Strategic management and organisational structure: transformational processes at work in hospitals.
There is a substantial amount of organisational restructuring presently occurring in Australian public hospitals. However, there has been a lack of systematic research conducted about this phenomenon. In Australia most literature about organisational restructuring has employed a case study approach. Although there has been a great deal of support for product line management organisational arrangements in recent literature from overseas, little investigation into the adoption of product line management has taken place in Australia. In this paper, a discussion about the relationship between strategic management and organisational structure is presented. Survey results of a sample of nine teaching hospitals in New South Wales are reported. Taken together with other more descriptive literature about organisational restructuring in Australian health care, the evidence from this survey suggests that there are vigorous transformational processes at work, perhaps especially in the larger hospitals. Despite support for it in the literature, product line management is not being adopted on a widespread scale. The shift toward restructuring occurring within Australian hospitals at the moment represents a bout of experimentation with new organisational designs which seems destined to continue. A number of management theorists conclude that there need to be strong linkages between strategic planning and the choice of organisational structure. However, the empirical evidence reported here did not identify such strong linkages. This phenomenon warrants further investigation. The view is put that where these linkages are weak there is a risk that whatever structure is chosen will not be robust or flexible enough to cope with mooted or predicted policy changes to the Australian health system.


Diagnostic accuracy of Fresno-Quebec Rules and risk factors for an associated fracture in patients presenting to the emergency department with anterior shoulder dislocation: A retrospective study.
Anterior shoulder dislocation is the most common shoulder injury in patients presenting to the emergency department (ED). Up to 25% of these injuries are fracture-dislocations. In general, the standard approach is to obtain plain radiographs before and after reduction. Fresno-Quebec Rules (FQR) are described to identify the patients who require an x-ray before reduction to reduce radiation exposure and delays in treatment. We aimed to evaluate the efficacy of clinical predictors used in the Fresno-Quebec algorithm for detecting a shoulder fracture-dislocation. Records of patients who presented to the Emergency Department with presumed shoulder dislocation were retrieved and retrospectively analyzed according to 'Fresno-Quebec Rule (FQR)'. Sensitivity, specificity, and predictive values of FQR for detecting associated injuries were calculated. Eighty-nine (65.9%) men and 46 (34.1%) women were included. The mean age of patients was 46 years (16-89). Ninety-nine (73.3%) of the cases had their shoulder dislocated for the first time, whereas 36 (26.7%) patients had a recurrent dislocation. Fifty percent of the patients (18 cases) with recurrent dislocation presented with an atraumatic episode. The remaining 18 patients with a history of recurrent dislocations had their shoulder dislocated as a result of trauma, and four (22%) of them had fracture-dislocation. Using the Fresno-Quebec rules yielded 100% specificity for the diagnosis of fracture-dislocation. The severity of the injury mechanism was not predictive in traumatic but recurrent dislocations. Only one of four patients with a fracture-dislocation in the traumatic recurrent dislocation group had high energy trauma. FQR has 100% sensitivity in detecting fracture-dislocations in patients admitted to ED with anterior shoulder dislocation. It utilizes simple parameters that are easy to use and recall. Using these rules, 30% of unnecessary radiographs can be avoided, saving time and money and reducing radiation exposure in anterior dislocations.


In vivo characterization of glycogen storage disease type III in a mouse model using glycoNOE MRI.
Glycogen storage disease type III (GSD III) is a rare inherited metabolic disease characterized by excessive accumulation of glycogen in liver, skeletal muscle, and heart. Currently, there are no widely available noninvasive methods to assess tissue glycogen levels and disease load. Here, we use glycogen nuclear Overhauser effect (glycoNOE) MRI to quantify hepatic glycogen levels in a mouse model of GSD III. Agl knockout mice (n = 13) and wild-type controls (n = 10) were scanned for liver glycogen content using glycoNOE MRI. All mice were fasted for 12 to 16 h before MRI scans. GlycoNOE signal was quantified by fitting the Z-spectrum using a four-pool Voigt lineshape model. Next, the fitted direct water saturation pool was removed and glycoNOE signal was estimated from the integral of the residual Z spectrum within -0.6 to -1.4 ppm. Glycogen concentration was also measured ex vivo using a biochemical assay. GlycoNOE MRI clearly distinguished Agl knockout mice from wild-type controls, showing a statistically significant difference in glycoNOE signals in the livers across genotypes. There was a linear correlation between glycoNOE signal and glycogen concentration determined by the biochemical assay. The obtained glycoNOE maps of mouse livers also showed higher glycogen levels in Agl knockout mice compared to wild-type mice. GlycoNOE MRI was used successfully as a noninvasive method to detect liver glycogen levels in mice, suggesting the potential of this method to be applied to assess glycogen storage diseases.


Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1.
Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized (1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.


[The anatomical characteristics and its applied significance of laparoscopic rectal surgery].
To realize the anatomical characteristics of laparoscopic rectum surgery and its clinical significance. 117 cases with benign and malignant diseases of rectum were operated by laparoscopic methods. The anatomy closely related with operation was analyzed. The median operative time were 144 min. 4 cases were converted to open operations, so the converted rate was 1.7%. The blood loss in operation was rather little with an average of 126 ml. No instant or delayed injury of ureters, large bleeding in front of sacrum and other operation-related severe complications happened intra- and after operation. Dissecting only in one case disrupted the anterior-left wall of rectum. Laparoscopic rectal surgery is clinically feasible. Mastering the anatomical characteristics of laparoscopic rectum surgery can make us reduce the operative mistakes and complications.


13C NMR analysis of a developmental pathway mutation in Saccharomyces cerevisiae reveals a cell derepressed for succinate dehydrogenase.
13C nuclear magnetic resonance (NMR) spectroscopy was used to study the metabolism of [2-13C]acetate in a diploid strain of Saccharomyces cerevisiae homozygous for the spo50 mutation. This mutation results in failure to initiate sporulation and suppresses spd mutations (which cause derepressed sporulation). By analysing the pattern of 13C-labelling in glutamate it was deduced that the glyoxylate cycle is responsible for most of the acetate utilization and that there is very little tricarboxylic acid cycle activity. The labelling of alpha,alpha'-trehalose indicated that gluconeogenesis and the hexose monophosphate pathway operate in a similar way to the wild-type. The mutant strain has higher levels of succinate dehydrogenase than the wild-type. All of the physiological alterations caused by the spo50 mutation can be explained by this difference.


Spectrum of renal vascular lesions among patients with lupus nephritis: An experience from a tertiary care center.
Lupus nephritis (LN) is the assemblage of glomerular, tubulointerstitial and vascular changes. Despite the fact that glomerular changes are overemphasized in pathological classification and scoring system, but the existence of vascular damage negatively impact the clinical course. This study was conducted to determine the clinicopathological spectrum of renal vascular lesions in lupus nephritis. Renal microvascular lesions in biopsy proven lupus nephritis were classified into 5 major categories-thrombotic microangiopathy, true vasculitis; lupus vasculopathy, uncomplicated vascular immune deposits, and arterial. Clinical details, laboratory parameters and histopathological variables were compared among all groups. Summary of chronic changes was also assessed. Biopsies from 56 patients revealed thrombotic microangiopathy (2), lupus vasculopathy (3), uncomplicated vascular immune deposit (6), PAN type vasculitis (1) and arterial sclerosis (13). No renal vascular lesions were found in 35.18% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older Nephritis subtype. Activity indices were higher in lupus vasculopathy group whereas patients with arteriosclerosis showed highest chronicity index. Renal vascular lesions are common in systemic lupus erythematosus patients with nephritis and may be associated with aggressive clinical course.


Globally diverse Toxoplasma gondii isolates comprise six major clades originating from a small number of distinct ancestral lineages.
Marked phenotypic variation characterizes isolates of Toxoplasma gondii, a ubiquitous zoonotic parasite that serves as an important experimental model for studying apicomplexan parasites. Progress in identifying the heritable basis for clinically and epidemiologically significant differences requires a robust system for describing and interpreting evolutionary subdivisions in this prevalent pathogen. To develop such a system, we have examined more than 950 isolates collected from around the world and genotyped them using three independent sets of polymorphic DNA markers, sampling 30 loci distributed across all nuclear chromosomes as well as the plastid genome. Our studies reveal a biphasic pattern consisting of regions in the Northern Hemisphere where a few, highly clonal and abundant lineages predominate; elsewhere, and especially in portions of South America are characterized by a diverse assemblage of less common genotypes that show greater evidence of recombination. Clustering methods were used to organize the marked genetic diversity of 138 unique genotypes into 15 haplogroups that collectively define six major clades. Analysis of gene flow indicates that a small number of ancestral lineages gave rise to the existing diversity through a process of limited admixture. Identification of reference strains for these major groups should facilitate future studies on comparative genomics and identification of genes that control important biological phenotypes including pathogenesis and transmission.


Plasma adrenaline increases in anesthetized patients given electro-acupuncture before surgery.
In anesthetized patients, electro-acupuncture (EA) has been found to reduce sevoflurane-induced suppression of cranial and spinal motor responses to surgery without influencing the level of anesthesia. The underlying mechanisms are unclear. In the present study, blood samples were analyzed to evaluate if the increased clinical motor responses to surgery in patients subjected to EA under sevoflurane anesthesia are also reflected in higher plasma levels of catecholamines, adrenocorticotrophic hormone (ACTH), or cortisol. Blood samples were obtained before anesthetic induction, soon after the study or control procedures had been completed under general anesthesia, and after 30 minutes of surgery under steady-state anesthesia with 1.8% of sevoflurane, in 45 healthy female patients, scheduled for sterilization by laparoscopy, randomized for bilateral 2 Hz-burst EA (study group; n = 22) or control (control group; n = 23) procedures. Plasma levels of adrenaline were found to approach the higher preanesthetic level after 30 minutes of surgery in patients given EA stimulation but to remain low in control patients (P < 0.05)-in agreement with the stronger clinical motor responses to skin incision in the EA group. Plasma levels of noradrenaline, ACTH, and cortisol did not change in or differ between the two groups. The clinical facilitation of both cranial and spinal motor responses to surgery in patients given acupuncture under sevoflurane anesthesia is associated with increased plasma levels of adrenaline, possibly reflecting sympathetic activation.


Diffusivity of the uncinate fasciculus in heroin users relates to their levels of anxiety.
Heroin use is closely associated with emotional dysregulation, which may explain its high comorbidity with disorders such as anxiety and depression. However, the understanding of the neurobiological etiology of the association between heroin use and emotional dysregulation is limited. Previous studies have suggested an impact of heroin on diffusivity in white matter involving the emotional regulatory system, but the specificity of this finding remains to be determined. Therefore, this study investigated the association between heroin use and diffusivity of white matter tracts in heroin users and examined whether the tracts were associated with their elevated anxiety and depression levels. A sample of 26 right-handed male abstinent heroin users (25 to 42 years of age) and 32 matched healthy controls (19 to 55 years of age) was recruited for this study. Diffusion tensor imaging data were collected, and their levels of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Our findings indicated that heroin users exhibited higher levels of anxiety and depression, but the heroin use-associated left uncinate fasciculus was only related to their anxiety level, suggesting that association between heroin and anxiety has an incremental organic basis but that for depression could be a threshold issue. This finding improves our understanding of heroin addiction and its comorbid affective disorder and facilitates future therapeutic development.


Tutorial on Biostatistics: Receiver-Operating Characteristic (ROC) Analysis for Correlated Eye Data.
To demonstrate methods for receiver-operating characteristic (ROC) analysis of correlated eye data. We applied the Obuchowski's nonparametric approach and cluster bootstrap for estimating and comparing the area under ROC curve (AUC) between different sets of predictors to three datasets with varying inter-eye correlation. In an optic neuritis (ON) study of 152 eyes (80 patients), the AUC of optical coherence tomography retinal nerve fiber layer thickness for diagnosing ON (inter-eye kappa = 0.13) was 0.71 [95% confidence interval (95% CI): 0.622, 0.792] from the naïve approach without accounting for inter-eye correlation was narrower than from nonparametric (95% CI: 0.613, 0.801) or cluster bootstrap (95% CI: 0.614, 0.797) approaches. In an analysis of 198 eyes (135 patients), the baseline Age-related Eye disease Study scale predicted 5-year incidence of advanced age-related macular degeneration (inter-eye kappa = 0.23) with AUC of 0.72. The 95% CI from the naïve approach was slightly narrower (0.645, 0.794) than from the nonparametric (0.641, 0.797) or cluster bootstrap (0.641, 0.793) approaches. In an analysis of 1542 eyes (771 infants), birthweight and gestational age predicted treatment-requiring retinopathy of prematurity (inter-eye kappa = 0.98) with AUC of 0.80. Furthermore, the 95% CI from the naïve approach was narrower (0.769, 0.835) than from the nonparametric (0.755, 0.848) or cluster bootstrap (0.755, 0.845) approaches. 95% CIs for AUC differences between different models were narrower in the naïve approach than the nonparametric or cluster bootstrap approaches. In ROC analysis of correlated eye data, ignoring inter-eye correlation leads to narrower 95% CI with underestimation dependent on magnitude of inter-eye correlation. Nonparametric and cluster bootstrap approaches properly account for inter-eye correlation.


Organic livestock production: an emerging opportunity with new challenges for producers in tropical countries.
Agrochemicals, veterinary drugs, antibiotics and improved feeds can increase the food supply while minimising production costs in various livestock production systems around the world. However, these days, quality-conscious consumers are increasingly seeking environmentally safe, chemical-residue-free healthy foods, along with product traceability and a high standard of animal welfare, which organic production methods are said to ensure. Organic production is not only a challenge for producers in developing countries, it offers new export opportunities as well. Organic agriculture is practised by 1.8 million producers in 160 countries, and production of organically grown food continues to increase steadily by 15% per year. Most tropical countries are now exporting organic agricultural products but, apart from organic beef from Brazil and Argentina, organic livestock products are yetto take off. Most trade in organic livestock products is restricted to the European Union and other developed nations. Nevertheless, tropical countries cannot afford to neglect this emerging system of animal production. Organic production is knowledge- and management-intensive. Producers must be well versed in organic production standards, principles and practices, which require a high degree of knowledge and skill. In organic production, it is not simply the final product but the whole production process that must be inspected and approved by the accredited certification bodies. Organic livestock farming is still evolving, and further research is needed to make it sustainable. In this paper, the authors review the prospects of organic animal husbandry and its possible constraints in developing and tropical countries.


Brain perfusion in encephalopathic newborns after therapeutic hypothermia.
Cerebral perfusion patterns in neonates with HIE after therapeutic hypothermia have not been well described. The objectives of this study were to compare global and regional perfusion between infants with HIE and neonate controls and to relate measures of cerebral perfusion to brain injury on conventional MR imaging in neonates with HIE. Term encephalopathic neonates meeting criteria for hypothermia between June 2011 and January 2012 were enrolled in this prospective observational study. MR imaging-ASL was performed in the second week of life. Comparisons were made with data from neonate controls who underwent the same imaging protocol. NIRS measures of cerebral oxygenation during and immediately after hypothermia were also evaluated in a subset of patients. Secondary analyses were performed to assess cerebral perfusion and oxygenation differences by pattern of injury on qualitative MR imaging interpretation. We enrolled 18 infants with HIE and 18 control infants. Mean global CBF and regional CBF in the basal ganglia, thalamus, and anterior white matter were higher in cases compared with controls. Infants with HIE with injury on MR imaging, however, had lower CBF (significant in the thalamus) compared with those with normal MR imaging. Decreased FTOE by NIRS further differentiated patients with HIE with injury on MR imaging. Disturbed cerebral perfusion is observed in the second week of life in some babies with HIE despite treatment with hypothermia. Infants with HIE with injury on MR imaging have lower regional CBF in the thalamus compared with those without injury, possibly representing pseudonormalization of CBF and low metabolic demand after progression to irreversible brain injury.


Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial.
Consumption of green kiwifruit is known to relieve constipation. Previous studies have also reported improvements in gastrointestinal (GI) comfort. We investigated the effect of consuming green kiwifruit on GI function and comfort. Participants included healthy controls (n = 63), patients with functional constipation (FC, n = 60), and patients with constipation-predominant irritable bowel syndrome (IBS-C, n = 61) randomly assigned to consume 2 green kiwifruits or psyllium (7.5 g) per day for 4 weeks, followed by a 4-week washout, and then the other treatment for 4 weeks. The primary outcome was the number of complete spontaneous bowel movements (CSBM) per week. Secondary outcomes included GI comfort which was measured using the GI symptom rating scale, a validated instrument. Data (intent-to-treat) were analyzed as difference from baseline using repeated measures analysis of variance suitable for AB/BA crossover design. Consumption of green kiwifruit was associated with a clinically relevant increase of ≥ 1.5 CSBM per week (FC; 1.53, P < 0.0001, IBS-C; 1.73, P = 0.0003) and significantly improved measures of GI comfort (GI symptom rating scale total score) in constipated participants (FC, P < 0.0001; IBS-C, P < 0.0001). No significant adverse events were observed. This study provides original evidence that the consumption of a fresh whole fruit has demonstrated clinically relevant increases in CSBM and improved measures of GI comfort in constipated populations. Green kiwifruits are a suitable dietary treatment for relief of constipation and associated GI comfort.


[Content of selected metals in forest fruits depending on the harvest site].
Contents of selected metals (Pb, Cd, Cu, Zn, Fe, Mn) were determined in samples of forest fruits: blueberry, raspberry and wild strawberry harvested in Lublin region from areas considered as potentially not exposed to pollution (Skierbieszów Landscape Park) and potentially polluted areas (Cement Factory Rejowiec S.A.). Analyzed fruits originating from stands more exposed to pollution were characterized by higher lead (except from raspberry) as well as other metals contents than those from Krasiczyn commune. Among studied fruits, blueberry was distinguished by the lowest contents of Pb, Zn, Fe, Mn, wild strawberry contained the highest levels of Pb, Zn and Mn. Cadmium content in analyzed plant materials was high.


Early-onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1-associated primary hyperparathyroidism.
Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT. However, studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking. In this cross-sectional study, performed in a tertiary academic hospital, 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual-energy X-ray absorptiometry (DXA) scanning of the proximal one-third of the distal radius (1/3DR), femoral neck, total hip, and lumbar spine (LS). The mean age of the patients was 38.9 ± 14.5 years. Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77.8%). In the younger group (<50 years of age), demineralization in the 1/3DR was more frequent, more severe, and occurred earlier (40%; Z-score -1.81 ± 0.26). The older group (>50 years of age) had a higher frequency of bone demineralization at all sites (p < .005) and a larger number of affected bone sites (p < .0001), and BMD was more severely compromised in the 1/3DR (p = .007) and LS (p = .002). BMD values were lower in symptomatic (88.9%) than in asymptomatic HPT patients (p < .006). Patients with long-standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. Urolithiasis occurred earlier (<30 years) and more frequently (75%) and was associated with related renal comorbidities (50%) and renal insufficiency in the older group (33%). Bone mineral- and urolithiasis-related renal complications in HPT/MEN1 are early-onset, frequent, extensive, severe, and progressive. These data should be considered in the individualized clinical/surgical management of patients with MEN1-associated HPT.


Aorta and liver changes in rats fed cholesterol-containing and raw vegetable-supplemented diets: experiments in vitro and in vivo.
The aim of this investigation was to compare the liver and aorta changes in rats fed cholesterol-containing diets and the possible improvement when diets would be supplemented with frequently used raw vegetables. The phenolic compounds of three vegetables in methanol-water (1:1) fraction were characterized using electrospray ionization mass spectra (ESI-MS). Results showed that the content of polyphenols, flavonoids, quercetin, flavanols, tannins, and ascorbic acid varied for garlic and white and red onions ranging from 6.68 to 18.08 mg GAE/g DW, 490.4-701.0 μg CE/g DW, 281.2-1100.0 μg, 32.40-41.30 μg CE/g DW, 2.88-3.12 mg CE/g DW, 1.87-2.33 mg AA/g DW, 1388.2-1442.3 μg CGE/g DW, respectively. The radical scavenging capacities (μM TE/g DW) for the same investigated vegetables for ABTS, FRAP, CUPRAC, and DPPH assays ranged from 48.78 to 92.42, 9.41-28.56, 3.06-10.41, and 6.49-23.42, respectively. Good correlations were observed between the phenolic contents and the radical scavenging capacities of the vegetables. The interaction between BSA and quercetin, BSA and garlic and onions extracts was measured by 3-dimensional fluorescence (3D-FL) and Fourier transform infrared (FT-IR) spectroscopy. The highest polyphenol content was found in methanol/water fraction of onions and garlic; therefore, for the investigation of in vitro interactions with BSA only polyphenols of this fraction were used. For in vivo studies, 30 male Wistar rats were divided into 5 groups each of 6 and named Control, Chol, Chol/Garlic, Chol/OnionRed, and Chol/OnionWhite. During 6 weeks, the rats of all 5 groups were fed a basal diet (BD). The rats of the Control group were fed the BD only. The BD of the Chol group was supplemented with 10 g/kg of nonoxidized cholesterol (NOC). Each of the other three groups was supplemented with 10 g/kg of NOC and 500 mg of raw fresh garlic, 500 mg of raw fresh red onion, and 500 mg of raw fresh white onion on 1 kg of body weight for Chol/Garlic, Chol/OnionRed, and Chol/OnionWhite diet groups, respectively. In order to detect the changes in the liver and aorta, a histological procedure was applied, and the liver enzymes were determined and compared. It was found that the main changes vs the Control group were in the liver of rats fed the cholesterol-containing diet without vegetable supplementation. Significantly less histological changes in the liver and lower level of liver enzymes vs those of the Chol group were detected in rats of the Chol/Garlic group (P < 0.05). The interaction between the polyphenol extract of garlic and BSA in vitro showed its strong ability comparable with that of quercetin to quench the intrinsic fluorescence of BSA. In conclusion, all studied vegetables showed protective effects, but raw garlic supplemented with cholesterol-containing diets significantly prevented the aorta and liver damages of rats.


On the Road from Phenotypic Plasticity to Stem Cell Therapy.
In 1981, I published a paper in the first issue of The Journal of Neuroscience with my postdoctoral mentor, Richard Bunge. At that time, the long-standing belief that each neuron expressed only one neurotransmitter, known as Dale's Principle (Dale, 1935), was being hotly debated following a report by French embryologist Nicole Le Douarin showing that neural crest cells destined for one transmitter phenotype could express characteristics of another if transplanted to alternate sites in the developing embryo (Le Douarin, 1980). In the Bunge laboratory, we were able to more directly test the question of phenotypic plasticity in the controlled environment of the tissue culture dish. Thus, in our paper, we grew autonomic catecholaminergic neurons in culture under conditions which promoted the acquisition of cholinergic traits and showed that cells did not abandon their inherited phenotype to adopt a new one but instead were capable of dual transmitter expression. In this Progressions article, I detail the path that led to these findings and how this study impacted the direction I followed for the next 40 years. This is my journey from phenotypic plasticity to the promise of a stem cell therapy.


Can cognitive psychological research on reasoning enhance the discussion around moral judgments?
In this article we will demonstrate how cognitive psychological research on reasoning and decision making could enhance discussions and theories of moral judgments. In the first part, we will present recent dual-process models of moral judgments and describe selected studies which support these approaches. However, we will also present data that contradict the model predictions, suggesting that approaches to moral judgment might be more complex. In the second part, we will show how cognitive psychological research on reasoning might be helpful in understanding moral judgments. Specifically, we will highlight approaches addressing the interaction between intuition and reflection. Our data suggest that a sequential model of engaging in deliberation might have to be revised. Therefore, we will present an approach based on Signal Detection Theory and on intuitive conflict detection. We predict that individuals arrive at the moral decisions by comparing potential action outcomes (e.g., harm caused and utilitarian gain) simultaneously. The response criterion can be influenced by intuitive processes, such as heuristic moral value processing, or considerations of harm caused.


Sustained participatory design and implementation of ITHC.
Participatory design includes engaging in large-scale information-systems development where participatory design approaches have been applied throughout design and organizational implementation. The keynote suggest to extend the iterative prototyping approach by (1) emphasizing participatory design experiments and pilot implementations as transcending traditional prototyping by evaluating fully integrated systems exposed to real work practices; (2) incorporating improvisational change management including anticipated, emergent, and opportunity-based change; and (3) extending initial design and development into a sustained and ongoing implementation that constitutes an overall technology-driven organizational change. This sustained participatory design and implementation approach is exemplified through a large-scale project in the Danish healthcare sector.


Terephthalate as a probe for photochemically generated hydroxyl radical.
Hydroxyl radical ( OH) production in sunlit natural waters is known to be an important factor in pollutant degradation and nutrient cycling, and various probes have been developed to study this species in aquatic systems. Many of these probes have limitations in sensitivity and/or selectivity for OH, leaving room for improvement. Terephthalate (TPA) is a known probe for OH that produces a fluorescent product, hydroxyterephthalate (hTPA), upon hydroxylation, but its suitability for studying photochemical OH production has not been fully tested. To that end, the photochemical behavior of TPA and hTPA was characterized. TPA and hTPA react with OH with rate constants of (4.4 +/- 0.1) x 10(9) M(-1) s(-1) and (6.3 +/- 0.1) x 10(9) M(-1) s(-1), respectively. They were found to react with singlet oxygen ((1)O(2)) with significantly lower rate constants of <<10(4) M(-1) s(-1) and (5.0 +/- 0.1) x 10(4) M(-1) s(-1), respectively, indicating that TPA is selective for OH versus(1)O(2). TPA did not undergo direct photolysis, while hTPA was shown to undergo direct photochemical degradation with a Phi(direct,365nm) of (6.3 +/- 0.1) x 10(-3). TPA was applied to monitoring photochemical OH production by nitrate, nitrite and dissolved organic matter (DOM), and OH quenching rate constants measured for DOM were similar to results from previous studies. TPA provides a stable and sensitive probe for OH under significantly shorter photo-exposure times than similarly structured probe molecules, such as benzoate. However, the photoinstability of the analyte, hTPA, makes TPA an unsuitable probe for the study of photochemical systems under ultraviolet irradiation with wavelengths shorter than 360 nm.


Desensitization to ANG II in guinea pig ileum depends on membrane repolarization: role of maxi-K(+) channel.
Desensitization of ANG II tonic contractile response of the guinea pig ileum is related to membrane repolarization determined by Ca(2+)-activated K(+) (maxi-K(+)) channel opening. ANG II-stimulated depolarized myocytes presented sustained activation of maxi-K(+) channels, characterized by reduction from 415 to 12 ms of the closed time constant. ANG II desensitization was prevented by 100 nM iberiotoxin, being reversible within 30 min. Depolarization by KCl, higher than 4 mM, impaired desensitization, suggesting that the membrane potential must attain a threshold to counteract the repolarization induced by maxi-K(+) channel opening. Once this value is attained, there is no time dependency because the desensitization process was shut off by addition of KCl along the time course of the tonic response. In contrast, the sustained ACh tonic component was not altered by these maneuvers. We conclude that desensitization of the ANG II tonic component is foremost due to the opening of maxi-K(+) channels, leading to membrane repolarization, thus closing the voltage-dependent Ca(2+) channels responsible for the Ca(2+) influx that sustains the tonic component in this muscle.


Patient and healthcare professionals' perceived barriers and facilitators to the implementation of psychosocial screening in cardiac practice: A Delphi study.
Psychosocial risk factors contribute to the incidence and progression of coronary heart disease (CHD). Psychosocial screening may identify individuals who are at risk and aid them with getting appropriate care. To successfully implement psychosocial screening in the cardiology practice, the current study aims to identify key barriers and facilitators to its implementation and evaluate their perceived importance among health care professionals (HCPs) and patients. We took a modified 3-round Delphi study approach to gain insight into key determinants that could either impede or ease implementation. Round 1 gathered data from HCPs (n = 9; cardiologists, medical psychologists, cardiac nurses) and CHD patients (n = 21), which we transcribed verbatim, coded, and processed into unique determinants. In rounds 2 and 3, participants were asked to select the most relevant determinants and rank them based on importance. Subsequently, determinants were classified by implementation level. Patients were generally more positive towards screening. HCP barriers included time-constraints, disruption of primary activities, and limited knowledge on psychosocial risk and screening, while patient barriers were commonly related to accessibility and patient characteristics (e.g., health literacy, motivation). Facilitators of both groups mainly pertained to the use of the screener and follow-up care, such as increasing the accessibility and the benefits of the screener. Barriers may be targeted by enhancing the effects of the facilitators. Increasing the accessibility to the screener and interventions, improving information provision, and appointing a contact person to oversee the screening process may ease the screening and care process for both patients and HCPs.


The accuracy vs. coverage trade-off in patient-facing diagnosis models.
A third of adults in America use the Internet to diagnose medical concerns, and online symptom checkers are increasingly part of this process. These tools are powered by diagnosis models similar to clinical decision support systems, with the primary difference being the coverage of symptoms and diagnoses. To be useful to patients and physicians, these models must have high accuracy while covering a meaningful space of symptoms and diagnoses. To the best of our knowledge, this paper is the first in studying the trade-off between the coverage of the model and its performance for diagnosis. To this end, we learn diagnosis models with different coverage from EHR data. We find a 1% drop in top-3 accuracy for every 10 diseases added to the coverage. We also observe that complexity for these models does not affect performance, with linear models performing as well as neural networks.


Perceived needs and satisfaction with care in people with multiple sclerosis: a two-year prospective study.
Considering the costs of multiple sclerosis (MS), it is crucial that the health-related services supplied are in accordance with needs as they are perceived by people with MS (PwMS). Satisfaction with care is related to quality of care and can provide health care providers with the means for improvement. The aim was to explore the perceived needs and satisfaction with care amongst PwMS over a two-year period, also taking sex and disease severity into consideration. The sample consisted of 219 outpatients at a MS specialist clinic. Data on perceived needs and satisfaction with care were collected every six months using a questionnaire which included various dimensions of care. The data was analysed for the whole sample and on an individual level, as well as in subgroups with regard to sex and disease severity. There were no statistically significant variations in the proportion of PwMS with perceived needs concerning different health-related services during the study period. However, individual variations were found with regard to both perceived needs and satisfaction with care. Few PwMS perceived a continuous need for a specific service. However, the majority perceived a need for rehabilitation, assistive devices, transportation service for the disabled, psychosocial support/counselling and information on social insurance/vocational rehabilitation at least sometimes. Severe MS was associated with a greater perceived need for almost all the services studied and women experienced a need for psychosocial support/counselling to a greater extent than men. In relation to the different categories of health care staff, PwMS were most satisfied with nurses with regard to all dimensions of care. They were least satisfied with the availability of psychosocial support/counselling; and information about social insurance/vocational rehabilitation. Despite the large proportion of individuals with mild disease severity in our sample, a considerable number of needs were identified of which many, on an individual level, varied over time. Key services demanded by PwMS were identified. Also the level of satisfaction with care varied and areas with a potential for improvement were identified such as the availability of rehabilitation services including an increase in the supply of psychosocial support and counselling.


Complications of hydrogel intracorneal lenses in monkeys.
We performed 32 hydrogel keratophakia procedures in rhesus monkey corneas. Surgery was technically successful in 20 eyes. Toxic stromal keratitis occurred in five eyes because of impurities on the lenticules. Fibrosis appeared around the implant in five eyes. Two eyes showed aseptic necrosis of the inferior cornea with extrusion of the implant, attributed to exposure keratitis. Complications during surgery included faulty microkeratome incisions (three eyes) and epithelial implantation in the lamellar bed (one eye). Three lenticules decentered, one extruding through the wound, probably because the monkeys rubbed their eyes excessively. Nine of the 11 eyes with postoperative refraction data showed overcorrection or undercorrection of more than 1.00 diopter. Most of these complications could have been prevented by better technique, design, and manufacture of the lenticule or cooperation of the subjects.


Leiomyosarcoma of the spermatic cord: a case report.
A 61-year-old man presented to our hospital with a 1.5-year history of a gradually enlarging mass in the left scrotum. The mass was apart from the testis and fixed to the spermatic cord. The firm consistency and heterogeneous expression on ultrasonography suggested a malignant tumor. Orchiectomy with high ligation of the spermatic cord was performed and a histological examination revealed leiomyosarcoma of the spermatic cord. Distant metastases were not observed. Because the incidence of local recurrence has been reported to be high, we performed irradiation to control the disease. At 32 months post-surgery he was alive with no evidence of disease.


Effect of methylation on expression of microinjected genes.
The cloned genes for the simian virus 40 large tumor antigen and for herpes simplex virus (HSV) thymidine kinase (TK) were methylated with EcoRI methylase. The genes were microinjected into the nuclei of TK-deficient (tk-) cells, and expression of the genes was determined by immunofluorescence staining for the simian virus 40 large tumor antigen and by [3H]thymidine incorporation followed by autoradiography for HSV TK. We found that methylation of the simian virus 40 gene, under EcoRI or EcoRI* conditions, resulting in methylation at sites within the gene and in the surrounding sequences, has no effect on expression of the large tumor antigen when the gene is manually microinjected into mammalian nuclei. However, methylation of the HSV tk gene at the two EcoRI sites markedly reduces or abolishes the expression of this gene. One of the EcoRI sites of HSV tk is approximately 1.1 kilobases downstream from the 3' end of the gene and is believed to have no regulatory function in the expression of the tk gene. The other EcoRI site is 79 base pairs upstream from the 5' end of the gene and has considerable homology to the regulatory sequence proposed by [Benoist C., O'Hare, K., Breathnach, R., & Chambon, P. (1980) Nucleic Acids Res. 8, 127-142]. Our results are direct proof that methylation can alter gene expression and also that the effect depends strictly on the sites that are methylated.


[Influence of human personal features on acoustic correlates of speech emotional intonation characteristics].
Comparative study of acoustic correlates of emotional intonation was conducted on two types of speech material: sensible speech utterances and short meaningless words. The corpus of speech signals of different emotional intonations (happy, angry, frightened, sad and neutral) was created using the actor's method of simulation of emotions. Native Russian 20-70-year-old speakers (both professional actors and non-actors) participated in the study. In the corpus, the following characteristics were analyzed: mean values and standard deviations of the power, fundamental frequency, frequencies of the first and second formants, and utterance duration. Comparison of each emotional intonation with "neutral" utterances showed the greatest deviations of the fundamental frequency and frequencies of the first formant. The direction of these deviations was independent of the semantic content of speech utterance and its duration, age, gender, and being actor or non-actor, though the personal features of the speakers affected the absolute values of these frequencies.


Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).
We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.


Differences in the total body clearance of lead compounds in the rat and mouse: impact on pharmacokinetic screening strategy.
1. The in vivo clearance (CL) for 498 compounds representing more than 40 lead optimization programmes were compared in the rat and mouse. 2. A total of 278 of the compounds had similar CL values in rat and mouse and 41 compounds had a high CL in one rodent species and a low CL in the other (median seven-fold difference). For this latter subset, comparative in vitro plasma protein binding, liver microsomal or hepatocyte intrinsic CL provided plausible explanations for the observed in vivo differences in many cases. 3. A considerable proportion of compounds with substantially different CL in rodents, and those with a high CL in both rat and mouse, had a low-to-moderate CL in dog and/or monkey (43%). A larger proportion (71%) had promising pharmacokinetics in higher species when CL was low in both rat and mouse. 4. Drug-discovery scientists should consider the potential for there to be substantial differences in the disposition of leads in different rodent species and design screening cascades to explore this possibility.


Chromosomal insertion of TOL transposons in Pseudomonas aeruginosa PAO.
Insertions of the TOL plasmid transposons Tn4651 and Tn4653 into the Pseudomonas aeruginosa PAO chromosome were isolated by a temperature selection technique. The locations and orientations of 16 insertions were determined by pulsed field gel electrophoresis and Southern hybridization with genomic and TOL DNA probes. All insertions occurred within a 334 kb region of the chromosome (representing less than 6% of the genome) with nine of the inserts clustered within a 10 kb area. Each transposon was able to insert in either orientation. An internal duplication of the 39 kb excisable region of pWW0 was seen in two independent insertions.


Contemporary awareness and understanding of cholesterol as a risk factor: results of an American Heart Association national survey.
Public awareness and understanding of risk factors for atherosclerotic vascular disease are essential for successful primary and secondary prevention. The American Heart Association is committed to reducing cardiovascular disease. A professional market survey company conducted a structured national telephone survey of English-speaking adults 40 years and older on behalf of the American Heart Association. Regional and sex quotas were imposed on the sample, and responses were weighted to match the 1999 census projections for region of the country, age, sex, and race. Interviews were completed with 1163 adults 40 years and older. A national probability sample of 1114 was created. Of the final sample, 28.5% were 65 years or older, 56.1% were women, and 86.5% were white. Although 91.2% of respondents stated that it was "important to them personally to have a healthy cholesterol level" (77.6% extremely or very important), 51% did not know their own level. Only 40.2% were aware of national guidelines for cholesterol management, and 53.1% either did not know or overestimated the correct desirable total cholesterol level for a healthy adult. When asked what sources of information they rely on the most, 66.8% identified physicians, while only 3.7% rely primarily on the Internet. Public understanding of cholesterol management is suboptimal. Physicians have a unique opportunity, on the basis of public attitudes and access, to improve cholesterol education.


Bioconversion of 2-hydroxy-6-oxo-6-(4'-chlorophenyl)hexa-2,4-dienoic acid, the meta-cleavage product of 4-chlorobiphenyl.
Bacterial conversion of 4-chlorobiphenyl (4-CB) usually proceeds through a pathway involving an initial oxidation of the unsubstituted ring in the 2,3 position followed by a 1,2 meta-cleavage. The meta-cleavage product (MCP) is converted through a single hydrolysis step into chlorobenzoic acid. However, several other acidic metabolites that were not expected as part of this pathway have already been described. In this paper, we used strains of Pseudomonas putida carrying cloned genes from Pseudomonas testosteroni B-356 that are involved in polychlorinated biphenyl (PCB) degradation to demonstrate that several acidic metabolites found in the culture media of various bacteria grown in the presence of 4-CB result from alternative novel bioconversion pathways of MCP. The degradation products of MCP through these pathways were identified as analogues with saturated or shorter side chains or as 4'-chlorophenyl-2-picolinic acid; pathways leading to their formation are proposed.


Crystal structure of the glycosyltransferase SnogD from the biosynthetic pathway of nogalamycin in Streptomyces nogalater.
The glycosyltransferase SnogD from Streptomyces nogalater transfers a nogalamine moiety to the metabolic intermediate 3',4'-demethoxynogalose-1-hydroxynogalamycinone during the final steps of biosynthesis of the aromatic polyketide nogalamycin. The crystal structure of recombinant SnogD, as an apo-enzyme and with a bound nucleotide, 2-deoxyuridine-5'-diphosphate, was determined to 2.6 Å resolution. Reductive methylation of SnogD was crucial for reproducible preparation of diffraction quality crystals due to creation of an additional intermolecular salt bridge between methylated lysine residue Lys384 and Glu374* from an adjacent molecule in the crystal lattice. SnogD is a dimer both in solution and in the crystal, and the enzyme subunit displays a fold characteristic of the GT-B family of glycosyltransferases. Binding of the nucleotide is associated with rearrangement of two active-site loops. Site-directed mutagenesis shows that two active-site histidine residues, His25 and His301, are critical for the glycosyltransferase activities of SnogD both in vivo and in vitro. The crystal structures and the functional data are consistent with a role for His301 in binding of the diphosphate group of the sugar donor substrate, and a function of His25 as a catalytic base in the glycosyl transfer reaction.


Evaluation of synergism in essential oils against the cattle tick Rhipicephalus microplus in Burkina Faso.
The cattle tick Rhipicephalus microplus affects animal production economically by reducing weight gain and milk production and causing diseases, such as babesiosis and anaplasmosis. Using synthetic acaricides to reduce their incidence has caused the emergence of resistant tick populations. The present study aimed to assess the in vitro acaricidal activity of combinations of essential oils (EOs) from Ocimum americanum, Ocimum gratissimum, and Lippia multiflora against R. microplus larvae. In fact, numerous biological properties have been reported on EOs from these three plants, including acaricidal properties. Hence, a larval immersion test was performed using a population of R. microplus resistant to synthetic acaricides used in Burkina Faso. Results revealed that EO from O. gratissimum was the most effective on R. microplus larvae with LC50 and LC90 values at 10.36 and 15.51 mg/mL, respectively. For EO combinations, the most significant synergistic effect was obtained by combination 6 (1/3 O. americanum + 2/3 O. gratissimum +1/6 L. multiflora), with a combination index value of 0.44. All combinations presented dose reduction index >1, indicating a favorable dose reduction. According to the literature, this is the first study to determine the combination effect of EOs from the abovementioned plants in controlling R. microplus activity in vitro. Thus, the combination of these EOs is an alternative to control the resistant populations of invasive cattle ticks.


Increased weight gain by C-section: Functional significance of the primordial microbiome.
Epidemiological evidence supports a direct association between early microbiota impact-including C-section-and obesity. We performed antibiotic-free, fostered C-sections and determined the impact on the early microbiota and body weight during development. Mice in the C-section group gained more body mass after weaning, with a stronger phenotype in females. C-section-born mice lacked the dynamic developmental gut microbiota changes observed in control mice. The results demonstrate a causal relationship between C-section and increased body weight, supporting the involvement of maternal vaginal bacteria in normal metabolic development.


Sequence diversity in the A domain of Staphylococcus aureus fibronectin-binding protein A.
Fibronectin-binding protein A (FnBPA) mediates adhesion of Staphylococcus aureus to fibronectin, fibrinogen and elastin. We previously reported that S. aureus strain P1 encodes an FnBPA protein where the fibrinogen/elastin-binding domain (A domain) is substantially divergent in amino acid sequence from the archetypal FnBPA of S. aureus NCTC8325, and that these variations created differences in antigenicity. In this study strains from multilocus sequence types (MLST) that spanned the genetic diversity of S.aureus were examined to determine the extent of FnBPA A domain variation within the S. aureus population and its effect on ligand binding and immuno-crossreactivity. Seven different isotype forms (I - VII) of the FnBPA A domain were identified which were between 66 to 76% identical in amino acid sequence in any pair-wise alignment. The fnbA allelic variants in strains of different multilocus sequence type were identified by DNA hybridization using probes specific for sequences encoding the highly divergent N3 sub-domain of different isotypes. Several isotypes were not restricted to specific clones or clonal complexes but were more widely distributed. It is highly likely that certain fnbA genes have been transferred horizontally. Residues lining the putative ligand-binding trench were conserved, which is consistent with the ability of each A domain isotype to bind immobilized fibrinogen and elastin by the dock-latch-lock mechanism. Variant amino acid residues were mapped on a three-dimensional model of the FnBPA A domain and were predicted to be surface-exposed. Polyclonal antibodies raised against the recombinant isotype I A domain bound that protein with a 4 - 7 fold higher apparent affinity compared to the A domains of isotypes II - VII, while some monoclonal antibodies generated against the isotype I A domain showed reduced or no binding to the other isotypes. The FnBPA A domain occurs in at least 7 different isotypes which differ antigenically and exhibit limited immuno-crossreactivity, yet retain their ligand-binding functions. Antigenic variation of the FnBPA A domain may aid S. aureus to evade the host's immune responses. These findings have implications for the development of vaccines or immunotherapeutics that target FnBPA.


Monotonicity-constrained species distribution models.
Flexible modeling frameworks for species distribution models based on generalized additive models that allow for smooth, nonlinear effects and interactions are of increasing importance in ecology. Commonly, the flexibility of such smooth function estimates is controlled by means of penalized estimation procedures. However, the actual shape remains unspecified. In many applications, this is not desirable as researchers have a priori assumptions on the shape of the estimated effects, with monotonicity being the most important. Here we demonstrate how monotonicity constraints can be incorporated in a recently proposed flexible framework for species distribution models. Our proposal allows monotonicity constraints to be imposed on smooth effects and on ordinal, categorical variables using an additional asymmetric L2 penalty. Model estimation and variable selection for Red Kite (Milvus milvus) breeding was conducted using the flexible boosting framework implemented in R package mboost.


US health care crisis.
The United States health care is presently challenged by a significant economic crisis. The purpose of this report is to introduce the readers of Medicinski Pregled to the root causes of this crisis and to explain the steps undertaken to reform health care in order to solve the crisis. It is hoped that the information contained in this report will be of value, if only in small measure, to the shaping of health care in Serbia.


Exercise Capacity and Response to Training Quantitative Trait Loci in a NZW X 129S1 Intercross and Combined Cross Analysis of Inbred Mouse Strains.
Genetic factors determining exercise capacity and the magnitude of the response to exercise training are poorly understood. The aim of this study was to identify quantitative trait loci (QTL) associated with exercise training in mice. Based on marked differences in training responses in inbred NZW (-0.65 ± 1.73 min) and 129S1 (6.18 ± 3.81 min) mice, a reciprocal intercross breeding scheme was used to generate 285 F2 mice. All F2 mice completed an exercise performance test before and after a 4-week treadmill running program, resulting in an increase in exercise capacity of 1.54 ± 3.69 min (range = -10 to +12 min). Genome-wide linkage scans were performed for pre-training, post-training, and change in run time. For pre-training exercise time, suggestive QTL were identified on Chromosomes 5 (57.4 cM, 2.5 LOD) and 6 (47.8 cM, 2.9 LOD). A significant QTL for post-training exercise capacity was identified on Chromosome 5 (43.4 cM, 4.1 LOD) and a suggestive QTL on Chromosomes 1 (55.7 cM, 2.3 LOD) and 8 (66.1 cM, 2.2 LOD). A suggestive QTL for the change in run time was identified on Chromosome 6 (37.8 cM, 2.7 LOD). To identify shared QTL, this data set was combined with data from a previous F2 cross between B6 and FVB strains. In the combined cross analysis, significant novel QTL for pre-training exercise time and change in exercise time were identified on Chromosome 12 (54.0 cM, 3.6 LOD) and Chromosome 6 (28.0 cM, 3.7 LOD), respectively. Collectively, these data suggest that combined cross analysis can be used to identify novel QTL and narrow the confidence interval of QTL for exercise capacity and responses to training. Furthermore, these data support the use of larger and more diverse mapping populations to identify the genetic basis for exercise capacity and responses to training.


Super-Gaussian conical refraction beam.
We demonstrate the transformation of Gaussian input beams into super-Gaussian beams with a quasi flat-top transverse profile by means of the conical refraction phenomenon by adjusting the ratio between the ring radius and the waist radius of the input beam to 0.445. We discuss the beam propagation of the super-Gaussian beam and show that it has a confocal parameter three times larger than the one that would be obtained from a Gaussian beam. The experiments performed with a KGd(WO4)2 biaxial crystal are in good agreement with the theoretical predictions.


Relative contribution of obesity and menopause to the association between serum adiponectin and incident metabolic syndrome.
Metabolic syndrome is closely linked to obesity. Menopause may play a critical role in understanding the pathophysiology of metabolic syndrome in women. We investigated the relative contribution of obesity and menopause to the association between serum adiponectin levels and the development of metabolic syndrome. A prospective cohort study was conducted in which a total of 1,219 women without metabolic syndrome were examined at baseline (2005-2008) and followed up (2008-2011). Women were divided according to tertiles of serum adiponectin levels and menopause status, and then stratified into four groups: the nonobese with high adiponectin; the nonobese with low adiponectin; the obese with high adiponectin; and the obese with low adiponectin. During an average 2.5-year follow-up, 44 premenopausal women (9.8%) and 161 postmenopausal women (20.9%) developed metabolic syndrome. The obese group with low serum adiponectin demonstrated an increased risk for developing metabolic syndrome in both premenopausal (odds ratio [OR] 5.92, 95% confidence interval [CI] 2.24-15.66) and postmenopausal women (OR 4.22, 95% CI 2.41-7.36). However, the inverse association between serum adiponectin levels and incidence of metabolic syndrome was observed in premenopausal women with obesity (OR 0.16, 95% CI 0.03-0.81), but not in postmenopausal women with obesity (OR 0.55, 95% CI 0.27-1.14). High serum adiponectin levels showed no inverse association with metabolic syndrome in postmenopausal women with obesity. These findings may suggest a need for closer management of metabolic risk in postmenopausal women.


Investigating a network model of word generation with positron emission tomography.
By using positron emission tomography (PET) we examined the biological validity of a network model describing changes in cerebral activity associated with intrinsic and extrinsic word generation. The production of words not specified by an extrinsic stimulus constitutes willed or intrinsic generation. Perceiving a heard word is an example of extrinsic generation. The model incorporates three neuronal systems: a pool that stores word representations in a distributed fashion, an afferent system conveying sensory input to the pool and a modulating system that alters the responsivity of neurons in the pool. Simulations based on the model suggested that intrinsic generation would be associated with low activity in the pool, consequent on reduced modulation, and extrinsic generation with high activity. We measured cerebral activity with PET during intrinsic (verbal fluency) and extrinsic (responding to heard words) word generation and found this pattern of changes in the left superior temporal region. We were able to designate this region the site of the distributed word store and implicate the left dorsolateral prefrontal cortex (DLPFC) as the source of modulation. The relation between the superior temporal gyrus and DLPFC was shown by examining the correlation between the two regions in terms of cerebral activity. We conclude that the left DLPFC is responsible for modulating the responsivity of a neural system in the superior temporal gyrus and is the probable mediator of changes in attentional and intentional states that underlies the intrinsic generation of words.


Pyoderma gangrenosum with IgA gammopathy.
A 46-year-old man with pyoderma gangrenosum and IgA gammopathy is described. This patient had no other identifiable associated systemic disease. His condition was unresponsive to oral corticosteroids, sulfones, and sulfapyridine therapy. His course was complicated by chronic sinusitis and necrotizing pneumonia. He was treated with clofazimine.


Histone acetyltransferase PCAF accelerates apoptosis by repressing a GLI1/BCL2/BAX axis in hepatocellular carcinoma.
P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), has been found to regulate numerous cell signaling pathways controlling cell fate by acetylating both histone and non-histone proteins. We previously reported that PCAF upregulates cell apoptosis by inactivating Serine/Threonine Protein Kinase 1 (AKT1) signaling and consequently inhibits hepatocellular carcinoma (HCC) cell growth. Here, we show that PCAF can directly acetylate cytoplasmic GLI1 protein at lysine 518, preventing its nuclear translocation and promoter occupancy, and consequently suppressing Hedgehog (Hh) signaling in HCC. Further, our results show that GLI1 can increase Bcl-2 expression and downregulate BAX. Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis. Further, we provide evidence that knockdown of GLI1 abrogates the inhibitory effect of PCAF on the growth of HCC in vitro. PCAF was also found to sensitize HCC cells to 5-fluorouracil (5-FU) treatment by regulating GLI1/Bcl-2/BAX axis-dependent apoptosis. In vivo experiments also confirmed the regulatory effect of PCAF on the GLI1/Bcl-2/BAX axis and its synergistic antitumor effects with 5-FU. Gene expression microarray studies showed that PCAF was downregulated in HCC tissues compared with adjacent liver tissues and that PCAF expression was significantly associated with longer overall survival and recurrence-free survival after surgery. Together, these results show that PCAF can induce cell apoptosis by modulating a GLI1/Bcl-2/BAX axis that in turn suppresses HCC progression, and suggest that 5-FU may exert a stronger anti-tumor effect in patients with PCAF expression in HCC tumors.


A comprehensive molecular characterization of the 8q22.2 region reveals the prognostic relevance of OSR2 mRNA in muscle invasive bladder cancer.
Technological advances in molecular profiling have enabled the comprehensive identification of common regions of gene amplification on chromosomes (amplicons) in muscle invasive bladder cancer (MIBC). One such region is 8q22.2, which is largely unexplored in MIBC and could harbor genes with potential for outcome prediction or targeted therapy. To investigate the prognostic role of 8q22.2 and to compare different amplicon definitions, an in-silico analysis of 357 patients from The Cancer Genome Atlas, who underwent radical cystectomy for MIBC, was performed. Amplicons were generated using the GISTIC2.0 algorithm for copy number alterations (DNA_Amplicon) and z-score normalization for mRNA gene overexpression (RNA_Amplicon). Kaplan-Meier survival analysis, univariable, and multivariable Cox proportional hazard ratios were used to relate amplicons, genes, and clinical parameters to overall (OS) and disease-free survival (DFS). Analyses of the biological functions of 8q22.2 genes and genomic events in MIBC were performed to identify potential targets. Genes with prognostic significance from the in silico analysis were validated using RT-qPCR of MIBC tumor samples (n = 46). High 8q22.2 mRNA expression (RNA-AMP) was associated with lymph node metastases. Furthermore, 8q22.2 DNA and RNA amplified patients were more likely to show a luminal subtype (DNA_Amplicon_core: p = 0.029; RNA_Amplicon_core: p = 0.01). Overexpression of the 8q22.2 gene OSR2 predicted shortened DFS in univariable (HR [CI] 1.97 [1.2; 3.22]; p = 0.01) and multivariable in silico analysis (HR [CI] 1.91 [1.15; 3.16]; p = 0.01) and decreased OS (HR [CI] 6.25 [1.37; 28.38]; p = 0.0177) in RT-qPCR data analysis. Alterations in different levels of the 8q22.2 region are associated with manifestation of different clinical characteristics in MIBC. An in-depth comprehensive molecular characterization of genomic regions involved in cancer should include multiple genetic levels, such as DNA copy number alterations and mRNA gene expression, and could lead to a better molecular understanding. In this study, OSR2 is identified as a potential biomarker for survival prognosis.


Genomic analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Vietnam in 2011 and 2015-16.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae, compromising gonorrhoea treatment, is a threat to reproductive health globally. South-East and East Asia have been major sources of emergence and subsequent international spread of AMR gonococcal strains during recent decades. We investigated gonococcal isolates from 2011 and 2015-16 in Vietnam using AMR testing, WGS and detection of AMR determinants. Two hundred and twenty-nine gonococcal isolates cultured in 2015-16 (n = 121) and 2011 (n = 108) in Vietnam were examined. AMR testing was performed using Etest and WGS with Illumina MiSeq. Resistance among the 2015-16 isolates was as follows: ciprofloxacin, 100%; tetracycline, 79%; benzylpenicillin, 50%; cefixime, 15%; ceftriaxone, 1%; spectinomycin, 0%; and 5% were non-WT to azithromycin. Eighteen (15%) isolates were MDR. The MIC range for gentamicin was 2-8 mg/L. Among the 2015-16 isolates, 27% (n = 33) contained a mosaic penA allele, while no isolates had a mosaic penA allele in 2011. Phylogenomic analysis revealed introduction after 2011 of two mosaic penA-containing clones (penA-10.001 and penA-34.001), which were related to cefixime-resistant strains spreading in Japan and Europe, and a minor clade (eight isolates) relatively similar to the XDR strain WHO Q. From 2011 to 2015-16, resistance in gonococci from Vietnam increased to all currently and previously used antimicrobials except ceftriaxone, spectinomycin and tetracycline. Two mosaic penA-containing clones were introduced after 2011, explaining the increased cefixime resistance. Significantly increased AMR surveillance, antimicrobial stewardship and use of WGS for molecular epidemiology and AMR prediction for gonococcal isolates in Vietnam and other Asian countries are crucial.


Hepatitis B virus capsid assembly is enhanced by naturally occurring mutation F97L.
In chronic hepatitis B virus (HBV) infections, one of the most common mutations to the virus occurs at amino acid 97 of the core protein, where leucine replaces either phenylalanine or isoleucine, depending on strain. This mutation correlates with changes in viral nucleic acid metabolism and/or secretion. We hypothesize that this phenotype is due in part to altered core assembly, a process required for DNA synthesis. We examined in vitro assembly of empty HBV capsids from wild-type and F97L core protein assembly domains. The mutation enhanced both the rate and extent of assembly relative to those for the wild-type protein. The difference between the two proteins was most obvious in the temperature dependence of assembly, which was dramatically stronger for the mutant protein, indicating a much more positive enthalpy. Since the structures of the mutant and wild-type capsids are essentially the same and the mutation is not involved in the contact between dimers, we suggest that the F97L mutation affects the dynamic behavior of dimer and capsid.


Nephrotic syndrome associated with malignant tumours.
The nephrotic syndrome complicating malignancy is an unusual occurrence. We report here four cases of nephrotic syndrome associated with malignant tumours. Three cases were associated with bronchogenic carcinoma and one with adenocarcinoma of colon. One of the four cases developed nephrotic syndrome before the discovery of bronchogenic carcinoma. All patients had renal biopsies with light microscopy, immunofluorescence and electron microscopy. The findings suggest an immune-complex disease complicating malignancy. The true incidence of nephrotic syndrome associated with malignant tumours is unknown. However it is clinically prudent to screen for malignancy in older patients presenting with nephrotic syndrome.


A design concept of parallel elasticity extracted from biological muscles for engineered actuators.
Series elastic actuation that takes inspiration from biological muscle-tendon units has been extensively studied and used to address the challenges (e.g. energy efficiency, robustness) existing in purely stiff robots. However, there also exists another form of passive property in biological actuation, parallel elasticity within muscles themselves, and our knowledge of it is limited: for example, there is still no general design strategy for the elasticity profile. When we look at nature, on the other hand, there seems a universal agreement in biological systems: experimental evidence has suggested that a concave-upward elasticity behaviour is exhibited within the muscles of animals. Seeking to draw possible design clues for elasticity in parallel with actuators, we use a simplified joint model to investigate the mechanisms behind this biologically universal preference of muscles. Actuation of the model is identified from general biological joints and further reduced with a specific focus on muscle elasticity aspects, for the sake of easy implementation. By examining various elasticity scenarios, one without elasticity and three with elasticity of different profiles, we find that parallel elasticity generally exerts contradictory influences on energy efficiency and disturbance rejection, due to the mechanical impedance shift thus caused. The trade-off analysis between them also reveals that concave parallel elasticity is able to achieve a more advantageous balance than linear and convex ones. It is expected that the results could contribute to our further understanding of muscle elasticity and provide a theoretical guideline on how to properly design parallel elasticity behaviours for engineering systems such as artificial actuators and robotic joints.


Efficacy of dietary treatments for epilepsy.
The ketogenic diet (KD) is a high fat, restricted carbohydrate regime that has been used as a treatment for seizures since the 1920s, when it was designed to induce a similar metabolic response to fasting. A modification of this early classical version of the KD was introduced in the 1970s using medium chain triglycerides as an alternative fat source. More recently, two alternative, less-restrictive dietary treatments have been developed: the modified Atkins diet and the low glycaemic index diet. There are many case reports and observational studies reporting successful use of the KD, and a growing number of studies reporting similar success with the modified Atkins protocol. A recent randomised controlled trial has shown a significant benefit of the KD compared to no change in treatment. The use of these dietary therapies in the UK is supported by literature evidence, although often is limited by a lack of resources; increasing awareness and knowledge is fundamental to ensure availability for those individuals with intractable epilepsy who may benefit from them.


The anandamide analog, Met-F-AEA, controls human breast cancer cell migration via the RHOA/RHO kinase signaling pathway.
The endocannabinoid system regulates cell proliferation and migration in human breast cancer cells. In this study, we showed that a metabolically stable analog of anandamide, 2-methyl-2'-F-anandamide (Met-F-AEA), inhibited the RHOA activity and caused a RHOA delocalization from the cell membrane to cytosol determining a decrease in actin stress fibers. Overexpression of a dominant negative of RHOA activity and treatment of these cells with a RHO-associated protein kinase (ROCK) inhibitor, Y 27632, mimicked Met-F-AEA effects on actin organization and cell migration. We suggest that the inhibitory effect of Met-F-AEA on tumor cell migration could be related to RHOA-ROCK-dependent signaling pathway.


Total antioxidant capacity of plant foods, beverages and oils consumed in Italy assessed by three different in vitro assays.
Epidemiologic studies have demonstrated an inverse association between consumption of fruits and vegetables and morbidity and mortality from degenerative diseases. The antioxidant content of fruits and vegetables may contribute to the protection they offer from disease. Because plant foods contain many different classes and types of antioxidants, knowledge of their total antioxidant capacity (TAC), which is the cumulative capacity of food components to scavenge free radicals, would be useful for epidemiologic purposes. To accomplish this, a variety of foods commonly consumed in Italy, including 34 vegetables, 30 fruits, 34 beverages and 6 vegetable oils, were analyzed using three different assays, i.e., Trolox equivalent antioxidant capacity (TEAC), total radical-trapping antioxidant parameter (TRAP) and ferric reducing-antioxidant power (FRAP). These assays, based on different chemical mechanisms, were selected to take into account the wide variety and range of action of antioxidant compounds present in actual foods. Among vegetables, spinach had the highest antioxidant capacity in the TEAC and FRAP assays followed by peppers, whereas asparagus had the greatest antioxidant capacity in the TRAP assay. Among fruits, the highest antioxidant activities were found in berries (i.e., blackberry, redcurrant and raspberry) regardless of the assay used. Among beverages, coffee had the greatest TAC, regardless of the method of preparation or analysis, followed by citrus juices, which exhibited the highest value among soft beverages. Finally, of the oils, soybean oil had the highest antioxidant capacity, followed by extra virgin olive oil, whereas peanut oil was less effective. Such data, coupled with an appropriate questionnaire to estimate antioxidant intake, will allow the investigation of the relation between dietary antioxidants and oxidative stress-induced diseases.


Impact of heat-treatment on wastewater analytical parameters.
Raw wastewater analysis is an important step in treatment assessment; however, it is associated with risks of personnel exposure to pathogens. Such risks are enhanced during virus outbreaks, such as the COVID pandemic, and heat-treatment is a commonly used mitigation measure. We examined whether heat-treatment compromises wastewater analytical parameters results. We found that heat-treatment of blackwater at 60 °C for 90 min in capped containers yielded no statistically different values (p > 0.05) for pH, chemical oxygen demand (COD), ammonia (NH3), total nitrogen (TN), total suspended solids (TSS), and turbidity for specimens from three different sources. This heat-treatment inactivated coliform bacteria (>4 log10 reduction) thus compromising the measurement of commonly used fecal contamination indicators. The observation of intact helminth eggs in heat-treated specimens suggests that the helminth egg enumeration assay is not compromised. These findings indicate that heat-treatment for the safe handling of wastewater, as may be needed in future virus outbreaks, does not affect the measurements of many common wastewater physico-chemical properties.


Coronary wedge pressure in relation to spontaneously visible and recruitable collaterals.
Coronary angiography demonstrates only collateral arteries that are already in use (spontaneously visible collaterals). Percutaneous transluminal coronary angioplasty (PTCA) provides an opportunity to uncover collaterals ready to become functional in case of occlusion of the recipient artery (recruitable collaterals). The incidence of recruitable collaterals and their relation to the distal pressure in the occluded artery (coronary wedge pressure) during a 30 sec or longer balloon occlusion was assessed in 57 coronary arteries of 49 patients undergoing PTCA for a proximal coronary stenosis or occlusion. Collateral to 75% of the arteries were present. Spontaneously visible collaterals were four times as frequent as recruitable collaterals. Coronary wedge pressure was significantly higher in arteries with spontaneously visible and recruitable collaterals (41 +/- 12 and 36 +/- 12 mm Hg, respectively) than in arteries without collaterals (18 +/- 4 mm Hg). A coronary wedge pressure of 30 mm Hg or higher was found exclusively in the presence of collaterals. Electrocardiographic changes during balloon occlusion were found more frequently with arteries without collaterals than with arteries with spontaneously visible or recruitable collaterals. Chest pain was more frequent in patients without collaterals or with recruitable collaterals than in those with spontaneously visible collaterals. Major in-hospital events occurred in three patients with collaterals, with a salutary influence of the collaterals in two. The coronary wedge pressure allows prediction of recruitable collaterals. Their clinical impact remains to be investigated in long-term studies on large patient populations.


Centromere-specifying nucleosomes persist in aging mouse oocytes in the absence of nascent assembly.
Centromeres direct genetic inheritance but are not themselves genetically encoded. Instead, centromeres are defined epigenetically by the presence of a histone H3 variant, CENP-A 1 . In cultured somatic cells, an established paradigm of cell cycle-coupled propagation maintains centromere identity: CENP-A is partitioned between sisters during replication and replenished by new assembly, which is restricted to G1. The mammalian female germline challenges this model because of the cell cycle arrest between pre-meiotic S-phase and the subsequent G1, which can last for the entire reproductive lifespan (months to decades). New CENP-A chromatin assembly maintains centromeres during prophase I in worm and starfish oocyte 2,3 , suggesting that a similar process may be required for centromere inheritance in mammals. However, we show that centromere chromatin is maintained long-term independent of new assembly during the extended prophase I arrest in mouse oocytes. Conditional knockout of Mis18α, an essential component of the assembly machinery, in the female germline at the time of birth has almost no impact on centromeric CENP-A nucleosome abundance nor any detectable detriment to fertility.


Lower body mass index and age are predictive of improved pain and health utility scores following arthroscopic management of femoroacetabular impingement.
To identify patient factors associated with improved pain scores, functional hip scores, health-related quality of life, and re-operation rates after arthroscopic management of femoroacetabular impingement (FAI). Using the comprehensive dataset from the multinational Femoroacetabular Impingement Randomized Controlled Trial (FIRST), a total of 13 prognostic factors that were chosen a priori were identified that would be expected to predict post-surgical outcomes. The primary outcome was pain assessed using a Visual Analogue Scale (VAS) and secondary outcomes included hip function (Hip Outcome Score [HOS] and International Hip Outcome Tool [iHOT-12]), health-related quality of life (Short Form-12 [SF-12] and Euro-Qol 5 Dimensions [EQ-5D]), and re-operation rate. A multivariable linear regression was used to analyse the change questionnaire scores from baseline to 12 months post-surgery including all 13 prognostic factors as independent variables. A total of 27 re-operation events were analysed at 24 months using a multivariable logistic regression including only the treatment group variable. Of the 154 patients that had VAS scores completed at 12 months, a lower BMI (adjusted mean difference [aMD], 4.48 for a 5-unit decrease in BMI; 95% confidence interval [CI] 0.33-8.63; p = 0.035) was significantly associated with less pain. There was a significant negative association between increasing age and 1-year EQ-5D scores (aMD, - 0.04 for every 10-year increase in age; 95% CI - 0.07 to - 0.006; p = 0.020). The degree of impingement, severity of osteoarthritis, type of procedure, and adjudicated quality of surgery were not significantly associated with improvement across all outcomes at 12 months. Furthermore, there was no significant association between the treatment variable and the incidence of re-operation at 24 months. This study identified that lower BMI and age are predictive of improved pain and health utility scores, respectively, following arthroscopic management of FAI at 12 months post-surgery. These results may be a helpful adjunct in clinical decisions for this patient population when determining candidacy for surgical intervention. I.


Hepatitis C virus core protein and hepatitis activity are associated through transactivation of interleukin-8.
We evaluated the association between variations in hepatitis C virus (HCV) core protein and hepatitis severity in patients with chronic HCV infection who achieved remission without viral eradication and had a biochemical response to interferon (IFN) therapy, to evaluate the effect of HCV core sequence in the absence of the influence of host factors. METHODS. Using serum from 10 patients with a biochemical response and 10 patients with no response, we measured serum levels of interleukin (IL)-1 beta , IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFN- gamma , and tumor necrosis factor- alpha before and after IFN therapy. Expression vectors with the core region were transfected into Huh7 cells, and cytokine induction was evaluated by reporter assay. In biochemical responders, only IL-8 levels decreased after IFN therapy (P=.04). Changes in the C-terminal hydrophobic region were observed more frequently in biochemical responders. Activation of the IL-8 promoter by HCV core protein was significantly decreased in biochemical responders after IFN therapy (P=.04). When 69 C-terminal amino acids from before IFN therapy were replaced with those from after IFN therapy in 3 biochemical responders, their ability to transactivate IL-8 decreased. Differences in amino acids in the HCV core protein correlates with hepatitis activity through the modulation of IL-8 induction in HCV-infected patients.


Spiral (helical) CT of the renal vasculature.
The renal arteries are among the most challenging of the major aortic branches to image with spiral CT. Optimization of CT acquisition parameters is critical to creating diagnostic renal CT angiograms. When careful attention is paid to prescribing these examinations, renal CT angiography can be a very useful, noninvasive alternative to conventional angiography for the assessment of renal artery stenosis, screening of potential renal donors, planning repair of ureteropelvic junction stenoses, and identification of relevant renal artery relationships to abdominal aortic lesions. This review outlines important technical considerations for performing renal CT angiography and examines currently published data on the utility of spiral CT in a variety of clinical conditions.


Applications of high content screening in life science research.
Over the last decade, imaging as a detection mode for cell based assays has opened a new world of opportunities to measure "phenotypic endpoints" in both current and developing biological models. These "high content" methods combine multiple measurements of cell physiology, whether it comes from sub-cellular compartments, multicellular structures, or model organisms. The resulting multifaceted data can be used to derive new insights into complex phenomena from cell differentiation to compound pharmacology and toxicity. Exploring the major application areas through review of the growing compendium of literature provides evidence that this technology is having a tangible impact on drug discovery and the life sciences.


Stigmasterol: An adjuvant for beta lactam antibiotics against beta-lactamase positive clinical isolates.
The emergence of beta lactamase producing bacterial strains eliminated the use of beta lactam antibiotics as chemotherapeutic alternative. Beta lactam antibiotics can be coupled with non-antibiotic adjuvants to combat these multidrug resistant strains. We study the synergistic antibiotic effect of stigmasterol as adjuvant of ampicillin against clinical isolates. Ampicillin was used in this study as a beta lactam antibiotic model. All test bacteria were beta lactamase producing clinical isolates. The combination showed significantly better antibiotic activity on all bacteria tested. The two test substances have synergistic antibiotic activity, and the effect was observed in both Gram positive and Gram negative bacteria. The synergistic antibiotic effect of stigmasterol and ampicillin was evident by the low fractional inhibitory concentration (FIC) index on Checkerboard Assay. The results suggest that the combination of ampicillin and stigmasterol acts additively in the treatment of infections caused by beta-lactamase producing pathogens. In bacterial growth reduction assay, ampicillin and stigmasterol alone exhibited very weak inhibitory effect on the bacterial growth, relative to ethanol control. Comparatively, combination of stigmasterol-ampicillin greatly reduced the colony counts at least by 98.7%. In conclusion, we found synergistic effects of stigmasterol and ampicillin against beta lactamase producing clinical isolates. This finding is important as it shows potential application of stigmasterol as an antibiotic adjuvant.


A segmentation-based predictive multiresolution image coder.
Recursive rectilinear tessellations like quadtree are widely used in image coding, but a regular tessellation, despite simple geometry, may not suit image compression because it is too rigid to reflect the scene structure of an image. The paper presents a new image pyramid formed by adaptive, tree-structured segmentation to be a framework of a predictive multiresolution image coder. Subjectively appealing compression results are obtained at different resolutions by scene-adaptive, tree-structured segmentation and by exploiting the statistical dependency between the layers of the image pyramid. The adaptive segmentation-based image coder is constructed by recursive, least-squares piecewise functional approximation. The seemingly expensive encoding process can be made efficient by an incremental least-squares computation technique. The decoding is simple and can be done in real time if assisted by existing hardware technology.


Cold shock before associative conditioning blocks memory retrieval, but cold shock after conditioning blocks memory retention in Caenorhabditis elegans.
The effects of cooling on associative learning and memory processes in Caenorhabditis elegans were investigated by giving the worms cold shock at various times before or after conditioning. A pretraining cold shock in the 30 min immediately before conditioning and a posttraining cold shock in the 30 min immediately after conditioning both disrupted learning and memory processes tested a short time after conditioning. However, if tested 3 hr after conditioning, worms given a pretraining cold shock demonstrated learned preferences, whereas worms given a posttraining cold shock still had memory deficits. These results suggest that the effects of cold shock on associative learning and memory can be dissociated into effects on memory retrieval and memory retention.


The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1.
Members of the cullin and RING finger ROC protein families form heterodimeric complexes to constitute a potentially large number of distinct E3 ubiquitin ligases. We report here that the highly conserved C-terminal sequence in CUL1 is dually required, both for nuclear localization and for modification by NEDD8. Disruption of ROC1 binding impaired nuclear accumulation of CUL1 and decreased NEDD8 modification in vivo but had no effect on NEDD8 modification of CUL1 in vitro, suggesting that ROC1 promotes CUL1 nuclear accumulation to facilitate its NEDD8 modification. Disruption of NEDD8 binding had no effect on ROC1 binding, nor did it affect nuclear localization of CUL1, suggesting that nuclear localization and NEDD8 modification of CUL1 are two separable steps, with nuclear import preceding and required for NEDD8 modification. Disrupting NEDD8 modification diminishes the IkappaBalpha ubiquitin ligase activity of CUL1. These results identify a pathway for regulation of CUL1 activity-ROC1 and the CUL1 C-terminal sequence collaboratively mediate nuclear accumulation and NEDD8 modification, facilitating assembly of active CUL1 ubiquitin ligase. This pathway may be commonly utilized for the assembly of other cullin ligases.


Rural residence and cancer outcomes in the United States: issues and challenges.
"Neighborhoods and health" research has shown that area social factors are associated with the health outcomes that patients with cancer experience across the cancer control continuum. To date, most of this research has been focused on the attributes of urban areas that are associated with residents' poor cancer outcomes with less focused on attributes of rural areas that may be associated with the same. Perhaps because there is not yet a consensus in the United States regarding how to define "rural," there is not yet an accepted analytic convention for studying issues of how patients' cancer outcomes may vary according to "rural" as a contextual attribute. The research that exists reports disparate findings and generally treats rural residence as a patient attribute rather than a contextual factor, making it difficult to understand what factors (e.g., unmeasured individual poverty, area social deprivation, area health care scarcity) may be mediating the poor outcomes associated with rural (or non-rural) residence. Here, we review literature regarding the potential importance of rural residence on cancer patients' outcomes in the United States with an eye towards identifying research conventions (i.e., spatial and analytic) that may be useful for future research in this important area.


[Pathomorphology of pulmonary aspergillosis in tuberculosis patients based on according to resection material].
To investigate various manifestations of broncho-pulmonary aspergillosis and to ascertain its association with a previous disease there were carried out histotopographic, histological and mycological studies of specimens of the lung tissue resected in 37 patients in connection with aspergillomas of the lungs and broncho-pulmonary aspergillosis. The investigations showed that aspergillosis was one of the forms of dysbacteriosis in the human organism and could develop against the background of post-tuberculous, tuberculous and nonspecific changes. The development of aspergillosis following post-tuberculous changes should be considered as a second nonspecific disease pathogenetically associated with tuberculosis, but with an etiological factor ot its own. There are the following forms of broncho-pulmonary aspergillosis: aspergillomas, isolated aspergillosis of the bronchi, extensive aspergillosis of the bronchi and cyst-like cavities, aspergillous pneumonia.


Protected DNA strand displacement for enhanced single nucleotide discrimination in double-stranded DNA.
Single nucleotide polymorphisms (SNPs) are a prime source of genetic diversity. Discriminating between different SNPs provides an enormous leap towards the better understanding of the uniqueness of biological systems. Here we report on a new approach for SNP discrimination using toehold-mediated DNA strand displacement. The distinctiveness of the approach is based on the combination of both 3- and 4-way branch migration mechanisms, which allows for reliable discrimination of SNPs within double-stranded DNA generated from real-life human mitochondrial DNA samples. Aside from the potential diagnostic value, the current study represents an additional way to control the strand displacement reaction rate without altering other reaction parameters and provides new insights into the influence of single nucleotide substitutions on 3- and 4-way branch migration efficiency and kinetics.


Cervical glandular atypia associated with squamous intraepithelial neoplasia: a premalignant lesion?
Recent studies have described premalignant changes in the endocervical epithelium, but morphological criteria for the diagnosis of cervical glandular atypia of lesser severity than adenocarcinoma in situ have not been established. Adenocarcinoma in situ is often associated with cervical intraepithelial neoplasia (CIN). The endocervical mucosa in 105 cases of CIN grade III was evaluated and compared with that of 100 controls. Sixteen cases of cervical glandular atypia and one case of adenocarcinoma in situ were identified, and it was possible to discriminate between these and a range of benign glandular lesions. Interestingly, the control series included two patients with cervical glandular atypia, one of whom on review had had a cone biopsy for CIN. The progression of cervical glandular atypia through adenocarcinoma in situ to invasive adenocarcinoma is known, but the natural history of cervical glandular atypia is as yet uncertain.