Characterization of habitats based on algal periphyton biomass in the upper Paraná River floodplain, Brazil.
Considering the relevant role played by the hydrological regime on the structure and functioning of floodplains, this study aims at characterizing different types of aquatic environments according to periphyton biomass and evaluating the influence of the fluviometric levels of the Paraná River and other forcing functions upon the periphytic community. Periphyton (chlorophyll a) was analyzed in 28 habitats, during the years 2000 and 2001, in high and low water seasons. Both years were characterized by lacking the characteristic high water season. The Principal Components Analysis revealed two groups. The first component was positively associated with hydrometric level, electric conductivity, pH and transparency, and negatively with total nitrogen and total phosphorus, dissolved organic carbon and turbidity. The second component separated the habitats of Paraná River in the period of low waters from other environments, mainly for hydrometric level and high transparency values. Periphytic biomass of the habitats demonstrated that the maintenance of the functional integrity of the Upper Paraná River floodplain is closely related to its hydrologic cycle.


Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors.
Three phencyclidine (PCP) analogues possessing a highly rigid carbocyclic structure and an attached piperidine ring which is free to rotate were synthesized. Each analogue has a specific fixed orientation of the ammonium center of the piperidinium ring to the centrum of the phenyl ring. The binding affinities of the rigid analogues 1-piperidino-7,8-benzobicyclo[4.2.0]octene (14), 1-piperidinobenzobicyclo[2.2.1]heptene (16), and 1-piperidinobenzobicyclo[2.2.2]octene (13) for the PCP receptor ([3H]TCP) and th-receptor (NANM) were determined. The three analogues show low to no affinity for the PCP receptor but good affinity for the th-receptor and can be considered th-receptor selective ligands with PCP/th ratios of 13, 293, and 368, respectively. The binding affinities for the th-receptor are rationalized in terms of a model for the th-pharmacophore.


A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies.
UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. Patients received irinotecan (75-125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7-30 weeks). UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.


Cardiac surgery for radiation associated heart disease in Hodgkin lymphoma patients.
Much of the modern focus of Hodgkin's Lymphoma (HL) treatment involves the prevention of secondary organ injury. Despite rationalisations of radiotherapy fields, many patients still develop late radiation-related cardiotoxicity that is severe and requires interventional management. No guidelines exist to direct management of these complex patients who often present with multiple concurrent cardiac pathologies. Despite possessing a greater mortality risk than in the general population, cardiac surgery has an important role in treating radiation-associated heart disease. This review summarises the body of literature surrounding cardiac surgery in HL survivors post-radiotherapy, highlighting the benefits and risks unique to this cohort. The pathophysiology and presentation of radiation-associated heart disease is also explored in relation to HL patients.


Novel Antibacterial and Biocompatible Nanostructured Gels Based on One-step Synthesis as a Potential Disinfectant for Endodontic Infection Control.
The objective of this study was to develop nanostructured gels as biocompatible intracanal disinfectants by one-step microwave radiation-assisted synthesis. Polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) were used as a support network, and polyethylene glycol (PEG) was used as a reducing agent. The gels were characterized by measuring the swelling ratio (SR) and rheological properties and by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The antibacterial effects of each gel were evaluated against the endodontic clinical strain Enterococcus faecalis. Then, the viability of the 21-day mature multispecies bacterial biofilm was assessed using confocal microscopy in an ex vivo model, where the biofilm was exposed to the mix of nanogels. The cell proliferation, viability, and morphology of human periodontal ligament (HPDL) cells were quantified using a real-time IncuCyte® S3 Live-Cell System. Viability was measured by confocal microscopy using an ex vivo model exposing a 21-day mature multispecies bacterial biofilm to the mix of nanogels. The antibacterial activity of the gels coincided with the superficial characterization and the solubility of the gel in the growth medium. Gels with higher viscosity (327.85-980.58 Pa s), higher dissolution (42-70%SR), and lower porosity (no porosity and 611.63 nm) showed excellent antibacterial activity against E. faecalis. Despite their physicochemical characteristics, CuNPs gels showed greater effectiveness against E. faecalis.These nanostructured gels with high PVA concentrations promote HPDL cells proliferation while still exerting antibacterial properties. Mix of nanogels showed an increase non-viable cells biomass from at of application. The use of biocompatible polymers influences the physicochemical, bactericidal, and cytotoxic response, making these materials potential disinfectant agents against resistant bacteria with good biocompatibility and improved HPDL cells proliferation.


The mechanism of myocardial damage following potassium citrate (Melrose) cardioplegia.
To determine the reasons for clinical failure of Melrose solution, potassium arrest was studied in isolated working rat hearts. Eight control hearts were stable for 2-1/2 hours. After 1/2 hour of work, 42 experimental hearts were subjected to 1 hour of ischemis by aortic cross-clamping with unmodified ischemia in eight hearts and ischemia with simultaneous intracoronary injection of 5 ml. of 4 degrees C. (1)Krebs-Henseleit buffer in seven hearts (2)potassium chloride buffer in six hearts, (3)potassium citrate buffer in eight hearts (both 26 mEq. per liter of K, approximately 300 mOsm. per liter), (4)Melrose solution in seven hearts (greater than 200 mEq. per liter of K, greater than 400 mOsm. per liter), (5)hypertonic potassium citrate buffer in six hearts (26 mEq. per liter of K, greater than 400 mOsm. per liter). The pH of all solutions was 7.8 plus or minus 0.1. After recovery isotonic potassium citrate- and potassium chloride-arrested hearts and time-matched control hearts showed no significant differences in cardiac output, coronary flow, systolic pressure, or heart rate. Hypertonic potassium citrate decreased the recovery of cardiac function after arrest and Melrose arrest was not significantly different from unmodified ischemia. Intracoronary cold isotonic Krebs-Henseleit buffer was better than Melrose arrest but inferior to 26 mEq. er liter of potassium arrest. Arrest with 26 mEq. per liter of potassium augments perfusion hypothermia and prevents significant functional and histologic myocardial damage during 1 hour of ischemis. Previous authors assumed that hypertonicity and citrate were responsible for poor results with Melrose solution, but high potassium concentration is the major deleterious factor with hypertonicity playing a contributory role.


Molecular mechanisms controlling lung morphogenesis.
The complex process of lung formation is determined by the action of numerous genes that influence cell commitment, differentiation, and proliferation. This review summarizes current knowledge of various factors involved in lung morphogenesis correlating their temporal and spatial expression with their proposed functions at various times during the developmental process. Rapid progress in understanding the pathways involved in lung morphogenesis will likely provide the framework with which to elucidate the mechanisms contributing to lung malformations and the pathogenesis of genetic and acquired lung diseases.


A Glycine soja ABA-responsive receptor-like cytoplasmic kinase, GsRLCK, positively controls plant tolerance to salt and drought stresses.
Receptor such as protein kinases are proposed to work as sensors to initiate signaling cascades in higher plants. However, little is known about the precise functions of receptor such as protein kinases in abiotic stress response in plants, especially in wild soybean. Here, we focused on characterization of the biological functions of a receptor-like cytoplasmic serine/threonine protein kinase gene, GsRLCK, which was previously identified as a putative salt-alkali stress-related gene from the transcriptome profiles of Glycine soja. Bioinformatic analysis showed that GsRLCK protein contained a conserved kinase catalytic domain and two transmembrane domains at the N-terminus, but no typical extracellular domain. Consistently, GsRLCK-eGFP fusion protein was observed on the plasma membrane, but eGFP alone was distributing throughout the cytoplasm in onion epidermal cells. Quantitative real-time PCR analysis revealed the induced expression of GsRLCK by ABA, salt, alkali, and drought stresses. However, the expression levels of GsRLCK seemed to be similar in different tissues, except soybean pod. Phenotypic assays demonstrated that GsRLCK overexpression decreased ABA sensitivity and altered expression levels of ABA-responsive genes. Furthermore, we also found that GsRLCK conferred increased tolerance to salt and drought stresses and increased expression levels of a handful of stress-responsive genes, when overexpressing in Arabidopsis. In a word, we gave exact evidence that GsRLCK was a novel receptor-like cytoplasmic protein kinase and played a crucial role in plant responses to ABA, salt, and drought stresses.


The effect of etomidate on rabbit liver microsomal drug metabolism in vitro.
Etomidate, an imidazole-containing anesthetic agent, is shown to be a reversible inhibitor of rabbit liver microsomal enzymes in vitro. Inhibition of aniline hydroxylation by etomidate follows competitive kinetics, while inhibition of microsomal N-demethylase and O-demethylase activities is of the mixed type. The concentrations of etomidate required to cause 50% inhibition of these enzyme activities are in the 7-10 microM range. NADPH-cytochrome c reductase is not inhibited by concentrations of etomidate below 100 microM. Spectrophotometric studies show that the addition of etomidate to liver microsomes results in a type II binding spectrum. We suggest that etomidate binds with high affinity to cytochrome(s) P-450, resulting in the inhibition of liver drug metabolism.


Cancer genetics and genomics: essentials for oncology nurses.
Cancer genetics and genomics are rapidly evolving, with new discoveries emerging in genetic mutations, variants, genomic sequencing, risk-reduction methods, and targeted therapies. To educate patients and families, state-of-the-art care requires nurses to understand terminology, scientific and technological advances, and pharmacogenomics. Clinical application of cancer genetics and genomics involves working in interdisciplinary teams to properly identify patient risk through assessing family history, facilitating genetic testing and counseling services, applying risk-reduction methods, and administering and monitoring targeted therapies.


Superoxide dismutase in ocular structures.
Specific immunohistochemical localization of superoxide dismutase in ocular tissue of Lewis rats revealed the presence of this enzyme predominantly in the corneal epithelium, endothelium, apical regions of the posterior epithelium of the iris, nonpigmented inner ciliary epithelium, lens epithelium, inner segments of photoreceptor cell layer of the retina, and retinal pigment epithelium. This enzyme is distributed primarily in those ocular structures which may be frequently exposed to superoxide or its metabolites under physiologic conditions and in such pathologic processes as intraocular inflammations. It thus appears that superoxide dismutase and other antioxidants may play a protective role in preventing the damaging effects of oxygen radicals.


[Assessment of independence in daily life in pediatric oncology by FMH-questionnaire].
Therapy-related late effects are important for therapeutic decisions in pediatric oncology. We quantified the degree of impairment of independence in daily life in children with cancer. The German questionnaire "Fertigkeitenskala Münster/Heidelberg (FMH)" is a standardized tool for measurement of motoric and verbal functioning. A point-score leads to an age-related percentile ranking similar to typical percentiles in pediatrics. We used the FMH in 215 cancer patients (mean age 10.3 years, range 0.5-23.5 years, 56.3% male). Diagnoses were leukaemia (n = 91), bone tumors (n = 33), nephro- and neuroblastoma (n = 21), brain tumors (n = 18), lymphoma (n = 23), rhabdomyosarcoma (n = 11) and others (n = 18). The average time to answer the questionnaire was 4.5 min. Patients with brain and bone tumors showed significant lower percentile scores compared to patients with other diagnoses (p < 0.05). The FMH-scores increased with time since diagnosis (n = 215). This trend was confirmed in a longitudinal study over one year (n = 29). Quantitative assessment of independence and functioning in patients with cancer--especially in multicenter-studies--is possible. Because of therapy-related late effects this seems to be of special importance in brain and bone tumor patients.


Vitamin D and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials.
The results of randomized controlled trials (RCTs) investigating supplemental vitamin D on aminotransferases and cardio-metabolic risk factors in subjects with non-alcoholic fatty liver disease (NAFLD) have been inconsistent. The present study aimed to quantitatively evaluate whether supplementation with vitamin D has beneficial effects in treatment of NAFLD. A systematical literature search was performed with Cochrane Library, PubMed, Scopus databases and Web of Science up to June 2020. The mean changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglyceride (TAG) were calculated as standard mean difference (SMD) using a random-effects model. Pre-specified subgroup and univariate meta-regression analyses were performed to identify the sources of heterogeneity. Ten trials with a total of 544 NAFLD subjects were included for data synthesis. The summary estimates indicated that supplemental vitamin D significantly reduced the levels of serum/plasma fasting glucose (-0.22; 95%CI: -0.39, -0.04), insulin (-0.68; 95%CI: -1.22, -0.14) and HOMA-IR (-1.32; 95%CI: -2.30, -0.34), and marginally reduced the ALT (-0.18; 95%CI: -0.39, 0.04) and TAG (-10.38; 95%CI: -21.09, 0.34) levels. However, the pooled effect did not support that supplemental vitamin D was beneficial for concentrations of AST, TC, HDL-C and LDL-C. The present study provides substantial evidence that supplemental vitamin D has favorable effects on glycemic control and insulin sensitivity in NAFLD patients. Vitamin D could be as an adjuvant pharmacotherapy of NAFLD.


[The treatment of patients with chronic bronchitis and bronchial asthma].
The authors analyzed treatment results in 82 patients with chronic bronchitis and 68 patients with bronchial asthma including association of inhalation of humid and dry sodium chloride aerosols with preliminary administration of a broncholytic drug. Improvement of the patients' condition was confirmed by results of functional examinations and data of immunological tests.


How effectively can the New Cooperative Medical Scheme reduce catastrophic health expenditure for the poor and non-poor in rural China?
China has implemented the New Cooperative Medical Scheme (NCMS) in rural areas since 2003 to provide financial protection to its rural population. This article explores the effect of NCMS on relieving catastrophic health expenditure (CHE) among the poor and non-poor groups. A questionnaire survey was conducted in three counties, with a random sample of 358 poor and 523 non-poor NCMS enrollees who used inpatient services and obtained NCMS reimbursement in 2005. Majority of NCMS enrollees suffered CHE because of using inpatient services; the occurrence and intensity of CHE was greater among poor inpatients. NCMS reimbursement helped relieve CHE to a certain degree. Poor inpatients benefited more from NCMS than non-poor, but the effects varied among counties. Cost control measures and other medical financial assistance (MFA) helped reduce inpatients' economic burden. The objective of NCMS is only partly achieved. However, NCMS has promoted equity in health financing as poor inpatients can acquire more protection than the non-poor. Our analysis suggests that efforts should be made to improve NCMS design, strengthen cost containment and extend other MFA to further relieve economic burden of disease.


Preserving functional capacity as opposed to tissue preservation in the diabetic patient: a single institution experience.
The authors performed a retrospective review of prospectively collected data of all diabetic patients who underwent transmetatarsal amputation (TMA) for toe gangrene or neuropathic ulceration from May 2006 to June 2009. Twenty-nine TMAs were performed in diabetic patients during the study period, including 24 men and 5 women with a mean +/- SD age of 66.3 +/- 7.5 years. The indications for TMA were gangrene of > or = 2 digits in 12 patients (41%) and neuropathic ulceration with underlying osteomyelitis or abscess and a concomitant dysfunctional forefoot in 17 patients (59%). Of the 12 patients who presented with toe gangrene, 7 (58%) underwent endovascular intervention and 5 (42%) underwent open vascular bypass. Equinus contracture was present in 27 patients (93%), and 26 (96%) of these patients underwent tendo-Achilles lengthening or gastrocnemius recession. Correction of equinus contracture was not performed in 1 patient as it was deemed not feasible. Forefoot varus deformity was present in 22 (76%) patients, and balancing was performed in 17 of these patients (77%) with skeletal stabilization or tendon transfer. Balancing was not performed in the remaining patients as it was not necessary or not feasible. Sixteen patients (55%) healed primarily and 5 patients (17%) developed minor wound separation that healed via secondary intention. An additional 4 patients were able to maintain functional revision procedures confined to the foot (1 TMA revision, 3 Chopart amputations). Three patients (10%) required below-knee amputation, and there were 2 deaths (7%) during the time period. Functional amputation confined to the foot was achieved in 86% of ambulatory diabetic patients. These results support a more aggressive initial approach in ambulatory diabetic patients with multiple digital ulcerations, allowing this patient population to remain functional and avoid multiple reoperations and ultimately major amputation.


Ghrelin in hypothalamic regulation of energy balance.
The novel peptide hormone ghrelin has recently been recognized as an important co-regulator of growth hormone secretion and energy homeostasis. The significance of ghrelin for obesity and cachexia as well as in the regulation of growth processes is the subject of ongoing basic research as well as clinical studies. It is our goal to emphasize the critical significance of the hypothalamic signaling modalities induced by ghrelin for a better understanding of how this novel hormone affects energy balance and metabolism.


Candidate gene polymorphisms (BoIFNG, TLR4, SLC11A1) as risk factors for paratuberculosis infection in cattle.
Paratuberculosis (Johne's disease) imposes a significant problem to the world dairy and beef industries and today is considered a potential zoonosis. The disease is caused by Mycobacterium avium subsp. paratuberculosis and is characterized by progressive weight loss and profuse diarrhoea. Susceptibility to infection is suspected to have a genetic component, and moderated values for heritability of infection have been reported. Interferon gamma is an inducible cytokine with a crucial role in the innate host response to intracellular bacteria. Toll-like receptors are trans-membrane structures responsible for coordination of innate and adaptive immune responses. The solute carrier family 11 member 1 (SLC11A1, formerly NRAMP1) gene plays an important role in innate immunity, preventing bacterial growth in macrophages during the initial stages of infection. The objective of this candidate gene case-control study was to characterize the distribution of polymorphisms in three candidate genes related to the immune function; interferon gamma (BoIFNG), toll-like receptor 4 (TLR4), and SLC11A1 genes and to test their role as potential risk factors for paratuberculosis infection in cattle. The statistical analysis demonstrated significant differences in allelic frequencies between cases and controls for BoIFNG-SNP(1)2781 and SLC11A1 microsatellites, indicating a significant association between infection and variant alleles. In the analysis of genotypes, a significant association was also found between infection status and BoIFNG-SNP(1)2781 and SLC11A1-275-279-281 microsatellites. However, when variables such as breed and age were included in the multivariate logistic regression analysis, a tendency toward statistical significance for the effect of polymorphisms in the odds of infection was only found for alleles SLC11A1-275 and 279.


Anthocyanin-rich extract from black rice (Oryza sativa L. Japonica) ameliorates diabetic osteoporosis in rats.
Diabetic osteoporosis (DOP) is a systemic endocrine-metabolic osteopathy which has the characteristics of bone mineral density (BMD) reduction and bone microstructural destruction. Although anthocyanin-rich extract from black rice (AEBR) was reported to have a beneficial effect on diabetic rats, no studies have been performed on whether black rice anthocyanins are beneficial for diabetic osteoporosis. Therefore, in this study, a streptozotocin-induced diabetic rat model was established to investigate the protective effect of AEBR on diabetes-induced osteoporosis and its possible mechanism. AEBR at three doses (0.5, 1.0, and 2.0 g kg-1 d-1) were administered by oral gavage to diabetic rats for 8 weeks. The blood glucose, BMD, bone histomorphometry parameters, serum bone turnover biomarkers, bone marrow adipocyte numbers, as well as osteoprotegerin (OPG), runt-related transcription factor 2 (RUNX 2), and receptor activator of nuclear factor-κ B ligand (RANKL) protein expression in bone and serum were detected. The results indicated that AEBR dose-dependently decreased the blood glucose, increased the BMD, and decreased the serum bone turnover markers. The bone microstructure and osteoclast numbers in bone tissues returned to normal in the high AEBR dosage group; at the same time, the AEBR dose-dependently suppressed bone marrow adipogenesis. The RUNX 2 as well as the OPG/RANKL ratio in diabetic rats' bone tissues increased significantly in the AEBR treatment group. Our results indicate that AEBR administration can ameliorate bone loss caused by diabetes; this is mainly attributed to its inhibition of bone turnover, suppression of bone marrow adipogenesis, and up-regulation of RUNX 2 and the OPG/RANKL expression ratio.


[Hyperventilation: not a cause of panic attacks].
To investigate the importance of hyperventilation in the pathogenesis of panic attacks. Descriptive. The Jelgersma Outpatient Clinic at Oegstgeest and the University Hospital Leiden, the Netherlands. In 57 psychiatric patients with a panic disorder and 96 somatic patients with unexplained somatic complaints suggestive of hyperventilation, a Hyperventilation Provocation Test (HVPT) was conducted. Of the somatic patients, 33 had recently experienced a panic attack. During the test, various physiological and symptom criteria for the Hyperventilation Syndrome were assessed. Several measures for concomitant psychopathology were collected as well. No significant differences were found in physiological criteria for the Hyperventilation Syndrome between psychiatric patients with a panic disorder (PD) and somatic patients with (PA+) or without (PA-) a recent panic attack. On all symptom criteria, however, PD and PA+ patients obtained comparable scores, while both groups scored higher than PA- patients. On most measures for concomitant psychopathology, PD patients scored higher than PA+ patients, who on their part scored higher than PA- patients. Hyperventilation is of secondary importance in the pathogenesis of panic attacks and an early diagnosis of panic attacks or panic disorder may be conducive to more adequate treatment.


[Mycoses as opportunistic infections in AIDS patients].
Since January 1985 more than 100 patients with deep fungal infections have been treated with itraconazole (200 to 400 mg/day) in Northern Italy. Evaluation of the drug efficacy and tolerance was possible in one patient with sporotrichosis, in 34 with aspergillosis, and in 36 with cryptococcosis (mainly patients positive for human immunodeficiency virus). Response to itraconazole alone was obtained in the case of sporotrichosis and in 24 of 34 patients with different forms of aspergillosis (of the 18 patients with invasive pulmonary aspergillosis, 15 were cured). Patients with cryptococcosis received itraconazole for active infection and/or for prevention of relapse. Active infection was treated successfully with itraconazole alone in nine of twelve patients and with itraconazole plus flucytosine in eight of ten patients. Of the 31 patients who received itraconazole maintenance therapy for up to 27 months, four (13%) had relapses; 14 (45%) did not have relapses, and decline of serum antigen was detected in twelve of them; and 13 (42%) were completely cured (serum antigen titer dropped to zero). With the exception of hypokalemia in one patient, itraconazole was well tolerated even in patients who received the drug for several months or years.


Effects of management system on beef heifer growth and reproductive performance.
This study evaluated the effect of heifer development system on body weight (BW), body condition score (BCS), fescue toxicosis symptoms, reproductive performance, and subsequent calf growth of fall-calving beef heifers. Angus × Simmental heifers [n = 399; 240 ± 20.0 kg initial BW; age = 252 ± 20 d] were stratified by BW and BCS and assigned to 1 of 12 groups in each of the two production years. The study utilized a stratified randomized design. Pens were randomly assigned to four treatments: drylot (DL) development (fed ad-libitum diet consisting of 90% hay and 10% DDGS on a dry matter basis), grazing endophyte-infected fescue supplemented daily (2.3 kg as-fed/heifer/d; 50:50 mix of soybean hulls and DDGS; E+/S), grazing endophyte-infected fescue and supplemented from the midpoint of treatment period until breeding (4.5 kg as-fed/heifer/d; 50:50 mix of soybean hulls and DDGS; E+/LS), and grazing novel endophyte-infected fescue with no supplement (NE+/NS). Treatments ceased on d 168 [time of artificial insemination (AI)] and heifers were commingled and managed as a group through second breeding season. Heifers in DL had greatest (P ≤ 0.05) BW and BCS from d 28 until d 254. Furthermore, E+/S heifers had greater (P ≤ 0.05) BW and BCS than both E+/LS and NE+/NS from d 28 until d 168. On d 56 and 84, E+/LS heifers had lower (P ≤ 0.05) BW and BCS compared to NE+/NS, but on d 148 treatments reranked and E+/LS remained at a greater (P ≤ 0.05) BW and BCS compared to NE+/NS through the first breeding season. Drylot heifers had greatest (P ≤ 0.05) percentage cycling and percentage of mature BW at AI (66.6%) and had greater (P ≤ 0.05) AI and overall pregnancy rates compared to E+/LS and NE+/NS. The E+/S (55%) and E+/LS (53.7%) heifers were developed to a greater (P < 0.01) percentage of mature BW than NE+/NS (49.3%). A greater (P ≤ 0.02) percentage of DL and E+/S heifers were pregnant at the end of the first breeding season (89.3 and 85.1%; respectively) compared to NE+/NS (61.5%). In summary, DL heifers had the greatest BW and BCS at AI, percentage cycling, and AI pregnancy rate. However, this strategy did not result in differing overall pregnancy rates between DL, E+/S, and E+/LS and there were no differences in milk production, rebreeding reproductive performance, and calf performance between all treatments. Finally, the poorest AI and overall pregnancy rates of the NE+/NS heifers suggests this is not a viable development strategy for fall-born heifers.


Evidence for altered synthesis of type II collagen in patients with osteoarthritis.
There is evidence to suggest that the synthesis of type II collagen is increased in osteoarthritis (OA). Using an immunoassay, we show that the content of the C-propeptide of type II procollagen (CPII), released extracellularly from the newly synthesized molecule, is directly related to the synthesis of this molecule in healthy and osteoarthritic articular cartilages. In OA cartilage, CPII content is often markedly elevated (mean 7.6-fold), particularly in the mid and deep zones, reaching 29.6% of the content in newborn. Synthesis is also directly related to total collagen II content in OA, suggesting its importance in maintaining collagen content and cartilage structure. The release of CPII from cartilage is correlated directly with cartilage content. However, the increase in CPII in OA cartilage is not reflected in serum, where a significant reduction is observed. Together these studies provide evidence for alterations in procollagen II synthesis in vivo in patients with OA.


Thoracoscopic lobectomy through a single incision.
Over the past two decades, video-assisted thoracic surgery (VATS) has revolutionized the way thoracic surgeons diagnose and treat lung diseases. The major advance in VATS procedures is related to the major pulmonary resections. The optimal VATS technique for lobectomy in lung cancer has not been well defined yet. Most of the authors describe the VATS approach to lobectomy via three to four incisions, but the surgery can be performed by only one incision with similar outcomes. This single incision is the same as we normally use for VATS lobectomies performed by double- or triple-port technique, with no rib spreading. As our experience with VATS lobectomy has grown, we have gradually improved the technique for a less-invasive approach. Consequently, the greater the experience we gained, the more complex the cases we performed were, thus expanding the indications for single-incision thoracoscopic lobectomy.


Ottawa 25 years on: a more radical agenda for health equity is still required.
This article revisits our 1995 assessment of the international health promotion agenda. Then we concluded that a more radical agenda for change was required in which responses were both technically sound and infused with an appreciation of the imperative for a change in politics and power. We conclude that this message is even more relevant in 2011 in an era when the continuing rise of transnational corporations (TNCs) poses a major threat to achieving improved and more equitable health. We support and illustrate this claim through the example of food and agriculture TNCs where the combination of producer subsidies, global trade liberalization and strengthened property rights has given increasing power to the corporate food industry and undermined national food security in many countries. We argue that a Health in All Policies approach should be used to monitor and enforce TNC accountability for health. Part of this process should include the use of a form of health impact assessment and health equity impact assessment on their activities. Civil society groups such as the People's Health Movement have a central role to play in monitoring the impacts of TNCs.


Theoretical study of oxidative additions of H2 and MeCN to a nickel(0) complex: significantly large correlation effects and characteristic features of the reaction.
Oxidative addition of H2 to Ni(PH3)2 was theoretically studied as a prototype of nickel-catalyzed sigma-bond activation reaction, where CASSCF, CASPT2, CCSD(T), broken symmetry (Bs) MP2 to MP4(SDTQ), and DFT methods were employed. The CASPT2 method yields a reliable potential energy curve (PEC) when the active space consists of 10 electrons and 10 orbitals including five outer 3d' orbitals. The CCSD(T) method presents almost the same PEC as the CASPT2-calculated one, when either the ANO or the cc-pVTZ basis set is used for Ni. Bs-MP4(SDTQ)-calculated PEC is similar to those calculated by the CASPT2/ANO method, while the PEC is not smooth around the transition state. In the DFT calculation, ANO, cc-pVTZ, and triple-zeta quality basis sets (SDB) with Stuttgart-Dresden-Bonn effective core potentials (ECPs) must be used for Ni. The DFT-calculated reaction energy is somewhat smaller than the CASPT2- and CCSD(T)-calculated values, while B3PW91 and mPW1PW91 present moderately better energy changes than BLYP, B1LYP, and B3LYP. Oxidative addition of MeCN to Ni(PH3)2 was investigated by the DFT(B3PW91) and CCSD(T) methods. Almost the same activation barrier was calculated by these methods, when cc-pVTZ was employed for Ni. However, the DFT method moderately underestimates the binding energy of the reactant complex and the reaction energy compared to the CCSD(T) method. This oxidative addition exhibits interesting characteristic features, as follows: The barrier height relative to infinite separation is lower, and the product is more stable than those of the oxidative addition of C2H6. These differences are discussed in detail in terms of Ni-Me and Ni-CN bond energies and the participation of the CN pi* orbital to stabilization interaction in the transition state.


Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis.
We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.


Activation of BK and SK channels by efferent synapses on outer hair cells in high-frequency regions of the rodent cochlea.
Cholinergic neurons of the brainstem olivary complex project to and inhibit outer hair cells (OHCs), refining acoustic sensitivity of the mammalian cochlea. In all vertebrate hair cells studied to date, cholinergic inhibition results from the combined action of ionotropic acetylcholine receptors and associated calcium-activated potassium channels. Although inhibition was thought to involve exclusively small conductance (SK potassium channels), recent findings have shown that BK channels also contribute to inhibition in basal, high-frequency OHCs after the onset of hearing. Here we show that the waveform of randomly timed IPSCs (evoked by high extracellular potassium) in high-frequency OHCs is altered by blockade of either SK or BK channels, with BK channels supporting faster synaptic waveforms and SK channels supporting slower synaptic waveforms. Consistent with these findings, IPSCs recorded from high-frequency OHCs that express BK channels are briefer than IPSCs recorded from low-frequency (apical) OHCs that do not express BK channels and from immature high-frequency OHCs before the developmental onset of BK channel expression. Likewise, OHCs of BKα(-/-) mice lacking the pore-forming α-subunit of BK channels have longer IPSCs than do the OHCs of BKα(+/+) littermates. Furthermore, serial reconstruction of electron micrographs showed that postsynaptic cisterns of BKα(-/-) OHCs were smaller than those of BKα(+/+) OHCs, and immunofluorescent quantification showed that efferent presynaptic terminals of BKα(-/-) OHCs were smaller than those of BKα(+/+) OHCs. Together, these findings indicate that BK channels contribute to postsynaptic function, and influence the structural maturation of efferent-OHC synapses.


Age and calving time affects production efficiency of beef cows and their calves.
The aim of this study was to evaluate the influence of two sub-periods of the calving season and two cow maturity stages on the efficiency of beef cows and their calves. A total of 159 cow-calf pairs were divided by calving time (early or late) within the calving season and maturity stage (young or adult). Calves were weaned at 42 or 63 days after birth and evaluated until 210 days of age. Cows and calves had their development examined based on their weight and body condition score at calving, at weaning, and at 210 days. Reproductive performance was evaluated on the basis of time to become pregnant again. Milk yield was assessed by the direct method on three occasions spaced 21 days apart. Adult cows were heavier than young cows, at calving (398.5 vs 327.5 kg, respectively), weaning (397.3 vs 324.1 kg, respectively) at the end breeding season (424.1 vs 342.1 kg, respectively). Reproductive performance was influenced by calving time. Adult cows had higher pregnancy rates (83.75 and 69.17%, for early and for late calving, respectively) than young cows (57.03 and 35.01% for early and for late-calving, respectively). Calves from early-calving young cows weighed 158.8 kg at 210 days of age vs. 123.7 kg for those born from late-calving adult cows. However, late-calving cows produced 10.7% more milk than those that calved early in the season (227.0 vs 205.0 liters, respectively). Early calving associated with non-requirement of growth determine higher productivity efficiency in beef cows.


High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas.
The homogeneous distribution of BRAF V600E in papillary thyroid carcinoma (PTC) has been called into question by recent reports. These studies claim that BRAF V600E is heterogeneous and is limited to tumor cell subsets in the majority of PTCs. The objective of the study was to understand the allele distribution of BRAF V600E by evaluating the percentage of mutated neoplastic cells in a group of PTCs using two different highly sensitive analytical approaches: allele-specific locked nucleic acid PCR and 454 next-generation sequencing targeted to BRAF exon 15. BRAF V600E was investigated using allele-specific locked nucleic acid PCR on 155 consecutive samples of PTC. Mutated cases were reanalyzed by 454 next-generation sequencing and immunohistochemistry. Because the evaluation of genetic heterogeneity in tumor samples can be profoundly biased by contamination with normal cells, all mutation frequency data were normalized to the real amount of neoplastic cells within each tumor. Eighty-five of 155 PTCs (54.8%) were BRAF V600E mutated. The distribution of mutated neoplastic cells within the tumor was as follows: greater than 80% in 37 of 85 (43.5%), 30-80% in 39 of 85 (45.9%), and less than 30% in 9 of 85 (10.6%). In most of the PTCs with less than 80% BRAF V600E-positive neoplastic cells, the mutation was present in large neoplastic cell subpopulations. Tumors with less than 30% mutated neoplastic cells were smaller than tumors with a percentage of mutated cells greater than 80% or between 30% and 80% (P < .05). BRAF V600E is heterogeneously distributed in some PTCs. The large BRAF V600E neoplastic cell subpopulations found in mutated cases is consistent with the view that the BRAF V600E is acquired early during PTC development.


Summary of the HESI consortium studies exploring circulating inhibin B as a potential biomarker of testis damage in the rat.
The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper. For roughly half of these exposures, lesions appeared well before Inhibin B changed. A few of the studies showed a good correlation between seminiferous tubule damage and reduced circulating Inhibin B levels, while for seven exposures, circulating Inhibin B was reduced with no detectable alteration in testis histology. Whether this indicates a prodromal response or a false-positive signal will require further investigation. These exceptions could plausibly suggest some value of circulating Inhibin B as a useful biomarker in some circumstances. However, for roughly half of these exposures, Inhibin B appeared to be a lagging biomarker, requiring significant damage to the seminiferous tubules before a consistent and credible reduction in circulating levels of Inhibin B was observed.


Surgical treatment of tumors involving the cervicothoracic junction.
Tumors involving the cervicothoracic junction can have a high propensity for causing instability, with kyphosis and spinal cord compression resulting. Treatment with decompression only can lead to further instability and worsening neurological status. In this article, the authors review their surgical experience in the treatment of 19 patients with tumors involving the cervicothoracic junction. The various approaches and instrumentation techniques involved in decompression and stabilization of the cervicothoracic junction are also reviewed. Aggressive instrumentation-augmented fusion after decompression of the cervicothoracic region can provide for immediate stabilization and early rehabilitation. Recent development of new hardware such as dual-diameter transition rods, polyaxial screws, and interlocking devices have enhanced the ability to fashion a strong construct for stabilization of the cervicothoracic junction. Familiarity with complex instrumentation techniques and various surgical approaches to the cervicothoracic junction will be required for effective treatment of tumors causing instability of this region.


Truth-telling in cancer: examining the cultural incompatibility argument in Turkey.
This article aims to examine critically the 'cultural incompatibility' argument, which asserts that disclosure of cancer-related information to patients is incompatible with Turkey's cultural context. For this purpose, a brief overview of the approach to truth-telling in Turkey will first be provided, followed by the claims of two different Turkish authors on the issue and a critical analysis of their approach. It will be contended that this argument has actually been formulated with paternalistic concerns and it may be playing an important role in shaping the approach of Turkish health care professionals to the issue. The article will then examine, in the light of study findings and case reports from Turkey, the concept of patient autonomy as it applies to truth-telling issues. It will be concluded that truth-telling can be compatible with Turkey's cultural context, provided that health care professionals place more emphasis on good communication with their patients.


Vaccine against human hepatitis B.
A highly purified and inactivated vaccine was made of hepatitis B virus surface antigen. The vaccine was tested exhaustively for safety by ordinary procedures and additionally in chimpanzees and marmosets. It was highly potent and induced antibody in guinea pigs, grivet monkeys, and chimpanzees after three doses of vaccine were given subcutaneously. Chimpanzees given three doses of vaccine were protected against challenge with 1,000 chimpanzee-infectious doses of live human hepatitis B virus given intravenously in controlled studies. Tests of the vaccine for control of hepatitis B in man are to be carried out.


Peak experiences of psilocybin users and non-users.
Maslow (1970) defined peak experiences as the most wonderful experiences of a person's life, which may include a sense of awe, well-being, or transcendence. Furthermore, recent research has suggested that psilocybin can produce experiences subjectively rated as uniquely meaningful and significant (Griffiths et al. 2006). It is therefore possible that psilocybin may facilitate or change the nature of peak experiences in users compared to non-users. This study was designed to compare the peak experiences of psilocybin users and non-users, to evaluate the frequency of peak experiences while under the influence of psilocybin, and to assess the perceived degree of alteration of consciousness during these experiences. Participants were recruited through convenience and snowball sampling from undergraduate classes and at a musical event. Participants were divided into three groups, those who reported a peak experience while under the influence of psilocybin (psilocybin peak experience: PPE), participants who had used psilocybin but reported their peak experiences did not occur while they were under the influence of psilocybin (non-psilocybin peak experience: NPPE), and participants who had never used psilocybin (non-user: NU). A total of 101 participants were asked to think about their peak experiences and complete a measure evaluating the degree of alteration of consciousness during that experience. Results indicated that 47% of psilocybin users reported their peak experience occurred while using psilocybin. In addition, there were significant differences among the three groups on all dimensions of alteration of consciousness. Future research is necessary to identify factors that influence the peak experiences of psilocybin users in naturalistic settings and contribute to the different characteristics of peak experiences of psilocybin users and non-users.


Water resources and the land-water interface.
Development and implementation of local and regional plans to control nonpoint sources of pollution from agricultural land are major mandates of section 208 of Public Law 92-500. Many planners tend to equate erosion control as measured by the universal soil loss equation with improvements in water quality. Others implement channel management practices which degrade rather than improve water quality and thereby decrease the effectiveness of other efforts to control nonpoint sources. Planners rarely recognize the importance of the land-water interface in regulating water quality in agricultural watersheds. More effective planning can result from the development of "best management systems" which incorporate theory from all relevant disciplines.


[Antibacterial activity of a lysozyme-like enzyme from staphylococci].
A lysozyme-like enzyme isolated from the culture broth of Staph. aureus 712 presented in its native state a lipoproteid complex. The lytic and antibacterial spectrum of the enzyme was similar to that of the egg albumin enzyme. However, the lipoproteid complex was somewhat superior to the egg albumin complex in its activity against Micrococcus lysodeikticus, a number of gramnegative bacteria and staphylococci. Out of the organisms studied Microccus lysodeikticus, Sarcina and Bac. subtilis proved to be most sensitive to the both enzymes. Comparison of the amount of the enzyme formed in the culture medium with its minimum inhibitory concentration with respect to most of the microbes tested provided a supposition that the lipoproteid enzyme did not play a significant role in the process of the microbial antagonism.


Distracting injuries in patients with vertebral injuries.
To describe the prevalence and types of distracting injuries associated with vertebral injuries at all levels of the spine in blunt trauma patients. A prospective cohort study was conducted at an urban Level I trauma center. All patients undergoing radiographic evaluation of the cervical, thoracic, or lumbar vertebrae after blunt trauma were enrolled. Patients had a data collection form completed by the treating physician before radiographic imaging and were evaluated for the following upon initial presentation: tenderness to the cervical, thoracic, or lumbar spine, distracting injuries, altered mental status, alcohol or drug intoxication, or neurological deficits. Patients with distracting injuries as the sole documented indication for vertebral radiographs were reviewed for the types of injuries present. A total of 4698 patients were enrolled in the study. There were 336 (7.2%) patients who had distracting injuries as the sole documented indication for obtaining radiographic studies of the vertebrae. Eight (2.4%, 95% CI 1.0-4.6%) of the 336 patients had 14 acute vertebral injuries including compression fractures (5), transverse process fractures (7), spinous process fracture (1), and cervical spine rotatory subluxation (1). There were 13 thoracolumbar injuries and one cervical spine injury. Distracting injuries in the eight patients with acute vertebral injuries included 13 bony fractures. Distracting injuries in those patients without vertebral injuries included bony fractures (333), lacerations (63), soft tissue contusions (62), head injuries (15), bony dislocations (12), abrasions (11), visceral injuries (8), dental injuries (5), burns (3), ligamentous injuries (3), amputation (1), and compartment syndrome (1). In conclusion, in patients with distracting injuries, bony fractures of any type were important for identifying patients with vertebral injuries. Other types of distracting injuries did not contribute to the sensitivity of the clinical screening criteria in the detection of patients with vertebral injuries.


Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).
Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.


Cervical cord myelin water imaging shows degenerative changes over one year in multiple sclerosis but not neuromyelitis optica spectrum disorder.
Spinal cord pathology is a feature of both neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (MS). While subclinical disease activity has been described in MS using quantitative magnetic resonance imaging measures, current evidence suggests that neurodegeneration is absent between relapses in NMOSD, although most evidence comes from brain studies. We aimed to assess cross-sectional differences and longitudinal changes in myelin integrity in relapse-free MS and NMOSD subjects over one year. 15 NMOSD, 15 MS subjects, and 17 healthy controls were scanned at 3 T using a cervical cord mcDESPOT protocol. A subset of 8 NMOSD, 11 MS subjects and 14 controls completed follow-up. Measures of the myelin water fraction (fM) within lesioned and non-lesioned cord segments were collected. At baseline, fM in lesioned and non-lesioned segments was significantly reduced in MS (lesioned: p = 0.002; non-lesioned: p = 0.03) and NMOSD (lesioned: p = 0.0007; non-lesioned: p = 0.002) compared to controls. Longitudinally, fM decreased within non-lesioned cord segments in the MS group (- 7.3%, p = 0.02), but not in NMOSD (+ 5.8%, p = 0.1), while change in lesioned segments fM did not differ from controls' in either patient group. These results suggest that degenerative changes outside of lesioned areas can be observed over a short time frame in MS, but not NMOSD, and support the use of longitudinal myelin water imaging for the assessment of pathological changes in the cervical cord in demyelinating diseases.


Electrophysiological Characteristics and Ablation Outcomes in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.
Catheter ablation of premature ventricular contractions (PVCs) that trigger polymorphic ventricular tachycardia (PVT) or ventricular fibrillation has been reported as a novel therapy to reduce the syncope events in patients with catecholaminergic PVT, whereas the long-term ablation outcome and its value in improving exercise-induced ventricular arrhythmias remain unclear. Fourteen consecutive selected patients with catecholaminergic PVT (mean±SD age, 16±6 years; 43% male patients) treated with maximum β-blockers with no possibility of adding flecainide were prospectively enrolled for catheter ablation. The primary end point was syncope recurrence, and the secondary end point was the reduction of the ventricular arrhythmia score during exercise testing. Twenty-six PVT/ventricular fibrillation-triggering PVCs were identified for ablation. The trigger beats arose from the left ventricle in 50% of the cases and from both ventricles in 36% of the cases. Purkinje potentials were observed at 27% of the targets. After a mean follow-up of 49 months after ablation, 8 (57%) patients were free from syncope recurrence. Ablation of trigger beat significantly reduced the syncope frequency (mean±SD, 4.3±1.6 to 0.5±0.8 events per year; P<0.001) and improved the ventricular arrhythmia scores at the 3-month (5 [range, 3-6] to 1.5 [range, 0-5]; P=0.002) and 12-month (5 [range, 3-6] to 2 [range, 0-5]; P=0.014) follow-ups. The induction of nontriggering PVCs postablation was closely associated with syncope recurrence (hazard ratio, 6.8 [95% CI, 1.3-35.5]; P=0.026). Catheter ablation of PVT/ventricular fibrillation-triggering PVCs in patients with catecholaminergic PVT who cannot receive flecainide treatment seems to be a safe and feasible adjunctive treatment that may reduce the syncope burden and improve exercise-related ventricular arrhythmias. Induction of nontriggering PVCs after ablation is associated with a higher risk of syncope recurrence.


Agreement between area- and individual-level income measures in a population-based cohort: Implications for population health research.
Socioeconomic status is an important determinant of health, the measurement of which is of great significance to population health research. However, individual-level socioeconomic factors are absent from much health administrative data, resulting in widespread use of area-level measures in their place. This study aims to clarify the role of individual- and area-level socioeconomic status in Ontario, Canada, through comparison of income measures. Using data from four cycles (2005-2012) of the Canadian Community Health Survey, we assessed concordance between individual- and area-level income quintiles using percent agreement and Kappa statistics. Individual-level characteristics were compared at baseline. Cumulative adult premature mortality was calculated for 5-years following interview. Rates were calculated separately for area-level and individual-level income, and jointly for each combination of income groups. Multivariable negative binomial models were fit to estimate associations between area- and individual-level income quintile and premature mortality after adjustment for basic demographics (age, sex, interview cycle) and key risk factors (alcohol, smoking, physical activity, and body mass index). Agreement between individual- and area-level income measures was low. Kappa statistics for same and similar (i.e. ±1 quintile) measures were 0.11 and 0.48, indicating low and moderate agreement, respectively. Socioeconomic disparities in premature mortality were greater for individual-level income than area-level income. When rates were stratified by both area- and individual-level income quintiles simultaneously, individual-level income gradients persisted within each area-level income group. The association between income and premature mortality was significant for both measures, including after full adjustment. Area-level socioeconomic status is an inappropriate proxy for missing individual-level data. The low agreement between area- and individual-level income measures and differences in demographic profile indicate that the two socioeconomic status measures do not capture the same population groups. However, our findings demonstrate that both individual- and area-level income measures are associated with premature mortality, and describe unique socioeconomic inequities.


[Immunologic response ot introduction of intact and formalinized erythrocytes].
Experiments were conducted on mice; there was revealed an increase in the immunogenicity of erythrocytes following their immunization illustrated by the difference in the circulating antibody titres and the plaque count in the spleen of the animals, and also by the results of immunization with formalin-treated erythrocytes mixed with the cells of the peritoneal exudate. A conclusion was drawn on the expediency of the immunization with formalinized erythrocytes of rabbits--producers of the hemolytic serum.


Monitoring sociodemographic inequality in COVID-19 vaccination uptake in England: a national linked data study.
The UK began an ambitious COVID-19 vaccination programme on 8 December 2020. This study describes variation in vaccination uptake by sociodemographic characteristics between December 2020 and August 2021. Using population-level administrative records linked to the 2011 Census, we estimated monthly first dose vaccination rates by age group and sociodemographic characteristics among adults aged 18 years or over in England. We also present a tool to display the results interactively. Our sample included 35 223 466 adults. A lower percentage of males than females were vaccinated in the young and middle age groups (18-59 years) but not in the older age groups. Vaccination rates were highest among individuals of White British and Indian ethnic backgrounds and lowest among Black Africans (aged ≥80 years) and Black Caribbeans (18-79 years). Differences by ethnic group emerged as soon as vaccination roll-out commenced and widened over time. Vaccination rates were also lower among individuals who identified as Muslim, lived in more deprived areas, reported having a disability, did not speak English as their main language, lived in rented housing, belonged to a lower socioeconomic group, and had fewer qualifications. We found inequalities in COVID-19 vaccination uptake rates by sex, ethnicity, religion, area deprivation, disability status, English language proficiency, socioeconomic position and educational attainment, but some of these differences varied by age group. Research is urgently needed to understand why these inequalities exist and how they can be addressed.


Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice.
The role of complement in immunoglobulin G-triggered inflammation was studied in mice genetically deficient in complement components C3 and C4. Using the reverse passive Arthus reaction and experimental models of immune hemolytic anemia and immune thrombocytopenia, we show that these mice have types II and III inflammatory responses that are indistinguishable from those of wild-type animals. Complement-deficient and wild-type animals exhibit comparable levels of erythrophagocytosis and platelet clearance in response to cytotoxic anti-red blood cell and antiplatelet antibodies. Furthermore, in the reverse passive Arthus reaction, soluble immune complexes induce equivalent levels of hemmorhage, edema, and neutrophillic infiltration in complement-deficient and wild-type animals. In contrast, mice that are genetically deficient in the expression of Fc receptors exhibit grossly diminished reactions by both cytotoxic antibodies and soluble immune complexes. These studies provide strong evidence that the activation of cell-based Fc gamma R receptors, but not complement, are required for antibody-triggered murine inflammatory responses.


Cotargeting signaling pathways driving survival and cell cycle circumvents resistance to Kit inhibitors in leukemia.
Oncogenic mutations leading to persistent kinase activities are associated with malignancies. Therefore, deciphering the signaling networks downstream of these oncogenic stimuli remains a challenge to gather insights into targeted therapy. To elucidate the biochemical networks connecting the Kit mutant to leukemogenesis, in the present study, we performed a global profiling of tyrosine-phosphorylated proteins from mutant Kit-driven murine leukemia proerythroblasts and identified Shp2 and Stat5 as proximal effectors of Kit. Shp2 or Stat5 gene depletion by sh-RNA, combined with pharmacologic inhibition of PI3kinase or Mek/Erk activities, revealed 2 distinct and independent signaling pathways contributing to malignancy. We demonstrate that cell survival is driven by the Kit/Shp2/Ras/Mek/Erk1/2 pathway, whereas the G(1)/S transition during the cell cycle is accelerated by both the Kit/Stat5 and Kit/PI3K/Akt pathways. The combined use of the clinically relevant drugs NVP-BEZ235, which targets the cell cycle, and Obatoclax, which targets survival, demonstrated synergistic effects to inhibit leukemia cell growth. This synergy was confirmed with a human mast leukemia cell line (HMC-1.2) that expresses mutant Kit. The results of the present study using liquid chromatography/tandem mass spectrometry analysis have elucidated signaling networks downstream of an oncogenic kinase, providing a molecular rationale for pathway-targeted therapy to treat cancer cells refractory to tyrosine kinase inhibitors.


Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes.
Repair of alkylated bases in DNA is performed by O6-methylguanine-DNA methyltransferase (MGMT) and a set of enzymes of the base excision repair pathway involving N-methylpurine-DNA glycosylase (MPG), apurinic endonuclease (APE), DNA polymerase beta (Pol beta) and DNA ligase. The level of expression of these enzymes may exert a profound effect on resistance of cells towards alkylating drugs. We have comparatively analyzed the expression of MGMT and the different base excision repair genes in rat hepatoma cells (line H4IIE) after exposure to alkylating agents, X-rays and the glucocorticoid hormone dexamethasone. Furthermore, the effect of these agents on the activity of the cloned human MGMT promoter was assayed. Exposure of cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or ionizing radiation increased MGMT mRNA levels up to 4.5-fold. Under the same conditions of treatment, exerting only a weak toxic effect, MPG and DNA ligase I mRNA levels were not enhanced, whereas the amounts of APE and Pol beta mRNA transiently increased by approximately 2-fold after X-ray and MNNG treatment, respectively. Dexamethasone induced both MGMT, APE and Pol beta mRNA and the induction paralleled the increase in mRNA of the glucocorticoid-dependent gene tyrosine aminotransferase. The observed increase in MGMT mRNA was due to promoter activation, which was shown in transient transfection assays with MGMT promoter-CAT reporter constructs in H4IIE cells. In these assays, the human MGMT promoter was found to be induced by methylating agents (MNNG and methyl methanesulfonate), ionizing radiation and dexamethasone. Weak induction of the promoter was observed after UV irradiation. Treatment with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate was ineffective in promoter activation. The transfected MGMT promoter was not inducible by mutagens in HeLa S3 cells, which do not respond with induction of the endogenous MGMT gene. This is the first report showing hormone induction of a DNA repair gene (MGMT). The induction of MGMT and other genes encoding enzymes involved in DNA alkylation damage repair may be relevant in cancer therapy by causing resistance of tumor cells to alkylating drugs.


Hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS of bone marrow-liver-spleen type: an autopsy case report.
Lymphoma-associated hemophagocytic lymphohistiocytosis (HLH) has a significantly poor prognosis among secondary HLH. We describe the rare case of a 74-year-old female with secondary HLH presenting with a rapidly fatal course. Post-mortem examination revealed Epstein-Barr virus (EBV) -positive diffuse large B-cell lymphoma (DLBCL). We were unable to make a definite antemortem diagnosis because the patient did not exhibit lymphadenopathy and bone marrow biopsy demonstrated hemophagocytosis without evidence of lymphoma. She died of multiple organ failure on the twelfth day of hospitalization despite a temporary response to steroids. Autopsy revealed diffuse lymphoma cell infiltration of the bone marrow, liver and spleen, suggesting "bone marrow-liver-spleen" (BLS)-type large B-cell lymphoma (LBCL). BLS-type LBCL is a rare and clinically aggressive lymphoma, usually associated with fever, cytopenia and HLH. The disease has a high mortality rate due to the delay in diagnosis and a highly aggressive clinical course. Further studies are required to improve our understanding of this rare extranodal DLBCL.


Recognizing problem sleepiness in your patients. National Center on Sleep Disorders Research Working Group.
Normal sleep is required for optimal functioning. Normal wakefulness should be effortless and free of unintended sleep episodes. Problem sleepiness is common and occurs when the quantity of sleep is inadequate because of primary sleep disorders, other medical conditions or lifestyle factors. Medications and substances that disturb sleep, such as caffeine and nicotine, or those that have sedating side effects, may also cause problem sleepiness. This condition can lead to impairment in attention, performance problems at work and school, and potentially dangerous situations when the patient is driving or undertaking other safety-sensitive tasks. However, problem sleepiness is generally correctable when it is recognized. Asking a patient and his or her bed partner about the likelihood of drowsiness or of falling asleep during specific activities, as well as questions that uncover factors contributing to the sleepiness, helps the physician to recognize the disorder. Accurate diagnosis of specific sleep disorders may require evaluation by a specialist. The primary care physician is in an ideal position to identify signs and symptoms of problem sleepiness and initiate appropriate care of the patient, including educating the patient about the dangers of functioning while impaired by sleepiness.


The O polysaccharide chain of the lipopolysaccharide from Vibrio cholerae O76 is a homopolymer of N-[(S)-(+)-2-hydroxypropionyl]-alpha-L-perosamine.
Chemical and serological studies of LPS from Vibrio cholerae O76 (O76) were performed. The LPS of O76 contained D-glucose, D-galactose, L-glycero-D-manno-heptose, D-fructose, D-glucosamine, D-quinovosamine (2-amino-2,6-dideoxy-D-glucose) and L-perosamine (4-amino-4,6-dideoxy-L-mannopyranose). The sugar composition of the LPS from O76 was quite similar to that of LPS from V. cholerae O1 with the exception of the presence of a small amount of D-galactose in the LPS of O76. However, perosamine, a major sugar component of the LPS from O76, was in the L configuration in contrast to the D configuration of the perosamine in the LPS of V. cholerae O1. The L-perosamine was N-acylated with an (S)-(+)-2-hydroxypropionyl group in the LPS from O76. Structural analysis by NMR spectroscopy, as well as GC/MS, revealed that the O polysaccharide chain of the LPS from O76 was an alpha(1-->2)-linked homopolymer of N-[(S)-(+)-2-hydroxypropionyl]-L-perosamine. The serological cross-reactivity between the LPS of O76 and the LPS from other strains, such as V. cholerae O1 (Ogawa and Inaba O forms), Vibrio bio-serogroup 1875 (Original and Variant strains), V. cholerae O140 (Hakata) and Yersinia enterocolitica O9, was examined in passive haemolysis tests with sheep red blood cells that had been sensitized with LPS and antisera raised against whole cells of these bacteria. The latter six strains have in common the O antigen that includes Inaba antigen factor C, in addition to their own O-antigenic factors. Thus, they crossreact serologically. The O polysaccharide chains of the LPS of these six trains are known to consist exclusively of alpha(1-->2)-linked D-perosamine homopolymers and differences are found only among the N-acyl substituents. In passive haemolysis tests, the LPS of O76 did not cross-react serologically with any of the other LPS examined. Thus, the results obtained in this study support the hypothesis that Inaba antigen factor C, associated with the O antigens of these six strains, which include V. cholerae O1, is related substantially and exclusively to their alpha(1-->2)-linked homopolymers of N-acylated D-perosamine, and not to such homopolymers of N-acylated L-perosamine.


Setting the global health agenda: The influence of advocates and ideas on political priority for maternal and newborn survival.
This study investigates a puzzle concerning global health priorities-why do comparable issues receive differential levels of attention and resources? It considers maternal and neonatal mortality, two high-burden issues that pertain to groups at risk at birth and whose lives could be saved with effective intrapartum care. Why did maternal survival gain status as a global health priority earlier and to a greater degree than newborn survival? Higher mortality and morbidity burdens among newborns and the cost-effectiveness of interventions would seem to predict that issue's earlier and higher prioritization. Yet maternal survival emerged as a priority two decades earlier and had attracted considerably more attention and resources by the close of the Millennium Development Goals era. This study uses replicative process-tracing case studies to examine the emergence and growth of political priority for these two issues, probing reasons for unexpected variance. The study finds that maternal survival's grounding as a social justice issue spurred growth of a strong and diverse advocacy network and aligned the issue with powerful international norms (e.g. expectations to advance women's rights and the Millennium Development Goals), drawing attention and resources to the issue over three decades. Newborn survival's disadvantage stems from its long status as an issue falling under the umbrellas of maternal and child survival but not fully adopted by these networks, and with limited appeal as a public health issue advanced by a small and technically focused network; network expansion and alignment with child survival norms have improved the issue's status in the past few years.


Increasing Surplus Food Redistribution to Improve Food Access Through a Partnership Between Public Health and a Technology-Based Company.
Redistributing surplus food that would otherwise be discarded represents a viable strategy both for increasing food access and for addressing climate change. This study describes a public-private partnership that scaled such an effort in Los Angeles County. Public health worked with a technology-based company to introduce a mobile app that connected various traditional (e.g., food pantries) and non-traditional (e.g., businesses with surplus food, food rescue organizations, community-based organizations that work in low-income communities) organizations with a countywide surplus food redistribution process. In 11 months, 50 food businesses participated, a total of 43,900 pounds of food were recovered, and surplus food was delivered to 34 community sites, serving 28,400 meals. Lessons from the experience suggest that mobile app use was a key component of the redistribution effort, and that diverting food waste while increasing food access, with a priority towards obtaining food of high nutritional value, was both feasible and practical. It has previously been shown that reducing food loss and waste by at least 50% in the food service sector could help reduce energy use and greenhouse gas emissions.


Psychiatric care in a general practice.
The morbidity and patient management in a small general practice in a suburb of Auckland was analysed over a period of three months, comparing medical and psychiatric cases. Psychiatric patients tend to be more often frmale, older (though not in the geriatric age group), make slightly greater demands on practice time and have somewhat more chronic illnesses, but these differences from medical patients are small and psychiatric patients do not form a major problem in practice in the community. The findings, while showing a slightly higher frequency of psychiatric patients, are otherwise comparable with those from other New Zealand studies.


Calcium accumulation by the sarcoplasmic reticulum in two populations of chemically skinned human muscle fibers. Effects of calcium and cyclic AMP.
In previous efforts to characterize sarcoplasmic reticulum function in human muscles, it has not been possible to distinguish the relative contributions of fast-twitch and slow-twitch fibers. In this study, we have used light scattering and 45Ca to monitor Ca accumulation by the sarcoplasmic reticulum of isolated, chemically skinned human muscle fibers in the presence and absence of oxalate. Oxalate (5 mM) increased the capacity for Ca accumulation by a factor of 35 and made it possible to assess both rate of Ca uptake and relative sarcoplasmic reticulum volume in individual fibers. At a fixed ionized Ca concentration, the rate and maximal capacity (an index of sarcoplasmic reticulum volume) both varied over a wide range, but fibers fell into two distinct groups (fast and slow). Between the two groups, there was a 2- to 2.5-fold difference in oxalate-supported Ca uptake rates, but no difference in average sarcoplasmic reticulum volumes. Intrinsic differences in sarcoplasmic reticulum function (Vmax, K0.5, and n) were sought to account for the distinction between fast and slow groups. In both groups, rate of Ca accumulation increased sigmoidally as [Ca++] was increased from 0.1 to 1 microM. Apparent affinities for Ca++ (K0.5) were similar in the two groups, but slow fibers had a lower Vmax and larger n values. Slow fibers also differed from fast fibers in responding with enhanced Ca uptake upon addition of cyclic AMP (10(-6) M, alone or with protein kinase). Acceleration by cyclic AMP was adequate to account for adrenaline-induced increases in relaxation rates previously observed in human muscles containing mixtures in fast-twitch and slow-twitch fibers.


Effect of antisense oligodeoxynucleotides for ICAM-1 on renal ischaemia-reperfusion injury in the anaesthetised rat.
An antisense oligodeoxynucleotide (As-ODN) to the 3' untranslated region of the mRNA sequence expressing the intracellular adhesion molecule-1 (ICAM-1) was employed to determine ICAM-1's role in renal ischaemia-reperfusion injury in the rat. Wistar-Kyoto rats receiving i.v. either lipofectin-As-ODN (As-ODN group), lipofectin-reverse ODN (Rv-ODN group) or lipofectin (ischaemia control group) 8 h prior to study were anaesthetized and subjected to 30 min of renal artery occlusion. Renal haemodynamic and excretory parameters were monitored before and after renal ischaemia. On termination of the study renal tissue was subjected to histological and Western blot analysis. Renal blood flow decreased in the 3 h post-ischaemia period in the ischaemia control and Rv-ODN groups, but was maintained in the As-ODN group. Glomerular filtration rate was depressed initially but gradually increased to 10% above basal levels in the ischaemia control and Rv-ODN groups, but was below basal levels (20%) in the As-ODN group. There was a three- to fourfold increase in sodium and water excretion following ischaemia in the ischaemia control and reverse-ODN groups but not in the As-ODN treated group. The As-ODN ameliorated the histological evidence of ischaemic damage and reduced ICAM-1 protein levels to a greater extent in the medulla than cortex. These observations suggested that in the post-ischaemic period afferent and efferent arteriolar tone was increased with a loss of reabsorptive capacity which was in part due to ICAM-1. The possibility arises that the action of ICAM-1 at vascular and tubular sites in the deeper regions of the kidney contributes to the ischaemia-reperfusion injury.


[Kallikrein secretion by the isolated perfused rat kidney. Role of perfusion pressure and the renin-angiotensin system].
The isolated perfused rat kidney (IPRK) releases kallikrein in urine and renin in perfusate. We have previously shown (Kidney Int 24: 58-65, 1983) and confirm here that kallikrein, as well as renin releases are influenced by changes in renal hemodynamics in this model: a rise in perfusion pressure (PP) from 80 to 98 mmHg increases renal perfusate flow (RPF) by 48 +/- 3 p. 100, inhibits renin release and stimulates kallikrein secretion to 234 +/- 84 p. 100 of control values (n = 8). Since the perfusate lacks angiotensinogen, we decided to study the effect on kallikrein of the reconstitution of the renin-angiotensin system in the IPRK by adding angiotensinogen + angiotensin converting enzyme (AG + ACE) to the perfusion medium. After AG + ACE, PP rose to 107 +/- 4 mmHg, RPF decreased by 82 +/- 3 p. 100 as a consequence of the vasoconstrictor effect of angiotensin II, and renin release was suppressed. Again kallikrein secretion was stimulated and increased to 333 +/- 153 p. 100 of control values (n = 4). It is concluded 1) that kallikrein release is influenced by changes in PP but not in RPF on the IPRK. 2) that reconstitution of the renin-angiotensin system by addition of AG + ACE to the perfusate leads to vasoconstriction, suppression of renin release and a marked increase in kallikrein secretion.


Stimuli-responsive spherical brushes based on D-galactopyranose and 2-(dimethylamino)ethyl methacrylate.
Stimuli-responsive spherical brushes composed of 6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-D-galactopyranose (MAIGal) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) are prepared via atom transfer radical polymerization (ATRP) using cross-linked polystyrene nanoparticles covered with a thin layer of 2-(2-bromoisobutyryloxy)ethyl methacrylate (BIEM) as ATRP initiator by the "grafting from" approach. The stimuli-responsive behavior of the deprotected spherical PMAGal-b-PDMAEMA block copolymer brushes is investigated by dynamic light scattering and cryogenic transmission electron microscopy. A brush with arms containing 160 MAGal and 170 DMAEMA monomer units shows a significant contraction of the hydrodynamic radius from 20 to 70 °C at pH = 8 with a cloud point at ≈40 °C, whereas no LCST is detected at pH = 6 and 7 due to the protonation of the DMAEMA units. Aggregates occur at low temperatures and pH 8 due to intermolecular interactions between the chains of different brushes, which disappear above LCST, when the PDMAEMA chains fold back to the core of the brushes, exposing the glycopolymer chains to the outside.


Plasma and Nanomaterials: Fabrication and Biomedical Applications.
Application of plasma medicine has been actively explored during last several years. Treating every type of cancer remains a difficult task for medical personnel due to the wide variety of cancer cell selectivity. Research in advanced plasma physics has led to the development of different types of non-thermal plasma devices, such as plasma jets, and dielectric barrier discharges. Non-thermal plasma generates many charged particles and reactive species when brought into contact with biological samples. The main constituents include reactive nitrogen species, reactive oxygen species, and plasma ultra-violets. These species can be applied to synthesize biologically important nanomaterials or can be used with nanomaterials for various kinds of biomedical applications to improve human health. This review reports recent updates on plasma-based synthesis of biologically important nanomaterials and synergy of plasma with nanomaterials for various kind of biological applications.


[Youth Health Care Services guideline 'Early screening for hearing impairment, 0-19 years'].
The Youth Health Care guideline 'Early screening for hearing impairment, ages 0-19 years' draws the attention of all parties involved to the case finding of, notably, perceptive hearing loss; it helps workers in the Youth Health Care argue their referrals and improve the next steps in the process. Referrals always aim at ruling out perceptive hearing impairment. It is essential to diagnose and subsequently treat children with perceptive hearing impairment. It is important to keep track of the process after the referral. Screening methods are the Ewing test, the 'Compacte Amsterdamse paedo-audiometrische screener' (CAPAS) test and audiograms. Each age category has groups at risk for hearing impairment. Problems in neonates are a low specificity of the Ewing/CAPAS tests, treatment of middle ear disease without ruling out perceptive hearing impairment and absence of interdisciplinary agreements regarding the steps to be taken and the necessary feedback. Children with perceptive hearing loss should be diagnosed before 18 months of age. In the near future neonatal screening may detect congenital perceptive hearing impairment, but hearing impairment may still develop after the screening. Alertness with respect to hearing impairment will remain necessary in every consultation of a child.


Involvement of CD44 in mast cell proliferation during terminal differentiation.
By using the recently established culture system that reproduces the terminal differentiation process of connective tissue-type mast cells, we found significant transcriptional induction of CD44. As CD44 is a primary receptor for hyaluronan (HA), which is one of the major extracellular matrix components, we investigated the role of CD44 in cutaneous mast cells. When co-cultured with fibroblasts, mouse bone marrow-derived cultured mast cells (BMMCs) were found to form clusters in an HA-dependent manner. As compared with BMMCs derived from the wild-type mice, those from the CD44(-/-) mice exhibited impaired growth during the co-cultured period. Furthermore, in the peritoneal cavities and ear tissues, mature mast cells were fewer in number in the CD44(-/-) mice than in the wild-type mice. We investigated roles of CD44 in mast cell proliferation by reconstituting BMMCs into the tissues of mast cell-deficient, Kit(W)/Kit(W-v) mice, and found that the number of metachromatic cells upon acidic toluidine blue staining in the tissues transplanted with CD44(-/-) BMMCs was not significantly changed for 10 weeks, whereas that in the tissues transplanted with the CD44(+/+) BMMCs was significantly increased. These results suggest that CD44 plays a crucial role in the regulation of the cutaneous mast cell number.


Immunogenicity and safety of three aluminium hydroxide adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) compared with standard IPV in young infants in the Dominican Republic: a phase 2, non-inferiority, observer-blinded, randomised, and controlled dose investigation trial.
Cost and supply constraints are key challenges in the use of inactivated polio vaccine (IPV). Dose reduction through adsorption to aluminium hydroxide (Al) is a promising option, and establishing its effectiveness in the target population is a crucial milestone in developing IPV-Al. The aim of this clinical trial was to show the non-inferiority of three IPV-Al vaccines to standard IPV. In this phase 2, non-inferiority, observer-blinded, randomised, controlled, single-centre trial in the Dominican Republic, healthy infants aged 6 weeks, not previously polio vaccinated, were allocated after computer-generated randomisation by block-size of four, to receive one of four IPV formulations (three-times reduced dose [1/3 IPV-Al], five-times reduced dose [1/5 IPV-Al], ten-times reduced dose [1/10 IPV-Al], or IPV) intramuscularly in the thigh at 6, 10, and 14 weeks of age. The primary outcome was seroconversion for poliovirus types 1, 2, and 3 with titres more than or equal to four-fold higher than the estimated maternal antibody titre and more than or equal to 8 after three vaccinations. Non-inferiority was concluded if the lower two-sided 90% CI of the seroconversion rate difference between IPV-Al and IPV was greater than -10%. The safety analyses were based on the safety analysis set (randomly assigned participants who received at least one trial vaccination) and the immunogenicity analyses were based on the per-protocol population. This study is registered with ClinicalTrials.gov registration, number NCT02347423. Between Feb 2, 2015, and Sept 26, 2015, we recruited 824 infants. The per-protocol population included 820 infants; 205 were randomly assigned to receive 1/3 IPV-Al, 205 to receive 1/5 IPV-Al, 204 to receive 1/10 IPV-Al, and 206 to receive IPV. The proportion of individuals meeting the primary endpoint of seroconversion for poliovirus types 1, 2, and 3 was already high for the three IPV-Al vaccines after two vaccinations, but was higher after three vaccinations (ie, after completion of the expanded programme of immunisation schedule): 1/3 IPV-Al 98·5% (n=202, type 1), 97·6% (n=200; type 2), and 99·5% (n=204, type 3); 1/5 IPV-Al: 99·5% (n=204, type 1), 96·1% (n=197, type 2), and 98·5% (n=202, type 3); and 1/10 IPV-Al: 98·5% (n=201, type 1), 94·6% (n=193, type 2), and 99·5% (n=203, type 3). All three IPV-Al were non-inferior to IPV, with absolute differences in percentage seroconversion for each poliovirus type being greater than -10% (1/3 IPV-Al type 1, -1·46 [-3·60 to 0·10], type 2, -0·98 [-3·62 to 1·49], and type 3, -0·49 [-2·16 to 0·86]; 1/5 IPV-Al type 1, -0·49 [-2·16 to 0·86], type 2, -2·45 [-5·47 to 0·27], and type 3, -1·46 [-3·60 to 0·10]; and 1/10 IPV-Al type 1, -1·47 [-3·62 to 0·10], type 2, -3·94 [-7·28 to -0·97], and type 3, -0·49 [-2·17 to 0·86]). Three serious adverse events occurred that were unrelated to the vaccine. The lowest dose (1/10 IPV-Al) of the vaccine performed well both after two and three doses. Based on these results, this new vaccine is under investigation in phase 3 trials. Bill & Melinda Gates Foundation.


[Second primary tumors in patients with carcinoma of the head and neck].
With improved loco-regional control of cancer of the head and neck, second primary tumors (SPT) have an increasingly negative impact on survival. The appearance of SPT depends on the location and extension of the primary and is associated with lower survival. SPT were studied in a series of 1493 previously untreated patients with carcinoma of the head and neck and a minimum follow-up of 2 years. SPT occurred in 6.3% (96/1493). SPT were associated with the following primary tumor sites: 10.8% (57/727) larynx, 4% (6/153) hypopharynx, 4% (16/404) oral cavity, and 4% (6/153) oropharynx. Forty-three percent (42.7%) of SPT were carcinomas of the head and neck, 27% bronchogenic carcinomas, and 17.7% esophageal carcinomas. Survival at 6 months, 1 year, 3 years, and 5 years of patients diagnosed as SPT was 62%, 43%, 21%, and 16%, respectively.


UV-b-induced cataract model in brown-Norway rat eyes combined with preadministration of buthionine sulfoximine.
In order to develop a more adequate ultraviolet (UV)-induced cataract model, a combination of l-buthionine sulfoximine (BSO) treatment was applied to experimental animals. A single administration of BSO 4 mmol/kg caused reduced glutathione concentration until experimental day 8. In the 0.067-J/cm2 UV-B irradiation experiment, the light-scattering intensity of the anterior lens cortex of the combination group was significantly higher than that of the other groups during the second week after irradiation commenced. After the fourth experimental week, however, there was no significant difference between the group treated by UV-B alone and the combination group. In the 0.2-J/cm2 UV-B irradiation experiment, anterior polar cataract was seen in the group receiving UV-B alone, as already reported, 6 weeks after starting UV irradiation. Meanwhile, in the combination group, shallow cortical opacity was seen at 26 weeks after the start of experiment in the deeper lenticular layer which was separated from the anterior subcapsular opacity. This anterior shallow cortical opacity seemed to move towards the nuclear region during the time course of the experiment. The results of this experiment suggested that the BSO treatment accelerated cataractogenesis through additional UV-B irradiation. Although more experiments are needed, this model is useful in investigating the connection between UV-B and other cocataractogenic factors in age-related cataract in humans.


[Smoking prevalence and the risk of developing ischemic heart disease in men aged 20 to 69].
The authors studied the incidence of smoking among 20-69 years old males and its relation to ischemic heart disease. Ischemic heart disease morbidity and intermittent claudication was highest in males who have been smoking for more than 30 years. Statistical data indicate that the age of beginning of smoking is of more importance in the development of ischemic heart disease as compared with the duration of smoking. Prophylactic measures are discussed with consideration of the obtained data.


Dural sinus thrombosis in melioidosis: the first case report.
Melioidosis which is infection with Burkholderia pseudomallei, is an important cause of sepsis in India, southeast Asia and northern Australia. Mortality is high and treatment is problematic. Neurological melioidosis is unusual but meningoencephalitis, encephalomyelitis and brain microabscess can occur Dural sinus thrombosis is not an uncommon cerebrovascular disorder with various etiologies. Hypercoagulable state, pregnancy, dehydration, certain blood dyscrasia and contraceptive pills are common causes however meningitis and local head & neck infections may lead to this condition. Dural sinus thrombosis complicating septicemic melioidosis has never been reported. The authors report a 42-year-old Thai man suffering from septicemic melioidosis with dural sinus thrombosis. He had high fever, headache, left hemiparesis, focal seizure and increased intracranial pressure. Diabetes and mild alcoholic cirrhosis were diagnosed in this admission. CT scan, MRI brain and MRV revealed superior saggital sinus thrombosis with complicating venous infarction over right posterior parietal lobe. Hemoculture demonstrated Burkholderia pseudomallei and CSF was acellular Investigations for causes of dural sinus thrombosis were all negative. This patient gradually improved after treatment with ceftazidime, antiepileptic drug and heparin without clinical recurrence. Neuromelioidosis is a rare syndrome that may present as brain abscess, encephalitis or meningoencephalitis. The authors report dural sinus thrombosis associated with septicemic melioidosis. The authors' hypothesis of venous thrombosis in the presented case is sepsis induced hypercoagulable state. Physicians should be aware of cerebral venous thrombosis in case of suspicious melioidosis with neurological involvement. Prompt treatment with intravenous heparin and antibiotic is potentially effective.


The development of a comprehensive risk-management program for prescription opioid analgesics: researched abuse, diversion and addiction-related surveillance (RADARS).
OBJECTIVE. Beginning in the late 1990's a marked increase in abuse of OxyContin emerged, which led to the development and establishment of a proactive surveillance program to monitor and characterize abuse, named the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS) System. The main goal of RADARS was to develop proactive, timely and geographically sensitive methods to assess the abuse and diversion of OxyContin, along with a number of other Schedule II and III opioids with the aim of using this information to guide risk reduction interventions. Thus, its major focus was the detection of abuse of OxyContin and other commonly prescribed opioid analgesics at the three-digit ZIP code level across the country utilizing a number of different detection systems. The detection systems selected were: (1) Quarterly-surveys of drug abuse experts who are knowledgeable about cases of prescription drug abuse; (2) Surveys of law enforcement agencies that detect diversion of prescription drugs; and (3) Poison Control Center reports of intentional misuse or abuse of prescription opioids. Collectively, the three systems provide overlapping coverage of over 80% of the nation's 973 three-digit ZIP codes. Preliminary results indicate that prescription drug abuse is prevalent nationwide, but it seems to be heavily localized in rural, suburban and small urban areas. Our results also indicate that hydrocodone and extended and immediate release oxycodone products are by far the most widely abused drugs in the country, but the abuse of all prescription opioids seems to have grown over the 14 quarters since the inception of RADARS. The next step in these studies is to develop regionally specific, risk-minimization-strategies, which is the goal of all risk-management programs. If successful, RADARS will serve as a prototype of such programs for any new drug approved that has measurable abuse potential.


Pathophysiology of Eosinophilic Esophagitis.
Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.


Twist mediates suppression of inflammation by type I IFNs and Axl.
Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFalpha production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFalpha production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFalpha production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-kappaB-dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFalpha production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.