375 in patients vs. 0.0816 in controls (p less than 0.0005). Linkage disequilibrium analysis proved the existence of a positive third-order linkage disequilibrium among IH, HLA-A3 and HLA-B35 alleles. Our data confirm the close association of IH and HLA-A3 and prove the peculiar association of the disease with A3,B35 haplotype in north-eastern regions of Italy. The positive third-order linkage disequilibrium suggests a remote event (mutation, recombination or immigration) as origin for IH and A3,B35 association.


Assessing the utilization of the decision to implement a palliative goal for the treatment of cancer patients during the last year of life at Helsinki University Hospital: a historic cohort study.
Background: To avoid aggressive treatments at the end-of-life and to provide palliative care (PC), physicians need to terminate futile anti-cancer treatments and define the palliative goal of the treatment in time. This single center study assesses the practices used to make the decision that leads to treatment with a palliative goal, i.e., the PC decision and its effect on anti-cancer treatments at the end of life.Material and methods: Patients with a cancer diagnosis treated in tertiary hospital during 1st January 2013 - 31st December 2014 and deceased by the end of 2014 were identified in the hospital database (N = 2737). Of these patients, 992 were randomly selected for this study. The PC decision was screened from patient records, i.e., termination of cancer-specific treatments and a focus on symptom-centered PC.Results: The PC decision was defined in 82% of the patients during the last year of life (49% >30 days and 33% ≤30 days before death, 18% with no decision). The median time from the decision to death was 46 days. Systemic cancer therapy was given during the last month of life in 1%, 36% and 38% (p < .001) and radiotherapy 22%, 40% and 31% (p = .03) cases, respectively; referral to a PC unit was made in 62%, 22% and 11%, respectively (p < .001). In logistic regression analyses younger age, shorter duration of the disease trajectory and type of cancer (e.g., breast cancer) were associated with a lack or late timing of the PC decision.Conclusion: The decision to initiate a palliative goal for the treatment was frequently made for cancer patients but occurred late for every third patient. Younger age and certain cancer types were associated with late PC decisions, thus leading to anti-cancer treatments continuing until close to the death with low access to a PC unit.


Localization of metallothionein I-II immunoreactivity in bovine pituitary gland.
Metallothioneins belong to a family of shock proteins characterized by an unusual high content of cystein, absence of aromatic amino acids and high metal content (Zinc and Copper). Metallothioneins are ubiquitously present in a large variety of prokaryotic and eukaryotic species as well as in all mammalian organs and tissues examined thus far. To the best of our knowledge this is the first report describing the presence of metallothioneins in the pituitary gland. Metallothioneins were identified immunohistochemically and chromatographically both in the neuro and adenohypophysis of the bovine pituitary gland. Metallothioneins are highly expressed in the neurohypophyseal glial cells, and in a subpopulation of folliculo-stellate cells located in the pars intermedia of the adenohypophysis. While the specific role of these proteins in the pituitary gland remains to be established, we hypothesize that, besides their protective action against free radicals, hypophyseal metallothioneins might be involved in the regulation of metal ion homeostasis with putative implication in release of hypothalamic peptide hormones in the neurohypophysis and synthesis/release of alpha-MSH by POMC-cells located in the pars intermedia of the adenohypophysis.


Flow cytometric analysis of Thy-1 expression in myelodysplastic syndrome.
We analyzed the expression of Thy-1 (CD90) antigen on CD34+ bone marrow mononuclear cells (BMMNC) obtained from 25 patients with myelodysplastic syndrome (MDS) by two-color flow cytometry. Five of nine patients (55.6%) with refractory anemia with excess of blasts (RAEB) and two of 16 (12.5%) with RAEB in transformation (RAEB-t) showed more than 20% of Thy-1 expression of their CD34+ BMMNC. Regarding chromosomal abnormalities, -5/5q- or -18 might be correlated with the expression of Thy-1 on CD34+ BMMNC in MDS. Nine patients were analyzed twice, once before and once after leukemic transformation and showed no significant change in Thy-1 expression. These results show that Thy-1 was expressed on CD34+ BMMNC in certain patients with MDS before leukemic transformation and that it was maintained during the disease progression. In contrast, expression of Thy-1 did not seem essential to the leukemic transformation in MDS though the patients with high Thy-1 expression might have poorer prognosis compared with those with low Thy-1 expression.


The start of an autoimmune disease: idiotypic network during early progression of myasthenia gravis.
Anti-acetylcholine-receptor antibodies of IgG and IgM classes and antiidiotypic antibodies were determined in patients with myasthenia gravis at various times after the start of the disease. Patients with a disease duration of less than one year had a higher prevalence of antiidiotypic antibodies (31/32) than patients who had had the disease for more than 5 years (49/79), and the concentration of antiidiotypic antibodies was also higher in patients with early disease (p less than 0.005). The concentrations of antiidiotypic antibodies decreased during progression of the disease concomittant with an increase in IgG anti-receptor antibodies. A change from IgM to IgG anti-receptor antibody production was also found. In two patients, who developed myasthenia after bone-marrow grafting and who were followed before start of disease, antiidiotypic antibodies appeared before anti-receptor antibodies and before symptoms of myasthenia were present. The high prevalence and concentration of antiidiotypic antibodies in early disease indicate that development and expression of antiidiotypic antibodies are important in early myasthenia gravis.


Fossils of the oldest diplodocoid dinosaur suggest India was a major centre for neosauropod radiation.
The Early Jurassic and Cretaceous deposits of India are known for their diverse sauropod fauna, while little is known from the Middle and Late Jurassic. Here we report the first ever remains of a dicraeosaurid sauropod from India, Tharosaurus indicus gen. et sp. nov., from the Middle Jurassic (early-middle Bathonian) strata of Jaisalmer Basin, western India. Known from elements of the axial skeleton, the new taxon is phylogenetically among the earlier-diverging dicraeosaurids, and its stratigraphic age makes it the earliest known diplodocoid globally. Palaeobiogeographic considerations of Tharosaurus, seen in conjunction with the other Indian Jurassic sauropods, suggest that the new Indian taxon is a relic of a lineage that originated in India and underwent rapid dispersal across the rest of Pangaea. Here we emphasize the importance of Gondwanan India in tracing the origin and early evolutionary history of neosauropod dinosaurs.


A stratified randomized study of intradermal BCG in patients with carcinoma of the bronchus: prolongation of quality but not length of life in inoperable patients.
This paper reports the results of a stratified, randomized trial of monthly intradermal injections of Glaxo BCG in addition to conventional therapy (surgery, radiotherapy or no treatment) in a consecutive series of 75 men with confirmed bronchial carcinoma. BCG treatment did not significantly prolong survival but had consistenly more effect in prolonging the period in good general condition and in "acceptable" clinical condition. These were significantly prolonged among the BCG patients (all histopathologies) treated with a full course of radiotherapy (p = 0.01, p = 0.005) and among the 43 patients with squamous carcinoma after adjustment for treatment and general prognostic factors (ratio of observed to expected deaths (O/E) for BCG 0.65, P = 0.025). There was a tendency for BCG patients with oat cell carcinoma to survive less well than controls (O/E for BCG 1.40 not significant). Within comparable groups of patients with squamous carcinoma the delay in decline of general condition was accompanied by reduced weight loss.


The effect of dietary n-3/n-6 polyunsaturated fatty acid ratio on salmonid alphavirus subtype 1 (SAV-1) replication in tissues of experimentally infected rainbow trout (Oncorhynchus mykiss).
Salmon pancreas disease (SPD) is one of the most commercially significant viral diseases of farmed Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss) in Europe. In this study, the potential for dietary mitigation of the disease using different polyunsaturated fatty acid (PUFA) profiles was assessed in rainbow trout. We experimentally infected fish with salmonid alphavirus subtype 1 (SAV-1), the causative agent of SPD. These fish were fed two diets with different n-3/n-6 PUFA ratio (high omega 3, 3.08, and high omega 6, 0.87). We assessed the influence of the diets on the fatty acid composition of the heart at 0 days post infection (d.p.i.) (after 4 weeks of feeding the experimental diets prior to SAV-1 infection), and sampled infected and control fish at 5, 15 and 30d.p.i. Viral E1 and E2 glycoprotein genes were quantified by two absolute real-time PCRs in all the organs sampled, and significantly lower levels of the virus were evident in the organs of fish fed with high omega 6. Characteristic pathological lesions were identified in infected fish as early as 5d.p.i., with no significant differences in the pathology lesion scores between the two dietary regimes. This study shows that decreasing the n-3/n-6 PUFA ratio in experimental diets of rainbow trout changes the fatty acid content of the fish, and is associated with reduced SAV-1 replication in rainbow trout.


Immunisation against panleukopenia: early development of immunity.
The time necessary to obtain the immunity of cats against Panleukopenia has been studied by means of a modified live vaccine. This vaccine makes it possible to obtain a very early post-vaccinal immunity: the full immunity is reached 72 hr after the inoculation of the vaccine by the subcutaneous route. Furthermore, we have demonstrated that a sensitive kitten can be admitted in a contaminated environment immediately after vaccination without showing any clinical evidence of the disease.


Epidemiology of injuries and poisonings in emergency departments in Iran.
There are few reports on epidemiological patterns of injury and injury-related mortality in developing countries. This study aimed to report the epidemiology of injuries and poisonings in emergency departments in Iran. Retrospective study using available data from 20 March 2005 to 19 March 2008. Recorded Injury Surveillance System (ISS) data including demographics, place of residence, type of injury, and outcome during emergency department stay were extracted from the databank of the national ISS and included in the final analysis. In total, 2,991,624 emergency department admissions due to injury were recorded at university hospitals during the study period. According to the national census in 2006, Iran had a population of 70,472,846, so the injury admission rate to university hospital emergency departments was 1.4%/year in Iran. The mean age of the patients was 26.5 [standard deviation (SD) 16.9] years, and 72.7% of the cases were male. The most common cause of injury was road traffic accidents (RTAs) (31.9%), followed by hit (25.5%) and falls (10.9%). Intoxication was associated with 5.3% of all injuries. The overall emergency department mortality rate was 0.6%. Of those who died, the mean age was 32.6 (SD 21.1) years. All fatal injuries, except burn injuries, were more common in males. Intoxication-related deaths occurred in 3.8% of cases. In patients aged <13, 13-65 and >65 years, hit (28.2%), RTAs (34%) and RTAs (27.9%) were, respectively, the most common causes of injury. In all age groups, RTAs were the most common cause of death. This study determined the epidemiology of injuries and poisonings in emergency departments in Iran. The mortality rate in this study was low in comparison with other research, which may be explained in the context of inappropriate prehospital or interhospital care in Iran. This finding can be employed to formulate targeted preventive strategies based on the incidence of the more common types of injury.


Barriers to screening for domestic violence.
Domestic violence has an estimated 30% lifetime prevalence among women, yet physicians detect as few as 1 in 20 victims of abuse. To identify factors associated with physicians' low screening rates for domestic violence and perceived barriers to screening. Cross-sectional postal survey. A national systematic sample of 2,400 physicians in 4 specialties likely to initially encounter abused women. The overall response rate was 53%. Self-reported percentage of female patients screened for domestic violence; logistic models identified factors associated with screening less than 10%. Respondent physicians screened a median of only 10% (interquartile range, 2 to 25) of female patients. Ten percent reported they never screen for domestic violence; only 6% screen all their patients. Higher screening rates were associated with obstetrics-gynecology specialty (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.31 to 0.78), female gender (OR, 0.51; CI, 0.35 to 0.73), estimated prevalence of domestic violence in the physician's practice (per 10%, OR, 0.72; CI, 0.65 to 0.80), domestic violence training in the last 12 months (OR, 0.46; CI, 0.29 to 0.74) or previously (OR, 0.54; CI, 0.34 to 0.85), and confidence in one's ability to recognize victims (per Likert-scale point, OR, 0.71; CI, 0.58 to 0.87). Lower screening rates were associated with emergency medicine specialty (OR, 1.72; CI, 1.13 to 2.63), agreement that patients would volunteer a history of abuse (per Likert-scale point, OR, 1.60; CI, 1.25 to 2.05), and forgetting to ask about domestic violence (OR, 1.69; CI, 1.42 to 2.02). Physicians screen few female patients for domestic violence. Further study should address whether domestic violence training can correct misperceptions and improve physician self-confidence in caring for victims and whether the use of specific intervention strategies can enhance screening rates.


On the perturbation effect and LET dependence of beam quality correction factors in carbon ion beams.
In a recent study, we reported beam quality correction factors, fQ , in carbon ion beams using Monte Carlo (MC) methods for a cylindrical and a parallel-plate ionization chamber (IC). A non-negligible perturbation effect was observed; however, the magnitude of the perturbation correction due to the specific IC subcomponents was not included. Furthermore, the stopping power data presented in the International Commission on Radiation Units and Measurements (ICRU) report 73 were used, whereas the latest stopping power data have been reported in the ICRU report 90. The aim of this study was to extend our previous work by computing fQ correction factors using the ICRU 90 stopping power data and by reporting IC-specific perturbation correction factors. Possible energy or linear energy transfer (LET) dependence of the fQ correction factor was investigated by simulating both pristine beams and spread-out Bragg peaks (SOBPs). The TOol for PArticle Simulation (TOPAS)/GEANT4 MC code was used in this study. A 30 × 30 × 50 cm3 water phantom was simulated with a uniform 10 × 10 cm2 parallel beam incident on the surface. A Farmer-type cylindrical IC (Exradin A12) and two parallel-plate ICs (Exradin P11 and A11) were simulated in TOPAS using the manufacturer-provided geometrical drawings. The fQ correction factor was calculated in pristine carbon ion beams in the 150-450 MeV/u energy range at 2 cm depth and in the middle of the flat region of four SOBPs. The kQ correction factor was calculated by simulating the fQo correction factor in a 60 Co beam at 5 cm depth. The perturbation correction factors due to the presence of the individual IC subcomponents, such as the displacement effect in the air cavity, collecting electrode, chamber wall, and chamber stem, were calculated at 2 cm depth for monoenergetic beams only. Additionally, the mean dose-averaged and track-averaged LET was calculated at the depths at which the fQ was calculated. The ICRU 90 fQ correction factors were reported. The pdis correction factor was found to be significant for the cylindrical IC with magnitudes up to 1.70%. The individual perturbation corrections for the parallel-plate ICs were <1.0% except for the A11 pcel correction at the lowest energy. The fQ correction for the P11 IC exhibited an energy dependence of >1.00% and displayed differences up to 0.87% between pristine beams and SOBPs. Conversely, the fQ for A11 and A12 displayed a minimal energy dependence of <0.50%. The energy dependence was found to manifest in the LET dependence for the P11 IC. A statistically significant LET dependence was found only for the P11 IC in pristine beams only with a magnitude of <1.10%. The perturbation and kQ correction factor should be calculated for the specific IC to be used in carbon ion beam reference dosimetry as a function of beam quality.


Randomized controlled studies of injection Gold Probes compared with monotherapies for hemostasis of bleeding canine gastric ulcers.
There is a significant interest in combination therapy using endoscopic epinephrine injection and thermal coagulation for nonvariceal hemostasis. The purpose of the study was to compare the relative effectiveness, ease of use, and safety of new Injection Gold Probes to other hemostasis techniques in three randomized, controlled laboratory studies of bleeding canine gastric ulcers. Fifteen dogs with prehepatic portal hypertension were heparinized and bleeding gastric ulcers were induced with jumbo biopsy forceps. Three different prototypes of Injection Gold Probes were compared with monotherapy (thermal, electrocoagulation, or epinephrine injection alone), control, or combination therapy with separate injector and thermal probes. The treatment times, total number of pulses or injections, volume of epinephrine injected, and ease of applications were recorded. Gastric ulcer size, ulcer healing, and complications were evaluated at 1 and 4 weeks. All endoscopic treatments were effective for acute hemostasis compared with control. Thermal coagulation alone was the fastest treatment to perform. The performance of the first Injection Gold Probe prototype was restricted by its small-gauge needle. The second and third Injection Gold Probe prototypes had a larger-gauge needle and irrigation channel which made them faster and easier to use than separate injection catheters and thermal probes. The advantages of Injection Gold Probes were the ability to irrigate, inject, and coagulate without probe removal. Combination therapy did not increase treatment-related complications compared with monotherapies.


Strontium-Substituted Bioceramics Particles: A New Way to Modulate MCP-1 and Gro-α Production by Human Primary Osteoblastic Cells.
To avoid morbidity and limited availability associated with autografts, synthetic calcium phosphate (CaP) ceramics were extensively developed and used as bone filling materials. Controlling their induced-inflammatory response nevertheless remained a major concern. Strontium-containing CaP ceramics were recently demonstrated for impacting cytokines' secretion pattern of human primary monocytes. The present study focuses on the ability of strontium-containing CaP to control the human primary bone cell production of two major inflammatory and pro-osteoclastogenic mediators, namely MCP-1 and Gro-α, in response to ceramics particles. This in vitro study was performed using human primary osteoblasts in which their response to ceramics was evaluated by PCR arrays, antibody arrays were used for screening and real-time PCR and ELISA for more focused analyses. Study of mRNA and protein expression highlights that human primary bone cells are able to produce these inflammatory mediators and reveal that the adjunction of CaP in the culture medium leads to their enhanced production. Importantly, the current work determines the down-regulating effect of strontium-substituted CaP on MCP-1 and Gro-α production. Our findings point out a new capability of strontium to modulate human primary bone cells' communication with the immune system.


Productive HBV infection of well-differentiated, hNTCP-expressing human hepatoma-derived (Huh7) cells.
Feasible and effective cell models for hepatitis B virus (HBV) infection are required for investigating the complete lifecycle of this virus, including the early steps of viral entry. Resistance to dimethyl sulfoxide/polyethylene glycol (DMSO/PEG), hNTCP expression, and a differentiated state are the limiting factors for successful HBV infection models. In the present study, we used a hepatoma cell line (Huh7DhNTCP) to overcome these limiting factors so that it exhibits excellent susceptibility to HBV infection. To achieve this goal, different hepatoma cell lines were tested with 2.5% DMSO / 4% PEG8000, and one resistant cell line (Huh7D) was used to construct a stable hNTCP-expressing cell line (Huh7DhNTCP) using a recombinant lentivirus system. Then, the morphological characteristics and differentiation molecular markers of Huh7DhNTCP cells with or without DMSO treatment were characterized. Finally, the susceptibility of Huh7DhNTCP cells to HBV infection was assessed. Our results showed that Huh7D cells were resistant to 2.5% DMSO / 4% PEG8000, whereas the others were not. Huh7DhNTCP cells were established to express a high level of hNTCP compared to liver extracts, and Huh7DhNTCP cells rapidly transformed into a non-dividing, well-differentiated polarized phenotype under DMSO treatment. Huh7DhNTCP cells fully supported the entire lifecycle of HBV infection. This cell culture system will be useful for the analysis of host-virus interactions, which should facilitate the discovery of antiviral drugs and vaccines.


Quantification of individual subgenomic mRNA species during replication of the coronavirus transmissible gastroenteritis virus.
A biotinylated-oligonucleotide-based method was used to isolate the subgenomic mRNAs of the coronavirus transmissible gastroenteritis virus (TGEV) to investigate the amounts of the mRNAs produced at early, middle and late times in the replication cycle. TGEV mRNA 6, which encodes the N protein, was observed to be the most abundant species throughout the replication cycle. The ratios of mRNA 6 to the other mRNAs were 1:0.11 (mRNA 2), 1:0.16 (mRNAs 3 and 4) and 1:0.37 (mRNA 5) at 12 h post-infection. All the mRNA species were differentially regulated throughout the replication cycle, although the rate of accumulation of mRNAs 4, 5 and 6, but not mRNA 3, increased markedly towards the end of the replication cycle. mRNA 7 was not detected in the system used. There was no observable correlation between the amounts of each mRNA synthesised and the potential degree of base pairing between the 3' end of the leader sequence and the transcription associated sequences on the genomic RNA at any time during the replication cycle. This indicates that the extent of base pairing was not the only factor involved in the control of subgenomic mRNA synthesis.


Spatial Inhibition of Return promotes changes in response-related mu and beta oscillatory patterns.
The possible role that response processes play in Inhibition of Return (IOR), traditionally associated with reduced or inhibited attentional processing of spatially cued target stimuli presented at cue-target intervals longer than 300 ms, is still under debate. Previous psychophysiological studies on response-related Electroencephalographic (EEG) activity and IOR have found divergent results. Considering that the ability to optimize our behavior not only resides in our capacity to inhibit the focus of attention from irrelevant information but also to inhibit or reduce motor activation associated with responses to that information, it is conceivable that response processes are also affected by IOR. In the present study, time-frequency (T-F) analyses were performed on EEG oscillatory activity between 2 and 40 Hz to check whether spatial IOR affects response preparation and execution during a visuospatial attention task. To avoid possible spatial stimulus-response compatibility effects and their interaction with the IOR effects, the stimuli were presented along the vertical meridian of the visual field. The results differed between lower and upper visual fields. In the lower visual field spatial IOR was related to a synchronization in the pre-movement mu band at bilateral precentral and central electrodes, and in the post-movement beta band at contralateral precentral and central electrodes, which may be associated with an attention-driven reduction of somatomotor processing prior to the execution of responses to relevant stimuli presented at previously cued locations followed by a post-movement deactivation of motor areas. In the upper visual field, spatial IOR was associated with a decrease in desynchronization around response execution in the beta band at contralateral postcentral electrodes that might indicate a late (last moment) reduction of motor activation when responding to spatially cued targets. The present results suggest that different response processes are affected by spatial IOR depending on the visual field where the target is presented.


Drugs used for euthanasia in Flanders, Belgium.
Our aim was to describe and assess the medicinal products and doses used for euthanasia in a series of cases, identified within an epidemiological death certificate study in Belgium, where euthanasia was until recently legally forbidden and where guidelines for euthanasia are not available. In a random sample of the deaths in 1998 in Belgium, the physicians who signed the death certificates were identified and sent an anonymous mail questionnaire. The questionnaires of the deaths classified as euthanasia cases were reviewed by a multi-disciplinary panel. A total of 22 among 1925 questionnaires pertained to voluntary euthanasia. In 17 cases, detailed information on the euthanatics (medicinal substances used for euthanasia) used was provided. Opioids were used in 13 cases (in 7 as a single drug). Time between last dose and expiry ranged from 4 to 900 min. The panel judged that only in 4 cases effective euthanatics were used. In the end-of-life decision cases perceived by Belgian physicians as euthanasia, pharmacological practices were disparate, although dominated by the use of morphine, in the very late phase of dying, in doses which were unlikely to be lethal. Most physicians clandestinely engaging in euthanasia in Belgium seemed unaware of procedures for guaranteeing a quick, mild and certain death. Information on the pharmacological aspects of euthanasia should be included in the medical curriculum and continuing medical education, at least in countries with a legal framework permitting euthanasia under specified conditions.


Phosphorylation of adenosine in aqueous solution by electric discharges.
Dehydration reactions involving condensing reagents in aqueous solution have been studied as models of chemical evolution, and one such reagent has been found to be produced in the supposed primitive Earth conditions. We assumed that the dehydration condensation in aqueous solution could occur if the condensing reagents, which appear to be produced by electric discharges in the gas phase, could be carried to the aqueous solution through the recycling of water washing the wall of the vessel. We present here an experimental study of the dehydration condensation between phosphate and adenosine in aqueous solution using a new discharge apparatus (Fig. 1) which simulates prebiotic chemical evolution. The apparatus was designed so that water recycles in a vessel containing a solution at a relatively low temperature (approximately 30 degrees C), achieved by showering water at 18 degrees C from above the vessel. This is a simulation of the recycling system of water on the Earth, depending on a large difference in temperature between the ocean surface and the sky.


Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype.
Hypoxia-induced intrauterine growth restriction increases the risk for cardiovascular, renal, and other chronic diseases in adults, representing thus a major public health problem. Still, not much is known about the fetal mechanisms that predispose these individuals to disease. Using a previously validated mouse model of fetal hypoxia and bottom-up proteomics, we characterize the response of the fetal kidney to chronic hypoxic stress. Fetal kidneys exhibit a dichotomous response to chronic hypoxia, comprising on the one hand cellular adaptations that promote survival (glycolysis, autophagy, and reduced DNA and protein synthesis), but on the other processes that induce a senescence-like phenotype (infiltration of inflammatory cells, DNA damage, and reduced proliferation). Importantly, chronic hypoxia also reduces the expression of the antiaging proteins klotho and Sirt6, a mechanism that is evolutionary conserved between mice and humans. Taken together, we uncover that predetermined aging during fetal development is a key event in chronic hypoxia, establishing a solid foundation for Barker's hypothesis of fetal programming of adult diseases. This phenotype is associated with a characteristic biomarker profile in tissue and serum samples, exploitable for detecting and targeting accelerated aging in chronic hypoxic human diseases.


Structure and anticancer activity of Cu(II) complexes with (bromophenyl)thiourea moiety attached to the polycyclic imide.
A series of nine copper complexes were synthesized by reacting 1,3-disubstituted thioureas with copper(II) chloride. The new compounds were characterized by elemental analysis, infrared, ultraviolet-visible and X-ray absorption spectroscopies as well as molecular modelling. The molecular structure of complexes in the solid state consists of two thiourea ligands chelated to the Cu(II) ion through the S and deprotonated N atoms (CuN2S2). The coordination polyhedron of metal cation in powdered samples exhibits two different geometries. Pseudo-tetrahedral structure is observed for noncentrosymmetric complexes with cis-N2S2 arrangement around Cu(II). A distorted square planar geometry is characteristic for centrosymmetric compounds with trans arrangements of chelating atoms around the central ion. All complexes after dissolving in dimethyl sulfoxide adopt a centrosymmetric coordination, while after diluting this solution with water, the reorganization of atoms around the metal cation is observed, leading to the formation of a tetrahedral compounds. Initial ligands and Cu(II) complexes were evaluated for their cytotoxicity. Two complexes with 4- and 3-bromophenyl attached to the (1,7,8,9,10-pentamethyl-3,5-dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl)thiourea moiety (Cu1, Cu3) are cytotoxic against SW480 and PC3 cells (IC50 4-19 μm), and non-cytotoxic against HaCaT cells (IC50 ≥ 84 μm), being more selective than doxorubicin and cisplatin used as references. The compounds induced apoptosis in cancer cells, however, Cu3 was estimated to be highly active inducer of late apoptosis in SW480 and PC3 cells at lower toxicity against normal cells. The likely mechanism of action of complexes is correlated with decreasing release of IL-6 in cancer cell lines.


Maternal Coping and Depressive Symptoms as Predictors of Mother-Child Communication About a Child's Cancer.
This study sought to identify possible associations between maternal coping and depression and subsequent mother-child communication about cancer following the child's diagnosis. Mothers (N = 100) reported on coping and depressive symptoms shortly after the child's diagnosis (M = 1.9 months). Subsequently, we observed children (age 5-17 years; M = 10.2 years; 48% female; 81% White) and mothers discussing cancer and coded maternal communication. Higher primary and secondary control coping, and lower depressive symptoms, were generally correlated with more positive, and less harsh and withdrawn communication. In regression models, higher primary control coping (i.e., coping efforts to change the stressor or one's emotional reaction to the stressor) independently predicted less withdrawn communication, and depressive symptoms mediated relations between coping and harsh communication. Maternal primary control coping and depressive symptoms predict mothers' subsequent harsh and withdrawn communication about cancer.


Ischemic maculopathy following intravitreal bevacizumab for refractory diabetic macular edema.
A 58-year-old male presented with decreased visual acuity from persistent diffuse diabetic macular edema despite multiple interventions including laser photocoagulation and intravitreal triamcinolone acetonide injections. Following treatment with 1.25 mg of intravitreal bevacizumab, reduction in macular leakage was shown by fluorescein angiography and resolution of edema was shown by optical coherence tomography (OCT); however, visual acuity deteriorated and fluorescein angiograms demonstrated progressive enlargement of the foveal avascular zone (FAZ), which had shown no abnormalities before the injection. Despite normalisation of macular thickness on OCT and cessation of leakage on angiography, visual acuity remained at the same level until 6 months of follow-up. Intravitreal bevacizumab must be used with caution in patients with chronic, persistent diabetic macular edema. Disruption of the fragile fine foveal network of capillaries with induction of macular ischemia may result following treatment even if there are no pre-existing defects in the FAZ and may be responsible for non-improvement or decrease in visual acuity.


Model of the long-term transport and accumulation of radionuclides in future landscapes.
Assessments of radiological impacts on humans and other biota from potential releases to the biosphere from a deep geologic repository for spent nuclear fuel are associated with several challenges. Releases, if any, will likely occur in a far future and to an environment that will have experienced substantial transformations. Such releases would occur over very long periods during which environmental conditions will vary continuously due to climate change and ecosystem succession. Assessments of radiological impacts must therefore be based on simulations using models that can describe the transport and accumulation of radionuclides for a large variety of environmental conditions. In this paper we describe such a model and show examples of its application in a safety assessment, taking into account results from sensitivity and uncertainty analyses of the model predictions.


Psychosocial impact of BRCA testing in young Black breast cancer survivors.
Prior studies demonstrating minimal psychological consequences for women receiving genetic counseling/genetic testing (GC/GT) for hereditary breast and ovarian cancer rely on predominantly Caucasian women. We conducted a prospective follow-up of a subset of participants from a population-based study of Black breast cancer (BC) survivors receiving GC/GT for BRCA1 and BRCA2 mutations. Black women with invasive BC at age ≤ 50 years diagnosed between 2009 and 2012 were recruited through the Florida Cancer Registry. Participants (n = 215, age M = 44.7, SD = 6.2) were offered telephone pre- and post-test GC, a subset completed questionnaires assessing sociodemographic, clinical, and psychosocial variables. There were no baseline differences in cancer-related distress, psychological distress, or quality of life between test result groups. Social well-being improved in women receiving negative results (P = .01), but no other outcomes demonstrated significant changes over time between groups. Our study is among the first to demonstrate minimal negative psychosocial outcomes following GC/GT among young Black BC survivors, irrespective of test results.


Appropriateness of end-of-life care for children with genetic and congenital conditions: a cohort study using routinely collected linked data.
This study aims to evaluate the appropriateness of end-of-life care for children with genetic and congenital conditions. This is a decedent cohort study. We used 6 linked, Belgian, routinely collected, population-level databases containing children (1-17) who died with genetic and congenital conditions in Belgium between 2010 and 2017. We measured 22 quality indicators, face-validated using a previously published RAND/UCLA methodology. Appropriateness of care was defined as the overall "expected health benefit" of given healthcare interventions within a healthcare system exceeding expected negative outcomes. In the 8-year study period, 200 children were identified to have died with genetic and congenital conditions. Concerning appropriateness of care, in the last month before death, 79% of children had contact with specialist physicians, 17% had contact with a family physician, and 5% received multidisciplinary care. Palliative care was used by 17% of the children. Concerning inappropriateness of care, 51% of the children received blood drawings in the last week before death, and 29% received diagnostics and monitoring (2 or more magnetic resonance imaging scans, computed tomography scans, or X-rays) in the last month. Conclusion: Findings suggest end-of-life care could be improved in terms of palliative care, contact with a family physician and paramedics, and diagnostics and monitoring in the form of imaging. What is Known: • Previous studies suggest that end-of life care for children with genetic and congenital conditions may be subject to issues with bereavement, psychological concerns for child and family, financial cost at the end of life, decision-making when using technological interventions, availability and coordination of services, and palliative care provision. Bereaved parents of children with genetic and congenital conditions have previously evaluated end-of-life care as poor or fair, and some have reported that their children suffered a lot to a great deal at the end of life. • However, no peer-reviewed population-level quality evaluation of end-of-life care for this population is currently present. What is New: • This study provides an evaluation of the appropriateness of end-of-life care for children who died in Belgium with genetic and congenital conditions between 2010 and 2017, using administrative healthcare data and validated quality indicators. The concept of appropriateness is denoted as relative and indicative within the study, not as a definitive judgement. • Our study suggests improvements in end-of-life care may be possible, for instance, in terms of the provision of palliative care, contact with care providers next to the specialist physician, and diagnostics and monitoring in terms of imaging (e.g., magnetic resonance imaging, computed tomography scans). Further empirical research is necessary, for instance, into unforeseen and foreseen end-of-life trajectories, to make definitive conclusions about appropriateness of care.


Enhancement by GOSPEL protein of GAPDH aggregation induced by nitric oxide donor and its inhibition by NAD(.).
Glyceraldehyde-3-phosphate dehydrogenase's (GAPDH's) competitor of Siah Protein Enhances Life (GOSPEL) is the protein that competes with Siah1 for binding to GAPDH under NO-induced stress conditions preventing Siah1-bound GAPDH nuclear translocation and subsequent apoptosis. Under these conditions, GAPDH may also form amyloid-like aggregates proposed to be involved in cell death. Here, we report the in vitro enhancement by GOSPEL of NO-induced GAPDH aggregation resulting in the formation GOSPEL-GAPDH co-aggregates with some amyloid-like properties. Our findings suggest a new function for GOSPEL, contrasting with its helpful role against the apoptotic nuclear translocation of GAPDH. NAD(+) inhibited both GAPDH aggregation and co-aggregation with GOSPEL, a hitherto undescribed effect of the coenzyme against the consequences of oxidative stress.


Syphilis prevalence has rapidly decreased in South Korea.
To determine the current prevalence of syphilis in the general population of South Korea and its trend over the past 20 years. 15,402 adults, who all were aged over 20 (6888 blood donors, 4951 physical examinees, and 3563 pregnant women) were examined from January 1999 to December 2000. All subjects were screened using a VDRL test, and positive results were confirmed by a FTA-ABS test. The prevalence was compared with the results of previous surveys in similar population groups performed by same authors. The prevalence of syphilis in South Korea was found to be 0.2%. Although has been consistent decreasing trend since 1977 (p<0.0001), there is no statistical difference between 1995 and 2000 (p=0.6992). The prevalence of syphilis has decreased significantly since 1977. However, it has not reduced much since 1995, and it seems that the prevalence has reached a plateau. Until now, not all syphilis patients were registered and followed up by the public health centres because there were so many syphilis patients. However, as this survey shows, the number of syphilis patients has reduced a great deal and it is believed that a more thorough management strategy including all newly diagnosed patients is necessary in order to further reduce the prevalence of syphilis in South Korea.


Ilimaquinone inhibits neovascular age-related macular degeneration through modulation of Wnt/β-catenin and p53 pathways.
Neovascular age-related macular degeneration (nAMD) is a common cause of irreversible vision loss in the elderly. Anti-vascular endothelial growth factor has been effective in treating pathological ocular neovascularization, but it has limitations including the need for repeated intraocular injections for the maintenance of therapeutic effects in most patients and poor or non-response to this agent in some patients. in vitro cellular studies were conducted using retinal pigment epithelial cell lines (ARPE-19 and hTERT-RPE1), human umbilical vein endothelial cells (HUVECs), and human umbilical vein smooth muscle cells (HUVSMCs). in vivo efficacy of ilimaquinone (IQ) was tested in laser-induced choroidal neovascularization mouse and rabbit models. Tissue distribution study was performed in male C57BL6/J mice. IQ, 4,9-friedodrimane-type sesquiterpenoid isolated from the marine sponge, repressed the expression of angiogenic/inflammatory factors and restored the expression of E-cadherin in retinal pigment epithelial cells by inhibiting the Wnt/β-catenin pathway. In addition, it selectively inhibited proliferation and tube formation of HUVECs by activating the p53 pathway. Topical and intraperitoneal administration of IQ significantly reduced choroidal neovascularization in rabbits and mice with laser-induced choroidal neovascularization. Notably, IQ by the oral route of exposure was highly permeable to the eyes and suppressed abnormal vascular leakage by downregulation of β-catenin and stabilization of p53 in vivo. Our findings demonstrate that IQ functions through regulation of p53 and Wnt/β-catenin pathways with conceivable advantages over existing cytokine-targeted anti-angiogenic therapies.


Biophysical and pharmacological aspects of K+ channels in T lymphocytes.
Voltage-gated Kv1.3 and Ca2+-activated IKCa1 K+ channels play a pivotal role in antigen-dependent activation and proliferation of lymphocytes. These channels primarily determine the membrane potential of T cells, and thus regulate the magnitude of the Ca2+ signal required for efficient gene transcription and subsequent proliferation. Although these facts are generally well described and acknowledged, some recent discoveries have motivated research in this field, which is reviewed herein along with the basic biophysical characterization of Kv1.3 and IKCa1. The discovery of T cell subset-specific expression of Kv1.3 points towards the potential therapeutic use of high affinity and high specificity Kv1.3 inhibitors as specific immunosuppressors in the management of autoimmune diseases, such as Multiple Sclerosis. In meeting the demands for an ideal immunosuppressor, several laboratories have discovered potent natural Kv1.3- specific inhibitors and engineered peptides which have a better pharmacological profile based on the biophysical characterization of the interaction surface between the channel pore and the toxins. In contrast to the generally accepted permissive role of Kv1.3 during lymphocyte activation, the discovery of the localization of Kv1.3 in the immunological synapse might open new opportunities in the regulation of T cell activation by this channel species.


Comparative analysis of Paenibacillus larvae genotypes isolated in Connecticut.
Ninety-six strains of Paenibacillus larvae, causative agent of American foulbrood in honey bee (Apis mellifera) larvae, collected from Connecticut, USA (CT), honey bees, and 12 P. larvae strains not from CT, were genotyped via ERIC-PCR and XbaI-RFLP analysis. All CT-isolates, five strains isolated in South America, three strains from North America (not CT), and one strain isolated in Australia grouped into the ERIC I genotype. Three P. larvae formerly subsp. pulvifaciens strains grouped into ERIC III and IV genotypes. XbaI-RFLP genotyping showed three genotypes within the CT-isolates, and two were identified as XbaI-RFLP Type I and III. The third XbaI-RFLP genotype (Type Ib) represented one of four new XbaI-RFLP genotypes identified. Comparison of genotype results for the P. larvae strains tested was used to develop a correlation between ERIC-PCR genotyping and XbaI-RFLP genotyping. Sixteen CT-isolates were tetracycline-resistant and demonstrated PCR amplification using oligonucleotide primers for tetL. All 16 isolates grouped within XbaI-RFLP Type Ib, suggesting limited introduction of a tetracycline-resistant strain into CT.


Enantioselective total synthesis of bioactive natural product (+)-Sch 642305: a structurally novel inhibitor of bacterial DNA primase and HIV-1 Tat transactivation.
The total synthesis of the bioactive natural product (+)-Sch 642305 has been achieved from a readily available chiral building block using an RCM protocol to construct the key decalactone moiety; our approach is notable for its built-in flexibility and is diversity oriented.


Validation of simple and efficient analytical methodology for estimation of forchlorfenuron residues.
A simple and efficient analytical methodology was standardised for the estimation of forchlorfenuron residues in rice leaves, grains, husk, straw and soil using LC-MS/MS. The methodology was validated in terms selectivity, sensitivity, linearity, limit of detection, limit of quantification, matrix effect, repeatability and reproducibility. The limit of detection and limit of quantification of forchlorfenuron in rice leaves, grains, straw, husk and soil were worked out to be 0.003 and 0.01 mg kg-1, respectively. Recoveries ranged between 81.54 and 99.05% with RSDr below 4.57 and RSDR below 4.19%. This validated method was applied for the determination of forchlorfenuron residues in paddy leaves after foliar application. The residues persisted for 0, 3 and 7 days after application of forchlorfenuron 0.12% EC @ 1.25, 2.50 and 5.00 ppm a.i. The half-life values were estimated to be 1.91 and 2.11 days for 2.50 and 5.00 ppm a.i. concentration. The residues were found to be below the limit of quantification of 0.01 mg kg-1 in straw, grain, husk and soil samples collected at harvest time.


Murine tumor-induced platelet aggregation and coagulation: mechanisms, inhibitors, and species differences.
This study examined the platelet-aggregating and procoagulant activities of two hematogenously disseminating tumors, a mouse lymphoblastic leukemia (L5178Y) and a mouse renal adenocarcinoma (RAG). Tumor-induced human platelet aggregation was inhibited by addition of the following agents to platelet-rich plasma (PRP): a calcium channel blocker (verapamil), a chelator of divalent cations (EDTA), stimulators of adenylate cyclase (2-fluoroadenosine and forskolin), and inhibitors of cAMP phosphodiesterase (oxagrelate and papaverine). The platelet-aggregating activities of both cell lines were completely blocked by treatment of the cells with heat, sonication, phospholipase A2, and Triton X-100. These data suggest that L5178Y and RAG cell-induced human platelet aggregation are dependent on a heat-labile phospholipid component of the tumor cell membrane. L5178Y cells had greater platelet-aggregating activity in human plasma than in rat or mouse plasma, whereas RAG cells had greater procoagulant activity in rat or mouse plasma than in human plasma. The procoagulant activity of RAG cells in rat and mouse plasma was demonstrated by three lines of evidence: RAG cells induced heparinized PRP to clot; the thrombin inhibitor DAPA lengthened of the clotting time and the lag time before aggregation; and RAG cells shortened of the recalcification time of the plasma. The above data indicate that RAG cell-induced murine platelet aggregation and coagulation is dependent on thrombin generation.


Kinetic model for phototransduction and G-protein enzyme cascade: understanding quantal bumps during inhibition of CaM-KII or PP2B.
We utilize a computer model derived directly from the phototransductive enzyme cascade involving rhodopsin (R), G-proteins (G) and ultimately the membrane channels. In photoreceptors, single photons activate single rhodopsin molecules (R*), resulting in the production of quantal bumps. A CaM-KII inhibitor may inhibit whereas calcineurin (PP2B) inhibitors may augment arrestin activity. Arrestin is known to inactivate R*. We voltage-clamped and digitized quantal bumps for comparison with the kinetic model and simulations. Inhibitors of CaM-KII and PP2B produce results consistent with altering arrestin activity. In sum, we have succeeded in constructing a mathematical description of the phototransduction cascade that is biochemically derived and useful in interpreting results.


Brainstem tethering with Ondine's curse.
Brainstem tethering is a rare disease. We report and discuss a 20-year-old patient who experienced paroxysmal apnea (a symptom of Ondine's curse) during sleeping, causing him to wake up and control his breathing consciously. A magnetic resonance imaging study revealed that his medulla oblongata was twisted and displaced posteriorly by an abnormal tissue cord. An operation was performed to detether the tethered brainstem, with a satisfying result reached. Brainstem tethering is a rare but late complication of occipital encephalocele with insufficient operation. The symptoms of this disease are related to the dysfunction of the medulla oblongata and their adjunctive nerves. Magnetic resonance imaging can be used to identify the abnormal region and distinguish it from other medulla oblongata diseases. Surgery in the early stage of the brainstem tethering is helpful, but ventriculoperitoneal shunting is unnecessary or cannot be performed before detethering, although these patients usually have ventricular dilation.


Isolates, Antimicrobial Susceptibility Profiles and Multidrug Resistance of Bacteria Cultured from Pig Submissions in New Zealand.
Data on the scope of bacterial pathogens present and the frequency of antimicrobial resistance (AMR) in New Zealand's pigs are limited. This study describes bacterial isolates, antimicrobial susceptibility data, and multidrug resistance (MDR; resistance to ≥3 antimicrobial classes) from New Zealand pig submissions. Porcine test data from June 2003 to February 2016 were obtained from commercial veterinary pathology laboratory records. In total, 470/477 unique submissions resulted in bacterial growth, yielding 779 isolates. Sample type was recorded for 360/477 (75.5%); lung (79/360; 21.9%), faecal (61/360; 16.9%) and intestinal (45/360; 12.5%) were most common. The most common isolates were Escherichia coli (186/779, 23.9%), Actinobacillus pleuropneumoniae (43/779; 5.5%), Streptococcus suis (43/779; 5.5%), unidentified Campylobacter spp. (38/779; 4.9%), alpha haemolytic Streptococci (32/779; 4.1%), coagulase negative Staphylococcus spp. (26/779; 3.3%), and Pasteurella multocida (25/779; 3.2%). Susceptibility results were available for 141/779 (18.1%) isolates from 62/470 (13.2%) submissions. Most were susceptible to trimethoprim-sulphonamide (75/81; 92.6%), but fewer were susceptible to penicillin (37/77; 48.1%), tilmicosin (18/43; 41.9%), or tetracyclines (41/114; 36.0%). No susceptibility data were available for Salmonella spp., Campylobacter spp., or Yersinia spp. isolates. MDR was present in 60/141 (42.6%) isolates. More data on sample submission drivers, antimicrobial drug use, and susceptibilities of important porcine bacterial isolates are required to inform guidelines for prudent antimicrobial use, to reduce their prevalence, human transmission, and to minimise AMR and MDR.


Intraoperative prediction of compensatory sweating for thoracic sympathectomy.
Postoperative compensatory sweating (PCS) is an important problem impacting on quality of life for patients after endoscopic thoracic sympathectomy (ETS). The present study investigated whether intraoperative palmar temperature and blood flow are useful for assessing PCS after ETS. Retrospectively, results were evaluated for ETS in 27 consecutive patients with primary palmar hyperhidrosis between 1996 and 2002. For all patients, bilateral nerve conduction to the palms was interrupted. The relationship between the range of PCS and intraoperative changes in palmar temperature and blood flow was investigated. PCS developed in all cases. After completion of ETS, mean blood flow and temperature increased respectively. Significant correlations were found between the range of PCS and increases in palmar temperature (p<0.05) and blood flow (p<0.05). Intraoperative monitoring of increases in palmar temperature and blood flow may be useful in patients with primary hyperhidrosis, to predict the range of PCS after ETS.


A Mild and Versatile Friedel-Crafts Methodology for the Diversity-Oriented Synthesis of Redox-Active 3-Benzoylmenadiones with Tunable Redox Potentials.
A series of highly diversified 3-aroylmenadiones was prepared by a new Friedel-Crafts acylation variant/oxidative demethylation strategy. A mild and versatile acylation was performed between 1,4-dimethoxy-2-methylnaphthalene and various activated/deactivated benzoic and heteroaromatic carboxylic acids, in the presence of mixed trifluoroacetic anhydride and triflic acid, at room temperature and in air. The 1,4-dimethoxy-2-methylnaphthalene-derived benzophenones were isolated in high yield, and submitted to oxidative demethylation with cerium ammonium nitrate to produce 3-benzoylmenadiones. All 1,4-naphthoquinone derivatives were investigated as redox-active electrophores by cyclic voltammetry. The electrochemical data recorded for 3-acylated menadiones are characterized by a second redox process, the potentials of which cover a wide range of values (500 mV). These data emphasize the ability of the generated structural diversity at the 3-aroyl chain of these electrophores to fine-tune their corresponding redox potentials. These properties are of significance in the context of antimalarial drug development and understanding of the mechanism of bioactivation/action.


Absolute characterization of high numerical aperture microscope objectives utilizing a dipole scatterer.
Measuring the aberrations of optical systems is an essential step in the fabrication of high precision optical components. Such a characterization is usually based on comparing the device under investigation with a calibrated reference object. However, when working at the cutting-edge of technology, it is increasingly difficult to provide an even better or well-known reference device. In this manuscript we present a method for the characterization of high numerical aperture microscope objectives, functioning without the need of calibrated reference optics. The technique constitutes a nanoparticle, acting as a dipole-like scatterer, that is placed in the focal volume of the microscope objective. The light that is scattered by the particle can be measured individually and serves as the reference wave in our system. Utilizing the well-characterized scattered light as nearly perfect reference wave is the main idea behind this manuscript.


Decomposition process in Negev ecosystems.
The effects of supplemental water and natural rainfall on decomposition were studied in the Negev Highland desert, Israel. There was a mass loss of approximately 40% in Hammada scoparia leaves and Salsola inermis litter placed on the soil surface and buried in fine mesh bags. There was an annual mass loss of 80% in S. inermis litter buried in large fiberglass mesh bags. Supplemental water provided during the wet season (January to March) did not result in more rapid decomposition of litter of the annual grass Stipa capensis but irrigation during the dry season (August to September) produced a marked increase in the decomposition rate of S. capensis. These data suggest that rain events, not water quantity, are the most important regulators of decomposition in the Negev. Annual rates of decomposition were higher than predicted by models utilizing actual evapotranspiration and lignin content as regulating variables. Rates of decomposition were equal to those reported for tropical wet forests.


Divorcing the puzzles: When group identities foster in-group cooperation.
We argue that general social psychological mechanisms (e.g., common group identity) can account for prosocial behavior and cooperative norms without the need for punishing Big Gods. Moreover, prosocial religions often do not prevent conflict within their religious groups. Hence, we doubt whether Big Gods and prosocial religions are more effective than alternative identities in enhancing high-level cooperation.


Biochemical characterization of Ia antigens encoded by the RT1.B and RT1.D loci in the rat MHC.
Ia antigens in rats are genetically associated with typical MHC-linked immune response (Ir) genes. One rat Ir gene (IR-GLT) has recently been mapped to the RT1.D locus in a rat MHC recombinant, WRC. We have studied the expression of Ia antigenic determinants in WRC and its parental strains BN and WRA using a panel of monoclonal antibodies. Our results suggest that the inheritance of IR-GLT corresponds with the inheritance of I-E-like, but not I-A-like, antigens in the WRC rat. These observations were confirmed when WRC I-E-like antigens were analyzed by two-dimensional gel electrophoresis. We propose that RT1.D shares both functional and antigenic homologies with the mouse I-E subregion.


Measurement of femoral torsion with ultrasound: evaluation of a new technique using reference lines on the posterior surface of the femur.
A technique of measuring femoral torsion employing reference lines on the posterior surface of the femur has been described. This technique was evaluated on 27 dry adult femora and then on 40 adult patients. The technique was found to be reliable and reproducible. The values of femoral torsion obtained by this technique is lower than that obtained when anterior reference lines are used.


Atomic Layer Deposition Process-Enabled Carrier Mobility Boosting in Field-Effect Transistors through a Nanoscale ZnO/IGO Heterojunction.
Low-temperature (≤400 °C), stackable oxide semiconductors are promising as an upper transistor ingredient for monolithic three-dimensional integration. The atomic layer deposition (ALD) route provides a low-defect, high-quality semiconducting oxide channel layer and enables accurate controllability of the chemical composition and physical thickness as well as excellent step coverage on nanoscale trench structures. Here, we report a high-mobility heterojunction transistor in a ternary indium gallium zinc oxide system using the ALD technique. The heterojunction channel structure consists of a 10 nm thick indium gallium oxide (IGO) layer as an effective transporting layer and a 3 nm thick, wide band gap ZnO layer. The formation of a two-dimensional electron gas was suggested by controlling the band gap of the IGO quantum well through In/Ga ratio tailoring and reducing the physical thickness of the ZnO film. A field-effect transistor (FET) with a ZnO/In0.83Ga0.17O1.5 heterojunction channel exhibited the highest field-effect mobility of 63.2 ± 0.26 cm2/V s, a low subthreshold gate swing of 0.26 ± 0.03 V/dec, a threshold voltage of -0.84 ± 0.85 V, and an ION/OFF ratio of 9 × 108. This surpasses the performance (carrier mobility of ∼41.7 ± 1.43 cm2/V s) of an FET with a single In0.83Ga0.17O1.5 channel. Furthermore, the gate bias stressing test results indicate that FETs with a ZnO/In1-xGaxO1.5 (x = 0.25 and 0.17) heterojunction channel are much more stable than those with a single In1-xGaxO1.5 (x = 0.35, 0.25, and 0.17) channel. Relevant discussion is given in detail on the basis of chemical characterization and technological computer-aided design simulation.


Characterisation offusarium graminearum andF. culmorum isolates by mycotoxin production and aggressiveness to wheat.
A total of 27Fusarium culmorum isolates from Germany and 41F. graminearum isolates from Kenya were investigated for aggressiveness and mycotoxin production on wheat ears. In addition, ergosterol content of the kernels from ears inoculated withF. graminearum was determined and theF. culmorum isolates were tested for mycotoxin productionin vitro. For both pathogens, isolates markedly differed in aggressiveness. 59% and 37% of theF. culmorum isolates produced NIV and DON, respectively,in vivo andin vitro. The DON-producing isolates also produced 3-acDONin vitro. The more aggressive isolates produced mainly DON while the less aggressive isolates produced mainly NIV. 12% and 85% of theF. graminearum isolates produced NIV and DON, respectively. The highly aggressive isolates produced higher amounts of DON, aggressiveness being highly correlated to DON content in the kernels. NIV-producing isolates were less aggressive. Ergosterol content of kernels was moderately correlated to aggressiveness but highly correlated to DON content. Disease severity was associated with kernel weight reduction.


Dynamic positioning accuracy of a novel multileaf collimator for volumetric modulated arc therapy.
We investigated the dynamic positioning accuracy of Agility (Elekta) for volumetric modulated arc therapy (VMAT). The accuracy of the multileaf collimator (MLC) leaf position during VMAT was evaluated using three different tests: (1) a dynamic multileaf collimator (DMLC) output test with various leaf speeds, and gantry angles; (2) a slit-fence test with and without gantry rotation; and (3) a complicated VMAT plans test with dose distributions compared with measurements using gamma analysis. The DMLC output was within 1.5 % under all test conditions. The agreement between the static and VMAT in the slit-fence test was within 0.5 mm. The pass rate of each complicated VMAT test plan was more than 93.9 % ± 0.36 for gamma analysis. We confirmed the dynamic positioning accuracy of Agility, which during VMAT delivery is within VMAT tolerances. The fastest MLC was found to have the potential to offer clinical advantages, such as high-quality rapid VMAT.


Predicting the use of individualized risk assessment for breast cancer.
The purpose of this study was to investigate the decision to obtain individualized risk assessment (IRA) after a breast cancer education session. A sample of both African American and Caucasian women was used to determine if there were differences by race/ethnicity in uptake of the assessment and differences in the variables that were most predictive of uptake. The sample included 166 women between the ages of 18 and 80. Sixty-two percent of the sample were African American women. The results suggested that African American women and Caucasian women used different factors and used other factors differently to decide whether or not to obtain an IRA. These results are discussed within the context of health disparities among ethnic minority and Caucasian women with implications for breast cancer control programs. The results of this study suggest that knowledge alone does not lead to opting for a personalized risk assessment, and that African American and Caucasian women use different pieces of information, or information differently to make decision about getting more personalized information about risk.


Stimulation of insulin release by an organic calcium agonist.
The calcium-agonist 4-[2-(difluoromethoxy)phenyl]-1,4,5,7-tetrahydro-2-methyl-5-oxo-fu ro[ 3,4-b]pyridine-3-carboxylic acid ethylester provoked, in the 1.0-100 mumol/l range, a dose-related increase of glucose-stimulated insulin release by rat pancreatic islets. A fixed concentration of the drug (50 mumol/l) caused a shift to the left of the sigmoidal curve relating insulin output to glucose concentration. The drug failed to affect insulin release evoked, in the absence of Ca2+, by the combination of Ba2+ and theophylline. The enhancing action of the calcium-agonist upon insulin release was rapid and sustained, and coincided with stimulation of both 45Ca net uptake and 45Ca efflux, the latter phenomenon being abolished in the absence of extracellular Ca2+. It is concluded that the gating of Ca-channels, as presumably provoked by the calcium-agonist, simulates the stimulant action of glucose upon both Ca influx into and insulin release from the pancreatic islets.


The effect of therapeutic footwear on the recurrence and new formation of foot ulcers in previously affected diabetic patients in Jeddah, Saudi Arabia.
Diabetic foot ulcers (DFUs), which are a common serious complication of diabetes mellitus, (lifetime occurrence, 19%-34%) account for at least 85% of all lower-limb amputations in diabetic patients. Special footwear (therapeutic footwear) is frequently recommended for such patients to adapt to changes in their foot structure. We aimed to, measure the effect of therapeutic footwear on DFU development and recurrence among previously affected patients in Saudi Arabia. A cross-sectional study was performed between June and September 2022. The study targeted patients aged ≥18 years previously diagnosed with DFU. Participants were contacted by telephone to complete a questionnaire assessing footwear use and foot care. This study included 115 participants with a mean age of 61.9 ± 11.63; overall, 47% of participants used therapeutic footwear and 46% were adherent with wearing it. The DFU recurrence rate among patients who used therapeutic footwear was 27.8% versus 52.5% among patients who did not (p = 0.013). While using therapeutic footwear, patients with foot deformities reported a lower ulcer healing rate than those who did not (50% vs. 81.8%, p = 0.04). Patients who examined their feet had a lower recurrence rate than those who did not (38.5% vs. 50%, p = 0.43). Therapeutic footwear use was significantly associated with decreased DFU recurrence. Further investigation to enhance the evidence for the effectiveness of therapeutic footwear in DFUs is warranted.


Regulation of citrate transport and pyruvate dehydrogenase in rat kidney cortex mitochondria by bicarbonate.
1. Bicarbonate increased citrate and 2-oxoglutarate accumulation when rat kidney cortex mitochondria were incubated with pyruvate or L(-)-palmitoyl carnitine in the presence of L-malate. 2. Bicarbonate stimulated the exit of citrate from mitochondria. The Km for bicarbonate was 13.5 mM and the Vmax was 0.59 nmol/min/mg of protein at 10 degrees. 3. The bicarbonate-stimulated exit of citrate from the mitochondria was prevented by inhibitors of the tricarboxylate, dicarboxylate, and phosphate transport systems. 4. The activity of pyruvate dehydrogenase was significantly increased by preincubation of rat kidney mitochondria with bicarbonate. This bicarbonate-induced activation was not observed in presence of inhibitors of citrate transport. Bicarbonate did not activate pyruvate dehydrogenase in rat heart mitochondria. Bicarbonate had no effect on pyruvate dehydrogenase activity in either broken mitochondria or whole tissue preparations. 5. The mechanism of this activation is discussed in the light of the known regulatory properties of pyruvate dehydrogenase, pyruvate carboxylase, and citrate synthase.


Safety review: dose optimization of somatostatin analogs in patients with acromegaly and neuroendocrine tumors.
Patients with either acromegaly or neuroendocrine tumors (NET) can be treated with somatostatin analogs to relieve symptoms and improve disease control. However, there is an absence of large clinical trials specifically designed to document the safety when increases in somatostatin analog dosing are needed in patients who do not achieve their treatment goals. To fully explore and communicate any potential risks, we conducted a literature review and present a summary of the studies documenting the safety and tolerability of dose optimization with somatostatin analogs in patients with acromegaly and NET. A literature search was undertaken to find clinical studies specifically reporting the effects of dose titration using the depot formulations of the somatostatin analogs, octreotide long-acting repeatable (LAR) or lanreotide, in patients with acromegaly and NET. Publications that described the treatment and management of patients with acromegaly and NET were reviewed. The rationale for dose optimization, including high-dose treatment in patients who are inadequately controlled on conventional doses and the safety and tolerability of somatostatin analogs, is discussed. A review of published clinical studies demonstrates that dose optimization provides additional biochemical control in patients with acromegaly and NET who are inadequately controlled with conventional starting doses of octreotide LAR and lanreotide ATG. The benefits of dose optimization include improved efficacy without a significant change in the recorded adverse events and the tolerability of the treatment. Therefore, patient response to treatment should be routinely monitored and their somatostatin analog dose increased or decreased thereafter according to their individual response.


Effects of glucose, anoxia, and adriamycin on the chemiluminescence of Ehrlich Ascites cells.
Glucose and anoxia accelerate the photocount due to luminescence of Ehrlich Ascites cells. Adriamycin also has this effect if glucose is present. Comparison with a chemical standard combined with estimates of cellular and population transmittance yield a photon generation rate of at least 10 . s-1 . cell-1 in the presence of 10(-2) M glucose, and twice this with anoxic conditions or 10(-5) M adriamycin. Effects of adriamycin on Ehrlich Ascites cell respiration may depend on the presence of glucose.


Older adults demonstrate superior vestibular perception for virtual rotations.
Adult ageing results in a progressive loss of vestibular hair cell receptors and afferent fibres. Given the robustness of vestibulo-ocular and vestibular-evoked whole-body responses to age-related deterioration, it was proposed that the vestibular system compensates centrally. Here we examine the potential for central compensation in vestibular sensitivity with adult ageing by using a combination of real and virtual rotation-based psychophysical testing at two stimulus frequencies (0.1 & 1Hz). Real rotations activate semi-circular canal hair cell receptors naturally via mechanotransduction, while electrical current used to evoke virtual rotations does not rely on mechanical deformation of hair cell receptors to activate vestibular afferents. This two-pronged approach allows us to determine the independent effects of age-related peripheral afferent receptor loss and potential compensatory mechanisms. Older adults had thresholds for discriminating real rotations that were significantly greater than young adults at 0.1Hz (7.2 vs. 3°/s), but the effect of age was weaker (non-significant) at 1Hz (2.4 vs. 1.3°/s). For virtual rotations, older adults had greater thresholds than young adults at 0.1Hz (1.2 vs. 0.5mA), however, older adults outperformed young adults at 1Hz (0.6 vs. 1.1mA). Based on these thresholds, we argue that central vestibular processing gain is enhanced in older adults for 1Hz real and virtual rotations, partially offsetting the negative impact of normal age-related hair cell receptor and primary afferent loss. We propose that the frequency dependence of this compensation reflects the physiological importance of the 1-5Hz range in natural vestibular input.


Recombinant granulocyte-macrophage colony-stimulating factor activates human macrophages to inhibit growth or kill Mycobacterium avium complex.
Organisms belonging to the Mycobacterium avium complex (MAC) are associated with life-threatening bacteremia in patients with the acquired immunodeficiency syndrome (AIDS). As these organisms survive within macrophages, we examined the ability of recombinant human granulocyte-monocyte colony-stimulating factor (GM-CSF) to activate human monocyte-derived macrophages to inhibit the intracellular growth or kill the most mouse-virulent MAC strain in our collection that belongs to serotype 1. While unstimulated cells did not inhibit intracellular growth of MAC, macrophages activated by GM-CSF (10-10(4) U/ml) inhibited or killed up to 58 +/- 5% of the initial inoculum. This activation was dose-dependent, with maximal change occurring with a dose of 100 U/ml after 72 hr exposure. Inhibition or killing was demonstrated if GM-CSF was given both before or after establishment of infection. The combination of GM-CSF (10(2) U/ml) plus TNF (10(2) U/ml) augmented macrophage killing (range, 31 +/- 4%) compared with GM-CSF (10(2) U/ml) alone, but the combination of recombinant human interferon-gamma (IFN gamma) plus GM-CSF resulted in a significant decrease in intracellular inhibition of growth or killing (13.3 +/- 2%) compared with 57.7 +/- 5% obtained with GM-CSF alone. These results indicate that: 1) GM-CSF can activate macrophages to inhibit intracellular growth or kill MAC; 2) killing may be augmented by TNF; and 3) IFN gamma may impair GM-CSF-dependent macrophage activation.