Redefining postoperative surveillance after endovascular aneurysm repair: recommendations based on 5-year follow-up in the US Zenith multicenter trial.
Recommended postoperative surveillance after endovascular aneurysm repair (EVAR) includes serial contrast-enhanced CT scans. The cumulative deleterious effect on renal function, radiation exposure, and significant cost of this surveillance regimen are all problematic. However, there are scant data to support modulation of current post-EVAR surveillance regimens. The study comprised patients who underwent EVAR as part of the prospective multicenter pivotal (phase II) and continued-access (phase III) US Zenith Endovascular (Cook, Bloomington, Ind) graft trials. A core lab prospectively recorded patient data. A composite aneurysm-related morbidity (ARM) variable was calculated to include aneurysm rupture, open conversion, any secondary intervention, limb thrombosis, migration, renal morbidity, or aneurysm-related death. The long-term freedom from ARM as a function of the presence or cumulative absence of any endoleak at 1, 6, and 12 months was analyzed. The potential additive predictive utility of aneurysm sac shrinkage (>/=5 mm) was assessed at 12 months. The instructions for use for aortic neck anatomy (>/=15 mm length, 18 to 28 mm diameter, </=60 degrees angulation) were followed. EVAR was done in 739 patients (mean follow-up, 29.9 +/- 17.1 months). Freedom from endoleak at 1 month was highly predictive (P < .001) of reduced ARM: freedom from ARM was 92.3%, 89.8%, 85.2%, 83.1% and 83.1 % at 1, 2, 3, 4, and 5 years, respectively, in patients without endoleak (83.1%) and 75%, 67.1%, 61.5%, 55.9%, and 55.9% in patients with endoleak (16.9%). Cumulative absence of endoleak at 1 year (77.6%) was associated with 94%, 91.5%, 88.1%, 85.8%, and 85.8% 1- to 5-year freedom from ARM vs 73.3%, 66.7%, 56.6%, 52.5%, and 52.5% in patients with endoleak </=1 year (22.4%), P < .001. In patients without endoleak at 12 months, the subsequent risk of any ARM was 8.2% (5-year risk, 14.2%; 1-year risk, 6.0%). In patients with significant sac shrinkage (>/=5 mm) and cumulative absence of endoleak at 12 months, the subsequent risk of an ARM was 5.3% (5-year risk, 11.1%; 1-year risk, 5.8%). Absence of endoleak at 30 and 365 days predicted greatly improved long-term freedom from ARM compared with early endoleak. A new EVAR surveillance regimen is recommended that modulates the intensity and frequency of postoperative imaging based on these early outcomes. In patients without early endoleak, the 6-month surveillance is eliminated, and aortic ultrasound is suggested for long-term surveillance >1 year. In most patients, this reduced surveillance regimen would be appropriate and could improve patient safety by reducing the cumulative deleterious effects of intravenous contrast and radiation exposure while also reducing health care costs. These subjective recommendations would be ideally validated in a randomized, prospective trial.


Differences in the fatty acid metabolism of visceral adipose tissue in postmenopausal women.
Visceral fat accumulation and metabolic syndrome incidence among women increase after menopause; therefore, fat metabolic changes and fat redistribution may occur according to menstrual status. The aim of our study was to clarify differences in subcutaneous and visceral adipose tissue metabolism between premenopausal and postmenopausal women, using metabolomics. Thirty-nine (16 premenopausal and 23 postmenopausal) women were recruited through elective gynecologic surgery, and both subcutaneous and visceral adipose tissues were collected during surgical operation. Metabolite profiling of adipose tissue was performed by capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Sedoheptulose 7-phosphate, a midproduct of the pentose phosphate pathway, was significantly higher (P < 0.05) in visceral adipose tissues of premenopausal women. Dihydroxyacetone phosphate and fructose-1,6-biphosphate, midproducts of glycolysis, were significantly higher (P < 0.05) in subcutaneous adipose tissues of postmenopausal women. The concentrations of fatty acid metabolites-heptanoate (C7:0; premenopausal vs postmenopausal, 4.07 [0.72] vs 2.64 [0.28] nmol/g), octanoate (C8:0; 3.52 [0.29] vs 5.20 [0.29] nmol/g), and pelargonate (C9:0; 8.03 [0.49] vs 10.66 [0.44] nmol/g)-in the visceral fat (but not in subcutaneous fat) of postmenopausal women were significantly higher (P < 0.05) than those in the visceral fat of premenopausal women. Fatty acid metabolites increase in visceral fat (but not in subcutaneous fat) after menopause. The change in fatty acid metabolism in visceral adipose tissues might be related to metabolic syndrome in postmenopausal women.


Lack of costimulation by both sphingomyelinase and C2 ceramide in resting human T cells.
Resting T cells require a signal transduced through their antigen-specific T-cell receptor (TCR) and an antigen-independent costimulatory signal in order to proliferate and become activated. Ligation of the CD28 receptor costimulates T-cell proliferation and is critical to correct T-cell function. A putative effector of CD28-mediated costimulation is the sphingomyelinase enzyme, which generates the potent second messenger ceramide. We have examined the role of sphingomyelinase and C2 ceramide for their ability to costimulate resting human T cells. We observed that neither sphingomyelinase nor C2 ceramide could costimulate human T-cell proliferation in combination with anti-CD3 antibody, whereas CD80, a natural CD28 ligand, was strongly costimulatory. Surprisingly, both sphingomyelinase and C2 ceramide strongly inhibited the proliferation of resting T cells stimulated through TCR and CD28 receptors. Despite these inhibitory effects, neither sphingomyelinase nor C2 ceramide induced apoptosis and we found that upregulation of activation markers CD25 and CD69 could still occur in the presence of sphingomyelinase/C2 ceramide. These data indicate that neither sphingomyelinase nor C2 ceramide can substitute for CD28 costimulation and that these molecules may be involved in negatively regulating T-cell proliferation.


Medicinal plants with anti-inflammatory activities from selected countries and regions of Africa.
Various nonsteroidal anti-inflammatory drugs have been shown to reduce pain and inflammation by blocking the metabolism of arachidonic acid by isoform of cyclooxygenase enzyme, thereby reducing the production of prostaglandin. Sadly, there are many side effects associated with the administration of nonsteroidal anti-inflammatory drugs. However, there are medicinal plants with anti-inflammatory therapeutic effects with low or no side effects. The Afri-can continent is richly endowed with diverse medicinal plants with anti-inflammatory activities that have been shown to be effective in the treatment of inflammatory conditions in traditional medicine. Interestingly, scientists have examined some of these African medicinal plants and documented their biological and therapeutic activities. Unfortunately, medicinal plants from different countries in Africa with anti-inflammatory properties have not been documented in a single review paper. It is important to document the ethnobotanical knowledge and applications of anti-inflammatory medicinal plants from selected countries representing different regions of the African continent. This paper therefore documents anti-inflammatory activities of various medicinal plants from different geographical regions of Africa with the aim of presenting the diversity of medicinal plants that are of traditional or therapeutic use in Africa.


Surfactant regulates pulmonary fluid balance in reptiles.
Reptilian lungs are potentially susceptible to fluid disturbances because they have very high pulmonary fluid filtration rates. In mammals, pulmonary surfactant protects the lung from developing alveolar edema. Reptiles also have an order of magnitude more surfactant per square centimeter of respiratory surface area compared with mammals. We investigated the role of reptilian surfactant 1) in the entry of vascularly derived fluid into the alveolar space of the isolated perfused lizard (Pogona vitticeps) lung and 2) in the removal of accumulated fluid from the alveolar space of the isolated perfused turtle (Trachemys scripta) lung by both the pulmonary venous and lymphatic circulations. The flux of fluorescent (fluorescein isothiocyanate) inulin from the vasculature into the alveolar compartment increased 60% after the removal of surfactant, but capillary fluid filtration over a 10-min period was not affected. Surfactant removal decreased alveolar inulin clearance by both the pulmonary venous circulation and the pulmonary lymphatic system approximately 1.5- and 3-fold, respectively. In reptiles, fluid flux from capillary to air space must occur indirectly via the interstitium. In the absence of surfactant, this may result in interstitial drying, which affects both pulmonary venous and pulmonary lymphatic clearance of alveolar fluid.


Scaling characteristics of one-dimensional fractional diffusion processes in the presence of power-law distributed random noise.
Here, we present results of numerical simulations and the scaling characteristics of one-dimensional random fluctuations with heavy-tailed probability distribution functions. Assuming that the distribution function of the random fluctuations obeys Lévy statistics with a power-law scaling exponent, we investigate the fractional diffusion equation in the presence of μ-stable Lévy noise. We study the scaling properties of the global width and two-point correlation functions and then compare the analytical and numerical results for the growth exponent β and the roughness exponent α. We also investigate the fractional Fokker-Planck equation for heavy-tailed random fluctuations. We show that the fractional diffusion processes in the presence of μ-stable Lévy noise display special scaling properties in the probability distribution function (PDF). Finally, we numerically study the scaling properties of the heavy-tailed random fluctuations by using the diffusion entropy analysis. This method is based on the evaluation of the Shannon entropy of the PDF generated by the random fluctuations, rather than on the measurement of the global width of the process. We apply the diffusion entropy analysis to extract the growth exponent β and to confirm the validity of our numerical analysis.


Pilot study of a school-based parent training program for preschoolers with ASD.
This study investigated the feasibility and preliminary effectiveness of a parenting training program designed for early intervention and early childhood special education (EI/ESCE) programs serving students with autistic spectrum disorders. Thirteen teachers representing three intermediate school districts implemented the intervention with 27 students and their parents. Eighty-nine percent of families completed the program. From pre- to post-intervention parents improved their use of the treatment strategies and children increased their rate of language during a parent-child interaction in their home. Parents and teachers reported significant gains in child mastery of social-communication skills and teachers, but not parents, reported a significant decrease in social impairment. Parents reported a significant decrease in parenting stress. Both groups rated the intervention highly in regard to treatment acceptability, perceived effectiveness, and usability. Findings suggest that this intervention can be feasibly implemented in public EI/ECSE settings, filling an important gap in services for intervention programs serving children with autistic spectrum disorders.


Development of an ELISA for Measurement of Urinary 3-Hydroxypropyl Mercapturic Acid (3-HPMA), the Marker of Stroke.
We previously observed an inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, through its measurement by liquid chromatography with tandem mass spectrometry (LC-MS/MS). However, the cost of equipment for LC-MS/MS and its maintenance fee is very expensive and a cost-efficient method is required. In this study, we have developed a sensitive enzyme-linked immunosorbent assay (ELISA) system to measure 3-HPMA using a chicken antibody recognizing 3-HPMA-conjugated chicken albumin as antigen. Linearity to measure 3-HPMA was obtained from 0 to 10 μM, indicating that this ELISA system is useful for measurement of urine 3-HPMA. It was confirmed that 3-HPMA in urine of stroke patients decreased significantly compared with that of control subjects using the ELISA system. Using the ELISA kit, it became possible to evaluate the risk of brain stroke by not only plasma but also by urine. These results confirm that shortage of glutathione to detoxify acrolein is one of the major causes of stroke incidence. Our method contributes to maintenance of quality of life (QOL) of the elderly.


Liposomal blockade of the reticuloendothelial system: improved tumor imaging with small unilamellar vesicles.
The reticuloendothelial system of mice bearing EMT6 tumors was effectively blocked by intravenous injections of small unilamellar vesicles that incorporated a 6-aminomannose derivative of cholesterol in the lipid bilayer. Neutral liposomes loaded with indium-111-nitrilotriacetic acid were then injected. Fifty percent more radioactivity was deposited in tumors of the animals with blocked reticuloendothelial systems than in controls. Twenty-four hours after the injection of radioactive vesicles, well-defined tumor images were observed in whole-body gamma camera scintigraphs. Biodistribution studies showed that tumors from animals with blocked reticuloendothelial systems had more than twice the radioactivity per gram than any other tissue analyzed.


Chromosome 9: linkage for borderline personality disorder features.
A large-scale twin study implicated genetic influences on borderline personality disorder (BPD) features, with a heritability estimate of 42%. To date, no genome-wide linkage study has been conducted to identify the genomic region(s) containing the quantitative trait loci that influence the manifestation of BPD features. We conducted a family-based linkage study using Merlin regress. The participating families were drawn from the community-based Netherlands Twin Register. The sample consisted of 711 sibling pairs with phenotype and genotype data, and 561 additional parents with genotype data. BPD features were assessed on a quantitative scale. Evidence for linkage was found on chromosomes 1, 4, 9, and 18. The highest linkage peak was found on chromosome 9p at marker D9S286 with a logarithm of odds score of 3.548 (empirical P=0.0001). To our knowledge, this is the first linkage study on BPD features and shows that chromosome 9 is the richest candidate for genes influencing BPD. The results of this study will move the field closer to determining the genetic etiology of BPD and may have important implications for treatment programs in the future. Association studies in this region are, however, warranted to detect the actual genes.


Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis.
There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Taken together, angiotensin II can promote vasoconstriction, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular risk factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effects of ACE inhibitors on cardiovascular events beyond blood pressure reduction.


Five-year longitudinal changes in quantitative spinal cord MRI in multiple sclerosis.
The spinal cord (SC) is highly relevant to disability in multiple sclerosis (MS), but few studies have evaluated longitudinal changes in quantitative spinal cord magnetic resonance imaging (SC-MRI). The aim of this study was to characterize the relationships between 5-year changes in SC-MRI with disability in MS. In total, 75 MS patients underwent 3 T SC-MRI and clinical assessment (expanded disability status scale (EDSS) and MS functional composite (MSFC)) at baseline, 2 and 5 years. SC-cross-sectional area (CSA) and diffusion-tensor indices (fractional anisotropy (FA), mean, perpendicular, parallel diffusivity (MD, λ⊥, λ||) and magnetization transfer ratio (MTR)) were extracted at C3-C4. Mixed-effects regression incorporating subject-specific slopes assessed longitudinal change in SC-MRI measures. SC-CSA and MTR decreased (p = 0.009, p = 0.03) over 5.1 years. There were moderate correlations between 2- and 5-year subject-specific slopes of SC-MRI indices and follow-up EDSS scores (Pearson's r with FA = -0.23 (p < 0.001); MD = 0.31 (p < 0.001); λ⊥ = 0.34 (p < 0.001); λ|| = -0.12 (p = 0.05), MTR = -0.37 (p < 0.001); SC-CSA = -0.47 (p < 0.001) at 5 years); MSFC showed similar trends. The 2- and 5-year subject-specific slopes were robustly correlated (r = 0.93-0.97 for FA, λ⊥, SC-CSA and MTR, all ps < 0.001). In MS, certain quantitative SC-MRI indices change over 5 years, reflecting ongoing tissue changes. Subject-specific trajectories of SC-MRI index change at 2 and 5 years are strongly correlated and highly relevant to follow-up disability. These findings suggest that individual dynamics of change should be accounted for when interpreting longitudinal SC-MRI measures and that measuring short-term change is predictive of long-term clinical disability.


Improving health care, Part 2: A clinical improvement worksheet and users' manual.
Small tests of change can be conducted in everyday clinical practice, thereby turning the health care delivery team into reflective practitioners who can learn from, and improve on, their work. CLINICAL IMPROVEMENT WORKSHEET AND USERS' MANUAL--CASE STUDY: The worksheet has been designed as a simple tool for applying clinical improvement to the core clinical delivery process. A carpal tunnel surgery (CTS) team was formed to improve outcomes and reduce costs for patients and to promote improvements in quality and value. The team wanted to determine if surgical patients treated with local anesthesia in an ambulatory setting have superior satisfaction with care, comparable clinical and functional outcomes, and lower medical (and social) costs. For the first time, standardized assessments of patient case mix, treatment processes, and health outcomes were designed into the delivery process by gathering data from the patient and from the surgeon presurgery and 4 weeks and 12 weeks postsurgery. Results for the first 49 of 50 to 100 consecutive patients show improved outcomes and reductions in costs, from $937 to $405 per patient. Even though CTS was selected to be a quick and noncontroversial opportunity, considerable effort had to be expended to ensure that all clinicians and other affected staff would understand and support "the new way". "Ramp up" improvements as time passes, more and more change trials are conducted and their complexity increases. To ease implementation of changes, teams can diagram core process "components" and attach measures, use flowcharts to plan and monitor implementation and use change management thinking to help sharpen the plan and anticipate problems.


L-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or L-Dopa history.
In Parkinson's disease, the efficacy of l-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson's disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of l-Dopa treatment determines development of l-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with l-Dopa (10mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to l-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting l-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with l-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying l-Dopa treatment until Parkinson's disease symptoms become more severe does not delay the development of l-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia.


32 species validation of a new Illumina paired-end approach for the development of microsatellites.
Development and optimization of novel species-specific microsatellites, or simple sequence repeats (SSRs) remains an important step for studies in ecology, evolution, and behavior. Numerous approaches exist for identifying new SSRs that vary widely in terms of both time and cost investments. A recent approach of using paired-end Illumina sequence data in conjunction with the bioinformatics pipeline, PAL_FINDER, has the potential to substantially reduce the cost and labor investment while also improving efficiency. However, it does not appear that the approach has been widely adopted, perhaps due to concerns over its broad applicability across taxa. Therefore, to validate the utility of the approach we developed SSRs for 32 species representing 30 families, 25 orders, 11 classes, and six phyla and optimized SSRs for 13 of the species. Overall the IPE method worked extremely well and we identified 1000s of SSRs for all species (mean = 128,485), with 17% of loci being potentially amplifiable loci, and 25% of these met our most stringent criteria designed to that avoid SSRs associated with repetitive elements. Approximately 61% of screened primers yielded strong amplification of a single locus.


History of Periodontitis Diagnosis and Edentulism as Predictors of Cardiovascular Disease, Stroke, and Mortality in Postmenopausal Women.
Few studies have reported associations between periodontitis and cardiovascular disease (CVD) risk in older women, which is the objective of the present investigation. Participants were 57 001 postmenopausal women ages 55 to 89 years (mean 68 years; >85% 60 and older) who were enrolled (1993-1998) in the Women's Health Initiative Observational Study, and were without known CVD when history of periodontitis and edentulism was assessed by questionnaire at study Year-5 (1998-2003). There were 3589 incident CVD events and 3816 total deaths during a mean follow-up of 6.7 years. In multivariable analysis, periodontitis was not associated with CVD events, but was associated with higher total mortality (hazard ratio (HR)=1.12, 95% CI: 1.05-1.21). Edentulism was associated with higher age- and smoking-adjusted risks of CVD (HR=1.42, 95% CI: 1.27-1.59) and mortality (HR=1.47, 95% CI: 1.32-1.63). Further adjustment eliminated the association with CVD, but mortality remained significantly increased (HR=1.17, 95% CI: 1.02-1.33). Stratification on age, race-ethnicity, smoking, and diabetes mellitus yielded comparable results; however, edentulism was more strongly associated with CVD in women reporting ≥1 dental visit (HR=1.57) compared with <1 visit (HR 1.03, interaction P=0.004) annually. In community-dwelling older women, edentulism was associated with increased risks of CVD and total mortality, and presence of periodontitis, which is more prevalent than edentulism, was associated with 17% higher mortality rate. These findings suggest that improving periodontal condition of the general population could reduce overall mortality.


[Worker diet in Brazil: a review of Brazilian scholarship on the topic].
Diet is a vital health question for workers. This review of the related literature sought to identify the elements that could contribute to an examination of the topic and help ascertain how it has been approached from a historical perspective. Our bibliographic research was based primarily on the Scientific Electronic Library On-line, from which pertinent articles were selected for analysis, without regard to year of publication. Among other findings, studies on worker health proved scarce; moreover, the few studies that have explored nutrition focus on the Worker's Food Program, primarily from a quantitative perspective and without taking the category of 'work process' into account in their analyses.


Anterior tibial tubercle elevation in the young adult.
A modification of Maquet's procedure, longitudinal proximal tibial osteotomy, was performed on 36 adults under the age of 40. The tibial tubercle was elevated between 2.0 and 2.5 cm. Fourteen were operated on for significant osteochondral injury to the underside of the patella, including patellar fracture; 16 were operated on because of osteoarthrotic change in the patellofemoral joint secondary to recurrent subluxation. Six were operated on because of pain persisting after previous patellectomy. Follow-up ranged between 2 and 5 years, was at least 2 years, and averaged 3.53 years. A good result was determined to be one in which the patient had no pain requiring medication or activity limitation; a poor result was designated when the patient had pain requiring medication or activity limitation. The success rate among the trauma or fracture group was 94 per cent, among the subluxation group 88 per cent, and among the postpatellectomy group 66 per cent. Failures included unrecognized osteoarthrosis of the tibiofemoral joint, psychiatric problems, a reflex sympathetic dystrophy, a compensation neurosis, a failure to correct excessive knee valgus with recurrent subluxation, and a fall displacing the operation. Serious complications, osteomyelitis and a displaced graft resulting from a postoperative fall, occurred at a rate of 5 per cent; minor complications, tenuous skin healing and tibial tubercle shingle fractures, occurred at a rate of 19 per cent. This operation is indicated only for patients with osteoarthrosis of the patellofemoral joint and is contraindicated in the presence of tibiofemoral osteoarthrosis. High success rates are attributed to careful attention to indications and contraindications and to the design and details of performing the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)


Glucagon fill rates and cost among children and adolescents with type 1 diabetes in the United States, 2011-2021.
To characterize glucagon fill rates and costs among youth with type 1 diabetes mellitus (T1DM). Claims-based analysis of commercially-insured youth with T1DM included in OptumLabs® Data Warehouse between 2011 and 2021. Glucagon fill rates and costs were calculated overall and by formulation (injectable, intranasal, autoinjector, and pre-filled syringe). Sociodemographic and clinical factors associated with glucagon fills were examined using Cox regression. We identified 13,267 children with T1DM (76.4% non-Hispanic White). Over mean follow-up of 2.81 years (SD 2.62), 70.0% filled glucagon, with stable fill rates from 2011 to 2021. Intranasal glucagon had rapid uptake following initial approval, and it accounted for almost half (46.6%) of all glucagon fills by 2021. Family income was positively associated with glucagon fills in a stepwise fashion (HR 1.39 [95% CI 1.27-1.52] for annual household income ≥$200,000 vs. <$40,000), while Black race was negatively associated with fills (HR 0.83 [95% CI 0.76-0.91]) compared to White race). Annual mean out-of-pocket costs ranged from $21-$68 (IQR $29-$44). Roughly 30% of commercially-insured youth with T1DM may lack access to unexpired glucagon, with significant disparities among Black and low-income patients. Health systems, clinicians, schools, and caregivers should work together to ensure children have reliable access to this critical medication.


Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication.
In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2'-C-methyl containing nucleosides, 2'-C-Me-cytidine, 2'-C-Me-uridine and 2'-C-Me-2'-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5'-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ∼550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.


[The intern's vein--the patient's nightmare?].
Punction of blood vessels is a necessity in modern medicine, but there is a paucity of knowledge about the close relation between vessels and nerves. We refer to two cases that show possible consequences of cannulation of v. cephalica and a. radialis. Both patients developed clinical symptoms and neurological findings indicating injury of the radial nerve. One of the patients is not likely to develop chronic neuropathic pain, but in the other patient the similar injury of the radial nerve has lead to chronic and disabling pain. We advise against using the distal part of v. cephalica (the intern's vein) as the first choice for training of inexperienced students. The vein should only be used in patients that lack other venous alternatives and in acute situations where quick infusions or blood transfusions are needed.


Conformational transitions of adsorption-responsive single diblock copolymers in homopolymer brushes.
Using self-consistent field calculations, we examine the effect of brush polydispersity on conformational transitions of single adsorption-active diblock copolymer chains embedded in inert polydisperse brushes. To represent the polydispersity, we adopt the continuous Schulz-Zimm chain length distributions, and three typical distributions are chosen such that a wide range of polydispersity is covered. A phase diagram of the diblock copolymer switches has been constructed showing that the first order phase transitions occupy a larger space in the case of polydisperse brushes. We further characterize these first order phase transitions by specifying their transition points, transition widths and transition barriers, where the latter two are particularly important as they determine the performance of the polymer switches. Our calculation indicates that polydispersity has different effect on the switching behavior depending on the lengths of both the active block and the inert block of the copolymer switch chain. In general, polydispersity improves the switching performance in the case of short active blocks, i.e. shorter or not very longer than the average length of the brush chains, and the corresponding energy barrier is smaller than a few kBT. In contrast, monodisperse brushes have the advantages when these two blocks are particularly long, i.e., lower transition barriers and fast switching. Notably, when the inert block approaches the average length of the brush chains, the transition barrier becomes almost zero in any case for monodisperse brushes, while a large finite value is still observed for that in polydisperse brushes. The complex interplay between the brush polydispersity and the switch behavior is attributed to the wide-range repulsions generated by the polydisperse brushes.


Establishment and Characterization of a Novel Caco-2 Subclone with a Similar Low Expression Level of Human Carboxylesterase 1 to Human Small Intestine.
Caco-2 cells predominantly express human carboxylesterase 1 (hCE1), unlike the human intestine that predominantly expresses human carboxylesterase 2 (hCE2). Transport experiments using Caco-2 cell monolayers often lead to misestimation of the intestinal absorption of prodrugs because of this difference, as prodrugs designed to increase the bioavailability of parent drugs are made to be resistant to hCE2 in the intestine, so that they can be hydrolyzed by hCE1 in the liver. In the present study, we tried to establish a new Caco-2 subclone, with a similar pattern of carboxylase expression to human intestine, to enable a more accurate estimation of the intestinal absorption of prodrugs. Although no subclone could be identified with high expression levels of only hCE2, two subclones, #45 and #78, with extremely low expression levels of hCE1 were subcloned from parental Caco-2 cells by the limiting dilution technique. Unfortunately, subclone #45 did not form enterocyte-like cell monolayers due to low expression of claudins and β-actin. However, subclone #78 formed polarized cell monolayers over 4 weeks and showed similar paracellular and transcellular transport properties to parental Caco-2 cell monolayers. In addition, the intestinal transport of oseltamivir, a hCE1 substrate, could be evaluated in subclone #78 cell monolayers, including P-glycoprotein-mediated efflux under nonhydrolysis conditions, unlike parental Caco-2 cells. Consequently, it is proposed that subclone #78 may provide a more effective system in which to evaluate the intestinal absorption of prodrugs that are intended to be hydrolyzed by hCE1.


The effect of Saffron supplementation on waist circumference, HA1C, and glucose metabolism: A systematic review and meta-analysis of randomized clinical trials.
Carotenoids (including zeaxanthin and lycopene) and phytosterols reportedly confer beneficial effects on metabolic profile and function, which is of clinical importance. Thus, we sought to review the saffron effects on waist circumstance (WC), fasting plasma glucose (FPG), and HA1C concentrations reported in Randomized Control Trials (RCTs). A comprehensive systematic electronic search was performed in PubMed/MEDLINE, Embase, Google Scholar, Cochrane, Web of sciences, and SCOPUS to identify RCTs up to February 2019 without any language restrictions. The pooled weighted mean difference (WMD) calculated with DerSimonian-Laird random. PRISMA guidelines adhered to for this meta-analysis. Nine articles with 12 arms containing 595 participants were included in this study. Our study found WC was significantly reduced (WMD: -2.18 cm, 95 % CI: -4.05, -0.32) and FPG (WMD: -6.54 mg/dl, 95 % CI: -10.22, -2.85) following saffron intervention. Subgroup analysis highlighted that FPG levels (WMD: -10.24 mg/dl, 95 % CI: -15.76, -4.72) reduced significantly when intervention duration was longer than twelve weeks. There was no significant effect on HA1C levels (WMD: -0.13 mg/dl, 95 % CI: -0.31, 0.04) following saffron intervention. In conclusion, the present study indicates beneficial effects on WC and FPG, following saffron supplementation.


Linear polynuclear helicates as a link between discrete supramolecular complexes and programmed infinite polymetallic chains.
The contribution of the solvation energies to the assembly of polynuclear helicates reduces the free energy of intermetallic repulsion, DeltaE(MM), in condensed phase to such an extent that stable D(3)-symmetrical tetranuclear lanthanide-containing triple-stranded helicates [Ln(4)(L4)(3)](12+) are quantitatively produced at millimolar concentrations, despite the twelve positive charge borne by these complexes. A detailed modelling of the formation constants using statistical factors, adapted to self-assembly processes involving intra- and intermolecular connections, provides a set of five microscopic parameters, which can be successfully used for rationalizing the stepwise generation of linear bi-, tri- and tetranuclear analogues. Photophysical studies of [Eu(4)(L4)(3)](12+) confirm the existence of two different binding sites producing differentiated metal-centred emission at low temperature, which transforms into single site luminescence at room temperature because of intramolecular energy funelling processes.


Elevated CO2 shifts the focus of tobacco plant defences from cucumber mosaic virus to the green peach aphid.
Elevation in CO(2) concentration broadly impacts plant physiological characteristics, which influences herbivores and biotrophic pathogens, which in turn regulate the plant defensive response. In this study, responses of tobacco plants to stress in the form of the green peach aphid, Myzus persicae (Sulzer), or cucumber mosaic virus (CMV), or both aphid and CMV combined were investigated in open-top chambers under ambient and elevated CO(2) concentrations. We measured aboveground biomass and foliar chlorophyll, nitrogen, non-structural carbohydrates, soluble protein, total amino acid and nicotine content in tobacco plants and also measured aphid population dynamics, body weight, honeydew production and anti-oxidative enzyme activities in individual aphids. Plants produced more secondary metabolites for defence in both CO(2) treatments when treated with aphid and CMV combined than with either alone. Aphid density significantly increased on CMV-infected tobacco plants (relative to uninfected plants) under ambient CO(2) but not under elevated CO(2). This suggests that plant defences against virus and aphid would be more efficient under elevated CO(2). Plant defence appears to shift from plant virus to aphid under increasing CO(2) levels, which highlights the potential influences of multiple biotic stressors on plants under elevated CO(2).


Raman spectroscopy, a potential tool in diagnosis and prognosis of castration-resistant prostate cancer.
We evaluated the feasibility of Raman spectroscopy (RS) in diagnosis and prognosis of castration-resistant prostate cancer (CRPC) in patients with prostate cancer (PC). Raman spectra are detected from PC cell lines (LNCaP and C4-2) and tissues using a Labram HR 800 RS. Then, principal component analysis (PCA) and support vector machine (SVM) are applied for prediction. A leave-one-out cross-validation is used to train and test the SVM. There are 50 qualified patients, including 33 with androgen-dependent prostate cancer (ADPC) and 17 with CRPC. The spectral changes at 1126, 1170, 1315 to 1338, and 1447 cm-1 between CRPC and ADPC are detected in both cells and tissues models, which are assigned to specific amino acids and DNA. PCA/SVM algorithm provided a sensitivity of 88.2% and a specificity of 87.9% for diagnosing CRPC tissues. Furthermore, 14 patients with ADPC progressed to CRPC within 12 months. These patients are separated into two groups depending on whether their cancers progressed to CRPC within 12 months. PCA/SVM could differentiate these two groups with a sensitivity of 85.7% and a specificity of 88.9%. RS has the potential in diagnosis and prognosis of CRPC in clinical practice.


Levels of TGFbeta1 in gingival crevicular fluid during a 21-day experimental model of gingivitis.
TGFbeta1 is a multifunctional growth factor with both pro- and anti-inflammatory properties. This study aimed to determine levels of TGFbeta1 in gingival crevicular fluid (GCF), serum and plasma in the early stages of gingival inflammation. A 21-day experimental model of gingivitis employing a split mouth design with a soft vinyl splint used to cover test teeth during brushing. Ten healthy volunteers (mean age 21 years; five males and five females). GCF and blood (with and without EDTA) was collected on days 0, 7, 14 and 21. GCF volumes were measured on a precalibrated Periotron 8000TM. Clinical indices of gingival inflammation and plaque levels were obtained after GCF sampling. Normal brushing resumed after GCF collection on day 21 and final samples were collected on day 35. TGFbeta1 and alkaline phosphatase (ALP) levels were determined using enhanced chemiluminescent methods. Clinical indices and GCF volumes increased at test sites during the 21-day test period. Concentrations of TGFbeta1 and ALP in GCF (test and control), serum and plasma did not change throughout the study (P > 0.3). However, total amounts of TGFbeta1 (pg sample-1) and ALP (mu IU sample-1) in GCF increased at test sites and were significantly higher than baseline values at days 7, 14 and 21 (P < 0.04). Control sites showed no variation in TGFbeta1 or ALP levels throughout the study period (P > 0.35). All parameters at test sites returned to control levels at day 35 (P > 0.3). The data indicate that GCF TGFbeta1 levels increase early in plaque-induced inflammation. Whether the biological consequence of this site-specific increase is pro- or anti-inflammatory in nature remains to be elucidated.


Improving the assessment of risk from pathogens in biosolids: fecal coliform regrowth, survival, enumeration, and assessment.
Reactivation or regrowth of fecal coliform bacteria in biosolids has recently become a concern due to knowledge that Class B materials may fail to meet this criterion after storage or even after land application. In this paper, data show the two types of fecal coliform increases that have been characterized: immediate reappearance of large concentrations directly after dewatering; and the rapid, but less immediate, increases that follow dewatering with some biosolids after dewatering. The latter phenomenon is shown to extend over a time period of days prior to gradual decrease in fecal coliform numbers. Modeling shows that anaerobic or fermentative growth cannot simulate the observed growth, but that a straightforward biokinetic model can duplicate the observed conditions if a doubling time of one hour is assumed, which is supported by literature. Thus regrowth cannot be ruled out as the underlying phenomenon.


Isolated traumatic avulsion of the flexor digitorum sublimis. A case report.
Like the FDP, the FDS may be avulsed at its insertion. The diagnosis can be made based on a history of resisted extension, palmar pain and tenderness, lack of FDS function, and inability to completely extend the DIP joint secondary to the looping affect of the FDS. In the seven reported cases of FDS rupture no surgical intervention was required. This case represents a case in which surgical intervention was required secondary to an isolated avulsion of the FDS in a football player.


Geometry of cell division in Staphylococcus aureus.
The process of division in Staphylococcus aureus was examined by phase-contrast microscopy. The organisms appeared to divide in three alternating perpendicular planes, with sister cells remaining attached to each other after division. The resulting point of attachment was usually not exactly at the point corresponding to the center of the previous septal disk. Moreover, sister cells often changed position with respect to one another while still remaining attached. These factors are apparently responsible for the irregularity of staphylococcal clumps. Studies with penicillin and the examination of thin sections in the electron microscope confirm the conclusion, based upon light microscopy, that successive divisions in S. aureus occur in perpendicular planes.


Congenitally corrected transposition of the great arteries in an 80 year old woman.
Congenitally corrected transposition of the great arteries (CCTGA) is a rare form of congenital heart disease characterised by atrioventricular as well as ventriculoarterial discordance. It is usually associated with a variety of severe intracardiac defects. Few patients with this abnormality survive past 50 years. An 80 year old woman was admitted to the hospital because of mild congestive heart failure. Cardiac examination revealed a 4/6 holosystolic and a 2/6 decrescendo diastolic murmur at the left sternal border. Radiography, echocardiography, and computed tomography confirmed newly diagnosed CCTGA without associated intracardiac defects.


Childhood obesity and adverse health effects in Hong Kong.
Hong Kong soon became aware of the importance of ensuring the optimum growth of their children with growth standards for Hong Kong being set out in 1962. By 1972 it was already clear that childhood obesity was emerging as a problem and increasing in prevalence and by 1987 an international workshop on nutrition, held in Hong Kong, was being alerted to this issue. Then 10 years later obesity featured as a major issue in the programme of the Asian Congress of Pediatrics with the local contributors highlighting the evidence already available in Hong Kong of the wide range of metabolic, cardiovascular, physical and psychological complications of obesity in the local community. The school health service was given a prominent role and there are now guidelines not only in relation to the standards of school lunches but also for the need to enhance the physical activity of children and involve a new educational community wide approach as part of a major co-coordinated effort within Hong Kong. Professional and community workers together with the government now have a comprehensive determination to tackle the challenge of obesity prevention. So Hong Kong intends to play a major role in the international response to the formation of the Global Alliance for the prevention of obesity and its associated chronic diseases.


Replacement of histidine 340 with alanine inactivates the group A Streptococcus extracellular cysteine protease virulence factor.
Streptococcus pyogenes expresses a highly conserved extracellular cysteine protease that is a virulence factor for invasive disease, including soft tissue infection. Site-directed mutagenesis was used to generate a His340Ala recombinant mutant protein that was made as a stable 40-kDa zymogen by Escherichia coli. Purified His340Ala protein was proteolytically inactive when bovine casein and human fibronectin were used as substrates. Wild-type 28-kDa streptococcal protease purified from S. pyogenes processed the 40-kDa mutant zymogen to a 28-kDa mature form, a result suggesting that the derivative protein retained structural integrity. The data are consistent with the hypothesis that His340 is an enzyme active site residue, an idea confirmed by recent solution of the zymogen crystal structure (T. F. Kagawa, J. C. Cooney, H. M. Baker, S. McSweeney, M. Liu, S. Gubba, J. M. Musser, and E. N. Baker, Proc. Natl. Acad. Sci. USA 97:2235-2240, 2000). The data provide additional insight into structure-function relationships in this S. pyogenes virulence factor.


Development of a plate-based assay for high-content analysis of individual untethered non-adherent cells.
Research involving non-adherent cell lines, primary cells and blood cells is definitely important, but its application in image-based assays, especially in high-content systems, is highly limited. Accordingly, efficient high-content methods to study non-adherent cells are needed not only to improve diagnostics but also for early screening of targeted drugs. A plate-based assay using adhesion reagents for multiparametric measurement with single non-adherent and non-anchored cells in a large cell population in high-content cytometry was developed and optimized. The cells preserved their identity even during extensive biomanipulations. The proposed method is highly robust for better imaging and can be used in various assays in different cellular backgrounds. Furthermore, as exemplary experiments, novel optimized assay protocols were used to study extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity after cell inhibition with imatinib in chronic myelocytic leukemia K562 cells, revealing the phosphorylation kinetics of ERK MAPK. The results showed that the proposed assay detects kinase phosphorylation with good sensitivity and may be used in rapid drug screening.


Experimentally induced bovine spongiform encephalopathy did not transmit via goat embryos.
Goats are susceptible to experimental challenge with bovine spongiform encephalopathy (BSE). This study set out to investigate whether the transmission of BSE could occur in goats following the transfer of embryos from experimentally infected donor females into uninfected recipient females. The results showed no evidence of transmissible spongiform encephalopathy disease in any of the offspring which developed from embryos from infected donors, nor indeed in any of the recipient females used as surrogate dams. In addition, there was no indication of experimental BSE spreading as either a venereal infection to males used in mating or by maternal transmission to offspring born naturally to experimentally infected donors, although numbers were small.


Connexin43 mutation causes heterogeneous gap junction loss and sudden infant death.
An estimated 10% to 15% of sudden infant death syndrome (SIDS) cases may stem from channelopathy-mediated lethal arrhythmias. Loss of the GJA1-encoded gap junction channel protein connexin43 is known to underlie formation of lethal arrhythmias. GJA1 mutations have been associated with cardiac diseases, including atrial fibrillation. Therefore, GJA1 is a plausible candidate gene for premature sudden death. GJA1 open reading frame mutational analysis was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing on DNA from 292 SIDS cases. Immunofluorescence and dual whole-cell patch-clamp studies were performed to determine the functionality of mutant gap junctions. Immunostaining for gap junction proteins was performed on SIDS-associated paraffin-embedded cardiac tissue. Two rare, novel missense mutations, E42K and S272P, were detected in 2 of 292 SIDS cases, a 2-month-old white boy and a 3-month-old white girl, respectively. Analysis of the E42K victim's parental DNA demonstrated a de novo mutation. Both mutations involved highly conserved residues and were absent in >1000 ethnically matched reference alleles. Immunofluorescence demonstrated no trafficking abnormalities for either mutation, and S272P demonstrated wild-type junctional conductance. However, junctional conductance measurements for the E42K mutation demonstrated a loss of function not rescued by wild type. Moreover, the E42K victim's cardiac tissue demonstrated a mosaic immunostaining pattern for connexin43 protein. This study provides the first molecular and functional evidence implicating a GJA1 mutation as a novel pathogenic substrate for SIDS. E42K-connexin43 demonstrated a trafficking-independent reduction in junctional coupling in vitro and a mosaic pattern of mutational DNA distribution in deceased cardiac tissue, suggesting a novel mechanism of connexin43-associated sudden death.


Correlating structure, morphology and properties of metal nanostructures by combining single-particle optical spectroscopy and electron microscopy.
The nanoscale morphology of metal nanostructures directly defines their optical, catalytic and electronic properties and even small morphological changes can cause significant property variations. On the one hand, this dependence allows for precisely tuning and exploring properties by shape engineering; next to advanced synthesis protocols, post-synthesis modification through tailored laser modification has become an emerging tool to do so. On the other hand, with this interconnection also comes the quest for detailed structure-property correlation and understanding of laser-induced reshaping processes on the individual nanostructure level beyond ensemble averages. With the development of single-particle (ultrafast) optical spectroscopy techniques and advanced electron microscopy such understanding can in principle be gained at the femtosecond temporal and atomic spatial scale, respectively. However, accessing both on the same individual nanostructure is far from straightforward as it requires the combination of optical spectroscopy and electron microscopy. In this Minireview, we highlight key studies from recent years that performed such correlative measurements on the same individual metal nanostructure either in a consecutive ex situ manner or in situ inside the electron microscope. We demonstrate that such a detailed correlation is critical for revealing the full picture of the structure-property relationship and the physics behind light-induced nanostructure modifications. We put emphasis on the advantages and disadvantages of each methodology as well as on the unique information that one can gain only by correlative studies performed on the same individual nanostructure and end with an outlook on possible further development of this field in the near future.


Prospective evaluation of positron emission tomography for the detection of groin node metastases from vulvar cancer.
We set out to determine the ability of positron emission tomography with fluorodeoxyglucose to detect groin lymph node metastases from vulvar cancer. From January 2000 to August 2001, patients with squamous cell cancer of the vulva undergoing radical excision and lymphadenectomy were offered preoperative positron emission tomography. The imaging and pathologic status of each patient and groin were compared, and the sensitivity, specificity, and predictive value of positron emission tomography in predicting nodal metastasis were determined. Fifteen patients underwent positron emission tomography prior to exploration of 29 groins. Six patients had positive scans, suggesting metastases in 8 groins. Pathologically, 5 patients had metastases in 9 groins, with positron emission tomography demonstrating metastases in 4 of 5 patients and 6 of 9 groins with disease. On a patient-by-patients basis, positron emission tomography had a sensitivity of 80%, specificity of 90%, positive predictive value of 80%, and negative predictive value of 90% in demonstrating metastases. On a groin-by-groin basis, positron emission tomography had a sensitivity of 67%, specificity of 95%, positive predictive value of 86%, and negative predictive value of 86%. Positron emission tomography was more accurate in detecting extranodal metastases than disease confined within the groin nodes (P = 0.048). Positron emission tomography is relatively insensitive in predicting lymph node metastasis, and a negative study is not a reliable surrogate for a pathologically negative groin. However, the high specificity suggests that positron emission tomography is useful in planning radiation therapy and as an adjunct to lymphatic mapping and sentinel lymph node dissection.


[Effects of Chinese onion' s root exudates on cucumber seedlings growth and rhizosphere soil microorganisms].
Taking the Chinese onion cultivars with different allelopathy potentials as the donor and cucumber as the accepter, this paper studied the effects of Chinese onion' s root exudates on the seedlings growth of cucumber and the culturable microbial number and bacterial community structure in the seedlings rhizosphere soil. The root exudates of the Chinese onion cultivars could promote the growth of cucumber seedlings, and the stimulatory effect increased with the increasing concentration of the root exudates. However, at the same concentrations of root exudates, the stimulatory effect had no significant differences between the Chinese onion cultivars with strong and weak allelopathy potential. The root exudates of the Chinese onion cultivars increased the individual numbers of bacteria and actinomyces but decreased those of fungi and Fusarium in rhizosphere soil, being more significant for the Chinese onion cultivar with high allelopathy potential (L-06). The root exudates of the Chinese onion cultivars also increased the bacterial community diversity in rhizosphere soil. The cloning and sequencing results indicated that the differential bacteria bands were affiliated with Actinobacteria, Proteobacteria, and Anaerolineaceae, and Anaerolineaceae only occurred in the rhizosphere soil in the treatment of high allelopathy potential Chinese onion (L-06). It was suggested that high concentration (10 mL per plant) of root exudates from high allelopathy potential Chinese onion (L-06) could benefit the increase of bacterial community diversity in cucumber seedlings rhizosphere soil.


Triage as an infrastructure of care: The intimate work of redistributing medical care in nursing homes.
This article explores how professionals in older persons care work on a triage system in the daily care setting. We follow how triage is introduced in older persons care organizations in The Netherlands, to deal with a scarcity of physicians and distribute care among health workers in the region. We offer a sociological analysis in which we use the notion of infrastructure and infrastructural work to study how professionals work with triage in the daily care setting. This study is based on a formative evaluation in which we as researchers both studied and contributed to the construction of the triage system by sharing and participating in reflexive infrastructural work practices. We show how this method enabled to gradually adjust the triage system to the daily practices of care delivery, taking the spatial-temporal setting of care into account. We argue that triage not only structures and simplifies but also opens up new ways of re-placing medical and care work, both professionally and geographically. As our results reveal, re-placing physicians has complex effects above and beyond the efficient deployment of medical staff. Triage as infrastructure not only changes the location, but also reconfigures the relationships physicians have with residents and nurse aids.


Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases.
Non-substrate-like inhibitors of glycosyltransferases are sought after as chemical tools and potential lead compounds for medicinal chemistry, chemical biology and drug discovery. Here, we describe the discovery of a novel small molecular inhibitor chemotype for LgtC, a retaining α-1,4-galactosyltransferase involved in bacterial lipooligosaccharide biosynthesis. The new inhibitors, which are structurally unrelated to both the donor and acceptor of LgtC, have low micromolar inhibitory activity, comparable to the best substrate-based inhibitors. We provide experimental evidence that these inhibitors react covalently with LgtC. Results from detailed enzymological experiments with wild-type and mutant LgtC suggest the non-catalytic active site residue Cys246 as a likely target residue for these inhibitors. Analysis of available sequence and structural data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.


A simple fluorimetric assay for pyridoxamine phosphate oxidase in erythrocyte haemolysates: effects of riboflavin supplementation and of glucose 6-phosphate dehydrogenase deficiency.
The formation of pyridoxal and its phosphate from pyridoxamine phosphate by red cell haemolysates was measured in a centrifugal analyser by the formation of the fluorescent adduct with semicarbazide. Pyridoxal phosphate was found to react more rapidly than pyridoxal, thus permitting a distinction between the two products, and hence the measurement of phosphatase activity. Activity of the enzyme, pyridoxamine phosphate:oxygen oxidoreductase (deaminating) EC 126.96.36.199 (PPO) was measured in haemolysates from 72 Gambian women with evidence of riboflavin deficiency, and was repeated after 6 weeks of placebo or riboflavin supplementation. Those who received the riboflavin supplement responded with a marked increase in PPO activity, which was matched by a decrease in the activation coefficient (AC) of erythrocyte NAD(P)H2:glutathione oxidoreductase, EC 220.127.116.11 (glutathione reductase, EGR). No difference between the supplemented and unsupplemented groups was observed in the capacity of haemolysates to hydrolyse pyridoxal 5-phosphate, nor in the extent of activation of erythrocyte L-aspartate:2-oxoglutarate aminotransferase EC 184.108.40.206. by pyridoxal phosphate. Although the three subjects with low levels of D-glucose 6-phosphate: NADP 1-oxidoreductase EC 18.104.22.168 (G6P-D) had, as expected, correspondingly low AC's of EGR, their unsupplemented activities of PPO were in the same low range as those of the G6P-D-normal subjects, and they responded as G6P-D-normal subjects did to riboflavin supplementation. PPO thus does not appear to resemble EGR in retaining its flavin coenzyme during riboflavin depletion.(ABSTRACT TRUNCATED AT 250 WORDS)


[Locoregional therapy with hypoxic liver perfusion in malignant neoplasms of the gallbladder. Preliminary experience].
We report four cases of advanced malignant cancer of the gallbladder treated with hypoxic hepatic perfusion. Hypoxic hepatic perfusion is currently used to treat diffuse hepatic metastases: the common hepatic artery is occluded with a balloon catheter and then a large amount of antiblastic solution is infused into the liver. Hypoxia and slow flow increase the effect of the drug on neoplastic tissue. Two sessions were performed in three patients with an interval ranging 2-4 months, while one patient underwent a single session. The drug was Mitomycin C, whose dose ranged 20-40 mg (mean: 30 mg). Blood filtration was performed after one of the six procedures only and can be considered unnecessary. Acute gastric bleeding appeared in a patient after the embolization of the right gastric artery with bucrylate during the first session performed to avoid drug reflux into gastric wall arteries. No other technical or clinical complications occurred. An objective morphological response (tumor necrosis or reduction in size > 50%) was observed in all patients after the first session. CT findings were stable in two of three patients submitted to a second session, while local progression was observed in the other patient. Complete clinical response was achieved in all symptomatic patients. No WHO toxicity was observed. The rate of positive morphological and/or clinical responses after hypoxic perfusion was very high in our experience, even though our series was small. Recurrences were found in two patients some months later, which suggests the need of long-term follow-up. Hypoxic perfusion can be nevertheless considered as a new and interesting therapeutic approach for advanced malignant gallbladder cancer, with a strong short-term effect on the lesion and good results on clinical symptoms.


Clinical effectiveness of currently available low-vision devices in glaucoma patients with moderate-to-severe vision loss.
The aim of this trial is to study the effectiveness of currently available low-vision devices in glaucoma patients with moderate-to-severe vision loss. This is a randomized pilot clinical trial. Sixteen low-vision glaucoma patients participated in this study. Patients with a best-corrected visual acuity between 20/70 and 20/400 in the better eye and a diagnosis of stable primary or secondary open-angle glaucoma were randomized to a low-vision treatment group or a nonintervention control group. A telephone interview was conducted before and after the 4-week testing period to assess functional vision. Patients placed in the treatment group received a low-vision examination and used various currently available low-vision aids. Patients placed in the control group received a low-vision examination only. Changes in patients' reading ability and overall visual ability were chosen as the primary outcomes. Other visual functioning domains (mobility, visual information processing and visual motor skills) were considered as secondary outcomes. Ten patients in the treatment group showed a significant improvement in reading ability and overall visual ability compared to the control group. The difference in mean score for reading ability was 2.52 logits (2.02; P<0.05) and overall visual ability was 0.78 logits (0.64; P<0.05). However, no significant improvement was noted in the other visual functioning domains involving mobility and visual motor skills. Currently available low-vision devices primarily enhance central vision with limited benefits to functional activities relying on peripheral vision.


Auditory Processing Disorder: What Does It Mean and What Can Be Done?
Julian, an 11-year-old boy in the sixth grade with a compliant disposition and a positive attitude, has had a significant decline in his academic performance over the last 2 years. He spends much of his time in the nurse's office with headaches and fatigue. He reports that he cannot concentrate or follow along in class. Vision and hearing screenings were normal.Julian's teachers report that although he has no behavior problem, he is inattentive and does not put forth the effort she feels he is capable of giving. He does not seem to be listening, and he is distracted by everyone around him. He often claims that he did not hear or understand the things that teachers explained several times. When teachers talk to him directly, he starts an assignment and usually finishes his work on time. Teachers observe that he has "attention-deficit hyperactive disorder (ADHD) like tendencies." A recent psychoeducational evaluation qualified Julian for special education services under specific learning disability in the area of auditory processing. An individual education plan will be developed within the next 2 weeks.Key indicators used to make this determination included the following: average standard scores on nonverbal tests of cognitive development, a below-average score in overall auditory processing (with particularly low scores in auditory reasoning and auditory memory), average scores in the areas of general memory and attention/concentration, and below-average composite scores in reading and written expression.Following a review of the assessment report, Julian's parents remain concerned about the possibility of ADHD. Prior to the special education assessment, the school provided the Vanderbilt Assessment Scales for Julian's parents to share with his doctors; it revealed elevated scores in ADHD symptoms (predominantly inattentive subtype). Julian's parents would like to learn about options for treatment that might improve his attention.


Different O and K serotype distributions among clinical and environmental strains of Serratia marcescens.
Recent revision of the O serotyping scheme for Serratia marcescens has allowed the definitive serological identification of a collection of 511 epidemiologically distinct strains in terms of both lipopolysaccharide (O) antigens and capsular (K) antigens. High levels of typability were achieved, 88% and 91% respectively, with only 2% failing to type with either method. In most cases, non-typability was due to a lack of antigen, i.e., the strains produced only rough LPS or were acapsular, suggesting that typability would be little improved by the discovery of additional serotypes. The distribution of the 58 O:K serotypes was very uneven, with O14:K14 accounting for 30% of the 423 clinical strains in the collection, but only 5% of the 88 non-clinical, environmental strains. Thus, the prevalence of O14:K14 strains in hospitals is not reflected in the environment. Similar conclusions were valid for O27:K14, O21:K3 and O21:K14 strains, as well as those with rough lipopolysaccharide. Conversely, the proportions of O6:K3, O6:K14, O8:K14 or O28:K28 strains were significantly lower among the clinical collection than among their environmental counterparts (12% in total rather than 65%). This suggests that O14:K14 may have a selective advantage in colonising or infecting hospitalised patients and, therefore, that the O14 and K14 polysaccharides themselves may contribute towards the apparent pathogenicity of these serotypes.


IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool.
Memory T cells are critical for immunity to various intracellular pathogens. Recent studies have indicated that CD8 secondary memory cells, induced by prime-boost approaches, show enhanced protective function compared with primary memory cells and exhibit phenotypic and functional characteristics that distinguish them from primary memory cells. However, little is known about the cytokine requirements for generation and maintenance of boosted memory CD8 T cells. We studied the role of IL-15 in determining the size and composition of the secondary (2 degrees) memory CD8 T cell pool induced by Listeria monocytogenes infection in mice. Following boosting, IL-15-deficient animals failed to generate a subset of CD8 effector memory cells, including a population of IL-7Ralpha(low) cells, which were prominent among secondary memory cells in normal mice. IL-15 deficiency also resulted in changes within the IL-7Ralpha(high)CD62L(low) subset of 2 degrees memory CD8 T cells, which expressed high levels of CD27 but minimal granzyme B. In addition to these qualitative changes, IL-15 deficiency resulted in reduced cell cycle and impaired Bcl-2 expression by 2 degrees memory CD8 T cells, suggesting a role for IL-15 in supporting both basal proliferation and survival of the pool. Analogous qualitative differences in memory CD8 T cell populations were observed following a primary response to Sendai virus in IL-15(-/-) animals. Collectively, these findings demonstrate that IL-15 plays an important role in dictating the composition rather than simply the maintenance of the CD8 memory pool.


Fusions of the Escherichia coli gyrA and gyrB control regions to the galactokinase gene are inducible by coumermycin treatment.
We have previously shown that the genes encoding the two subunits of Escherichia coli DNA gyrase are regulated in a manner which is dependent on DNA conformation. When the DNA encoding the gyrA and gyrB genes is relaxed, both genes are expressed at a high level; in negatively supercoiled DNA they are expressed at a low level. In this paper we describe fusions of both the gyrA and gyrB 5' sequences to the E. coli galactokinase gene. In such fusions we found that galactokinase can be induced by treating the cells with coumermycin A1, an inhibitor of DNA gyrase. Our results suggest that the regulation occurs at the transcriptional level and that only a small region of DNA is necessary for coumermycin-induced gene expression.


Anxiety, Depression, and the Interpersonal Theory of Suicide in a Community Sample of Adults with Autism Spectrum Disorder.
The present study examines occurrence of depression, anxiety, and suicidality in adults with autism spectrum disorder (ASD), relationships between social difficulties and mental health, and application of the Interpersonal Theory of Suicide in this population. Ninety-eight adults with ASD completed an online survey. Data were analyzed using bivariate correlations, independent samples t-tests, and simple mediational analyses. A substantial proportion reported a lifetime history of anxiety (63%), depression (55%), and suicide attempts (19%), as well as recent suicidal ideation (12%). Social difficulty was associated with higher psychiatric concerns. Thwarted belongingness and perceived burdensomeness were associated with social dissatisfaction, current suicidal ideation, and history of depression. Results suggest the need for widespread screening and intervention services for co-occurring psychiatric conditions in this population.


Aeration of anaerobically digested sewage sludge for COD and nitrogen removal: optimization at large-scale.
The paper will report about the experiences at an Austrian large wastewater treatment plant of 720,000 population equivalents, where anaerobically digested sewage sludge is further stabilised under aerobic conditions. Enhanced stabilisation of the anaerobically digested sludge was required at the plant in order to get a permit for landfill disposal of the dewatered stabilized sludge. By implementing a post-aeration treatment (SRT approximately 6d; 36 degrees C) after anaerobic digestion the organic content of the anaerobically well digested sludge can be decreased by 16%. Investigations on site showed that during digested sludge post-aeration anoxic phases for denitrification are needed to provide stable process conditions. In this way the pH value can be kept in a more favourable range for micro-organisms and concrete structures. Additionally, inhibition of the biological process due to nitrite accumulation can be avoided. By optimising the aeration/pause ratio approximately 45% of total nitrogen in digested sludge can be removed. This significantly improves nitrogen removal efficiency at the wastewater treatment plant. NH(4)-removal occurs mainly through nitritation and denitritation with an efficiency of 98%. The costs/benefit analysis shows that post-aeration of digested sludge results in an increase of total annual costs for wastewater treatment of only 0.84%, corresponding to 0.19 Euro/pe/a. Result of molecular biological analyses (DGGE) indicate that all four ammonium-oxidizing bacteria species present in activated sludge can survive anaerobic digestion, but only two of them can adapt in the digested sludge post-aeration tanks. Additionally, in the post-aerated digested sludge a further ammonium-oxidizing bacteria species was identified.


Comparison of Medical Costs of Patients With Atrial Fibrillation Unsuitable for Warfarin Treatment With Apixaban or Aspirin Based on AVERROES Trial.
The AVERROES trial name is the following: The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that apixaban reduced the risk of stroke relative to aspirin, without significantly increasing major bleeding risk in patients with atrial fibrillation (AF) considered unsuitable for warfarin therapy. Based on AVERROES trial results, this study compared the medical costs for clinical end points among patients with AF treated with either apixaban or aspirin. Medical costs per patient-year for clinical events were determined. Based on clinical event rates for patients in the AVERROES trial, medical costs excluding drug costs were estimated for apixaban- and aspirin-treated patient groups. Based on AVERROES trial results, among patients with AF unsuitable for warfarin therapy, apixaban use was estimated to be associated with a mean medical cost avoidance of US$735 in a patient-year relative to aspirin. The primary driver was the significant reduction in ischemic stroke rate. The medical cost reduction associated with apixaban use was consistent in sensitivity analyses.


Cholera in coastal Africa: a systematic review of its heterogeneous environmental determinants.
According to the "cholera paradigm," epidemiology of this prototypical waterborne disease is considered to be driven directly by climate-induced variations in coastal aquatic reservoirs of Vibrio cholerae. This systematic review on environmental determinants of cholera in coastal Africa shows that instead coastal epidemics constitute a minor part of the continental cholera burden. Most of coastal cholera foci are located near estuaries, lagoons, mangrove forests, and on islands. Yet outbreaks often originate in coastal cities, where cholera is more likely to be imported from distant areas. Cholera outbreaks also may intensify in densely populated slum quarters before spreading to adjacent regions. Frequent seasonality of cholera incidence appears driven by the rainfall-induced contamination of unprotected water sources through latrine overflow and sewage, as well as by the periodicity of human activities like fishing or traveling. Lulls in transmission periods of several years are repeatedly recorded even in high-risk coastal areas. To date, environmental studies have failed to demonstrate a perennial aquatic reservoir of toxigenic V. cholerae around the continent. Finally, applicability of the cholera paradigm therefore appears questionable in Africa, although available data remain limited. Thorough surveys with microbiological analyses of water samples and prospective genotyping of environmental and clinical strains of V. cholerae are needed to understand determinants of cholera in coastal Africa and better target prevention and control measures.


Intestinal genetic inactivation of caspase-8 diminishes migration of enterocytes.
To verify the hypothesis that caspase-8 (Casp8), which regulates cellular apoptosis and necroptosis, is critically involved in enterocyte migration. Casp8-silenced Caco2 cells were used in migration assays. In addition, enterocyte-specific Casp8 heterozygous (Casp8(+/∆int)) or homozygous knockout mice (Casp8(∆int)) were generated by crossing genetically modified mice carrying loxP recombination sites in intron 2 and 4 of the murine Casp8 gene with transgenic animals expressing a cre-transgene under control of the villin promoter in a pure C57/BL6 genetic background. The nucleoside analog BrdU was injected i.p. in male Casp8(+/∆int) and Casp8(∆int) animals 4 h, 20 h, or 40 h before performing morphometric studies. Locations of anti-BrdU-immunostained cells (cell(max)) in at least 50 hemi-crypts of 6 histoanatomically distinct intestinal mucosal regions were numbered and extracted for statistical procedures. For the mice cohort (n = 28), the walking distance of enterocytes was evaluated from cell(max) within crypt (n = 57), plateau (n = 19), and villus (n = 172) positions, resulting in a total of 6838 observations. Data analysis was performed by fitting a three-level mixed effects model to the data. In cell culture experiments with Caco2 cells, Casp8 knockdown efficiency mediated by RNA interference on Casp8 transcripts was 80% controlled as determined by Western blotting. In the scratch assay, migration of Casp8-deleted Caco2 cells was significantly diminished when compared with controls (Casp8(∆scramble) and Caco2). In BrdU-labeled Casp8(∆int) mice, cell(max) locations were found along the hemi-crypts in a lower position than it was for Casp8(+/∆int) or control (cre-negative) animals. Statistical data analysis with a three-level mixed effects model revealed that in the six different intestinal locations (distinct segments of the small and large intestine), cell movement between the three mice groups differed widely. Especially in duodenal hemi-crypts, enterocyte movement was different between the groups. At 20 h, duodenal cell(max) location was significantly lower in Casp8(∆int) (25.67 ± 2.49) than in Casp8(+/∆int) (35.67 ± 4.78; P < 0.05) or control littermates (44.33 ± 0.94; P < 0.01). Casp8-dependent migration of enterocytes is likely involved in intestinal physiology and inflammation-related pathophysiology.


Mechanism of the serotonin effect on lung transvascular fluid and protein movement in awake sheep.
To see how serotonin affects filtration from lung vessels, we measured vascular pressures, lung lymph flow, lung lymph and blood plasma protein concentrations, arterial blood gases, cardiac output, and lung water content in unanesthetized sheep before and during intravenous serotonin infusions and compared serotonin effects with the effects of inflating a balloon in the left atrium in the same sheep. Serotonin caused a dose-related increase in lung lymph flow and a dose-related decrease in lymph-plasma protein concentration ratios. Steady-state 4-hour serotonin infusions at 4 mu-g/kg min-1 caused lymph flow to increase from 5.4 plus or minus 0.7 (SE) ml/hour to 8.3 plus or minus 1.3 ml/hour, lymph-plasma albumin ratios to fall from 0.78 plus or minus 0.05 to 0.72 plus or minus 0.04, lymph-plasma globulin ratios to fall from 0.64 plus or minus to 0.56 plus or minus 0.02, and pulmonary arterial and left atrial pressures to increase by 3 cm H-20 each. Lymph clearance and permeability-surface area products for eight protein fractions ranging from 36 A to 96 A in molecular radius during steady-state serotonin infusion studies were not significantly different from those during steady-state increased pressure studies. Four-hour infusions of serotonin at 4 mu-g/kg/kg min-1 caused a moderate fall in arterial Po-2 and a slight increase in arterial pH but did not affect cardiac output or cause pulmonary edema. We conclude that serotonin increases lung transvascular filtration primarily by increasing the transmural pressure gradient in exchanging vessels rather than by increasing vascular permeability.


Comparison of mechanical and chemical properties of extra- and intralobar canine pulmonary arteries.
Segments of pulmonary arteries from five extralobar and intralobar sites in the form of circumferential rings were used for the determination of active and passive mechanics, analysis of connective tissue, and determination of water and electrolyte content. Measurements of ring length and tension were made under conditions of active (145 mM K+) and passive (Ca2+ free and 2 mM EGTA) smooth muscle and were used to compute values of segment stress and strain. Passive stress-strain relations among the various sites studied were not significantly different. Collagen and total connective tissue content increased from the largest extralobar to the smallest intralobar sites studied. This suggests differences in the organization of the connective tissue proteins at the secondary and tertiary levels in the various sites studied. The maximum active stress (force/area) developed in response to high K+ was largest in the intralobar arteries and lower in the larger extralobar arteries. The K+ content of these arteries decreased significantly with distance from the heart. The extracellular water content decreased with distance from the heart, whereas total water content was unchanged. These results suggest that relative cell volume decreased with distance from the heart in pulmonary arteries. Thus differences in the relative cell content per se were not responsible for the differences in maximum active stress development among the various arteries.


Effect of a polycyclic aromatic hydrocarbon on the phytoremediation of zinc by two plant species (Brassica juncea and Festuca arundinacea).
The redevelopment of contaminated land is becoming increasingly necessary under sustainable- development legislation; however, many of the contaminated sites are "orphan" sites and therefore require a low-cost remediation technology. These sites often contain a cocktail of pollutants including organics and inorganics. Phytoremediation provides a possible solution, but there is little information available on the tolerance of plant species to multiple pollutants and their ability to remediate in mixed-contaminant soils. The effect of a polycyclic aromatic hydrocarbon (pyrene) in soil upon the remediation of zinc by Brassica juncea and Festuca arundinacea was investigated under normal climatic conditions in the United Kingdom. Zinc was effectively removed from mixed-contaminant soils in the presence of both species, in comparison to a control treatment. Both species accumulated zinc in plant tissues in the presence of pyrene, but the growth of B. juncea was significantly reduced when zinc and pyrene were supplied in combination. Zinc was predominantly associated with root tissues for F. arundinacea, whereas B. juncea contained higher concentrations in shoot tissues. F. arundinacea provides a possible species to be used for the phytoremediation of brownfield sites, but further research is required to determine a range of species that may be used and their applicability to different contaminants.


Alpha-Synuclein defects autophagy by impairing SNAP29-mediated autophagosome-lysosome fusion.
Dopaminergic (DA) cell death in Parkinson's disease (PD) is associated with the gradual appearance of neuronal protein aggregates termed Lewy bodies (LBs) that are comprised of vesicular membrane structures and dysmorphic organelles in conjunction with the protein alpha-Synuclein (α-Syn). Although the exact mechanism of neuronal aggregate formation and death remains elusive, recent research suggests α-Syn-mediated alterations in the lysosomal degradation of aggregated proteins and organelles - a process termed autophagy. Here, we used a combination of molecular biology and immunochemistry to investigate the effect of α-Syn on autophagy turnover in cultured human DA neurons and in human post-mortem brain tissue. We found α-Syn overexpression to reduce autophagy turnover by compromising the fusion of autophagosomes with lysosomes, thus leading to a decrease in the formation of autolysosomes. In accord with a compensatory increase in the plasma membrane fusion of autophagosomes, α-Syn enhanced the number of extracellular vesicles (EV) and the abundance of autophagy-associated proteins in these EVs. Mechanistically, α-Syn decreased the abundance of the v-SNARE protein SNAP29, a member of the SNARE complex mediating autophagolysosome fusion. In line, SNAP29 knockdown mimicked the effect of α-Syn on autophagy whereas SNAP29 co-expression reversed the α-Syn-induced changes on autophagy turnover and EV release and ameliorated DA neuronal cell death. In accord with our results from cultured neurons, we found a stage-dependent reduction of SNAP29 in SNc DA neurons from human post-mortem brain tissue of Lewy body pathology (LBP) cases. In summary, our results thus demonstrate a previously unknown effect of α-Syn on intracellular autophagy-associated SNARE proteins and, as a consequence, a reduced autolysosome fusion. As such, our findings will therefore support the investigation of autophagy-associated pathological changes in PD.


Indigenous land management as primary health care: qualitative analysis from the Interplay research project in remote Australia.
For Indigenous Australians, health transcends the absence of disease, and includes the health and wellbeing of their community and Country: their whole physical, cultural and spiritual environment. Stronger relationships with Country and greater involvement in cultural practices enhance the wellbeing of Indigenous Australians, and those in more remote regions have greater access to their Country and higher levels of wellbeing. However this does not translate into improvements in clinical indicators, and Indigenous Australians in more remote regions suffer higher levels of morbidity and mortality than Indigenous people in non-remote areas, and other Australians. The Interplay research project aimed to explore how Indigenous Australians in remote regions experience high levels of wellbeing despite poor health statistics, and how services could more effectively enhance both health and wellbeing. Indigenous Australians in remote regions, together with researchers and government representatives developed a wellbeing framework, comprising government and community priorities: education, employment and health, and community, culture and empowerment respectively. To explore these priorities Indigenous community researchers recruited participants from diverse Indigenous organizations, including Indigenous land management, art, business development, education, employment, health and municipal services. Fourteen focus groups and seven interviews, involving 75 Indigenous and ten non-Indigenous service providers and users were conducted. These were recorded, transcribed and analyzed, using thematic analysis, based on the wellbeing framework. Research participants highlighted Indigenous land management as a source of wellbeing, through strengthened identity and empowerment, access to traditional food sources, enjoyable physical activity, and escape from communities where high levels of alcohol are consumed. Participants described how collaboration and partnerships between services, and recognition of Indigenous languages could enhance wellbeing, while competition between services undermines wellbeing. Indigenous land management programs work across different sectors and promote collaboration between services, serving as a source of comprehensive primary health care. Developing primary health care to reflect distinctive health needs of Indigenous Australians will enhance their health and wellbeing, which includes their communities and Country. Indigenous land management consolidates aspects of comprehensive primary health care, providing both clinical benefits and wellbeing, and can provide a focus for service collaboration.


Integrating mindfulness in supportive cancer care: a cohort study on a mindfulness-based day care clinic for cancer survivors.
The aim of this study was to investigate the effects of a mindfulness-based day care clinic group program for cancer survivors on health-related quality of life and mental health; and to investigate which psychological variables are associated with changes in health variables. One hundred seventeen cancer survivors (91.0 % female; mean age 53.9 ± 10.7 years; 65.0 % breast cancer; mean time since diagnosis 27.2 ± 46.5 months) participated in an 11-week mindfulness-based day care clinic group program, 6 h per week. The intervention incorporated mindfulness-based meditation, yoga, cognitive-behavioral techniques, and lifestyle modification. Outcome measures including health-related quality of life (EORTC QLQ-C30), depression and anxiety (HADS); and psychological variables including life satisfaction (BMLSS), mindfulness (FMI), adaptive coping styles (AKU), spiritual/religious attitudes in dealing with illness (SpREUK), and interpretation of illness (IIQ) were assessed before, after, and 3 months after the intervention. Using mixed linear models, significant improvements in global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning were found. Cancer-related symptoms, including fatigue, pain, insomnia, constipation, anxiety, and depression, also improved significantly. Mindfulness, life satisfaction, health satisfaction, all coping styles, all spiritual/religious attitudes, and interpretation of illness as something of value increased; interpretation of illness as punishment decreased significantly (all p < 0.05). Improved outcomes were associated with increases in psychological variables, mainly life satisfaction, health satisfaction, and trust in medical help (R (2) = 7.3-43.6 %). Supportive mindfulness-based interventions can be considered as an effective means to improve cancer survivors' physical and mental health. Functional improvements are associated with improved satisfaction and coping styles.


The cystine/cysteine cycle and GSH are independent and crucial antioxidant systems in malignant melanoma cells and represent druggable targets.
Cancer chemoresistance is often due to upregulation of antioxidant systems. Therapeutic targeting of these systems is however hampered by their redundancy. Here, we have performed a functional dissection of the antioxidant systems in different melanoma cases aimed at the identification of the most effective redox active drug. We have identified two crucial antioxidant mechanisms: glutathione (GSH), the major intracellular redox buffer, and the cystine/cysteine cycle, which switches the extracellular redox state from an oxidized to a reduced state. The two mechanisms are independent in melanoma cells and may be substitutes for each other, but targeting both of them is lethal. Exposure to the pro-oxidant compound As(2)O(3) induces an antioxidant response. However, while in these cells the intracellular redox balance remains almost unaffected, a reduced environment is generated extracellularly. GSH depletion by buthioninesulfoximine (BSO), or cystine/cysteine cycle inhibition by (S)-4-carboxyphenylglycine (sCPG), enhanced the sensitivity to As(2)O(3). Remarkably, sCPG also prevented the remodeling of the microenvironment redox state. We propose that the definition of the prevalent antioxidant system(s) in tumors is crucial for the design of tailored therapies involving redox-directed drugs in association with pro-oxidant drugs. In melanoma cells, BSO is the best enhancer of As(2)O(3) sensitivity. However, since the strong remodeling of the microenvironmental redox state caused by As(2)O(3) may promote tumor progression, the concomitant use of cystine/cysteine cycle blockers is recommended.


Effects of vasopressin and corticosterone on fatty acid metabolism and on the activities of glycerol phosphate acyltransferase and phosphatidate phosphohydrolase in rat hepatocytes.
The effects of vasopressin on the short-term control of fatty acid metabolism were studied in isolated rat hepatocytes. Vasopressin increased the oxidation of oleate to CO2 and decreased the formation of ketones in hepatocytes from Wistar rats, but not from Brattleboro rats. Incubation with vasopressin for 30 min increased the conversion of oleate into triacylglycerol by 17% and 32% in hepatocytes from Wistar and Brattleboro rats respectively. The corresponding increases for the phospholipid fraction were 19% and 42%. When Wistar-rat hepatocytes were incubated with corticosterone for 6 h there was a 19% increase in triacylglycerol synthesis, and a 52% increase if vasopressin was added 30 min before the end of the incubation. Glycerol phosphate acyltransferase activity was not significantly increased by vasopressin. Incubation for 5-60 min with vasopressin increased the Vmax. of phosphatidate phosphohydrolase by 48% and 32% respectively in hepatocytes from Wistar and Brattleboro rats. These increases were antagonized if EGTA was added to the medium used for incubating the hepatocytes. The replacement of vasopressin by 5 microM-ionophore A23187 produced a significant increase of 13% in the phosphohydrolase activity. It is therefore likely that the effects of vasopressin on the phosphohydrolase are mediated by Ca2+. These results are discussed in relation to the possible function of phosphatidate phosphohydrolase in controlling the turnover of phosphoinositides, the synthesis of phosphatidylethanolamine, phosphatidylcholine and triacylglycerol, and the secretion of very-low-density lipoproteins.


Loss of GluN2A-containing NMDA receptors impairs extra-dimensional set-shifting.
Glutamate neurotransmission via the N-methyl-D-aspartate receptor (NMDAR) is thought to mediate the synaptic plasticity underlying learning and memory formation. There is increasing evidence that deficits in NMDAR function are involved in the pathophysiology of cognitive dysfunction seen in neuropsychiatric disorders and addiction. NMDAR subunits confer different physiological properties to the receptor, interact with distinct intracellular postsynaptic scaffolding and signaling molecules, and are differentially expressed during development. Despite these known differences, the relative contribution of individual subunit composition to synaptic plasticity and learning is not fully elucidated. We have previously shown that constitutive deletion of GluN2A subunit in the mouse impairs discrimination and re-learning phase of reversal when exemplars are complex picture stimuli, but spares acquisition and extinction of non-discriminative visually cued instrumental response. To investigate the role of GluN2A containing NMDARs in executive control, we tested GluN2A knockout (GluN2A(KO) ), heterozygous (GluN2A(HET) ) and wild-type (WT) littermates on an attentional set-shifting task using species-specific stimulus dimensions. To further explore the nature of deficits in this model, mice were tested on a visual discrimination reversal paradigm using simplified rotational stimuli. GluN2A(KO) were not impaired on discrimination or reversal problems when tactile or olfactory stimuli were used, or when visual stimuli were sufficiently easy to discriminate. GluN2A(KO) showed a specific and significant impairment in ventromedial prefrontal cortex-mediated set-shifting. Together these results support a role for GluN2A containing NMDAR in modulating executive control that can be masked by overlapping deficits in attentional processes during high task demands.


Thyroid hormones and adult interpersonal violence among women with borderline personality disorder.
Elevated T3 levels have been reported in men with antisocial behavior. The aim of the present study was to investigate the relationship between thyroid hormones and expressed adult interpersonal violence in female patients with borderline personality disorder (BPD). Furthermore, expressed adult interpersonal violence in female BPD patients was compared to healthy female controls. A total of 92 clinically euthyroid women with BPD and 57 healthy women were assessed with the Karolinska Interpersonal Violence Scales (KIVS). Baseline thyroid function was evaluated by measuring plasma free and bound triiodothyronine (FT3 and T3), thyroxine (FT4 and T4), and thyroid-stimulating hormone (TSH) with immunoassays in patients. Plasma cortisol was also measured. Among females with BPD, expressed interpersonal violence as an adult showed a significant positive correlation with the T3 levels. The mean expression of interpersonal violence as an adult was significantly higher in BPD patients as compared to healthy controls. The multiple regression model indicated that two independent predictors of KIVS expressed interpersonal violence as an adult: T3 and comorbid diagnosis of alcohol abuse. Association between T3 levels and violent/aggressive behavior earlier reported exclusively in male samples may be valid also in females with BPD.