Assessment of echocardiographic left atrial size: accuracy of M-mode and two-dimensional methods and prediction of diastolic dysfunction.
Despite the American Society of Echocardiography recommendation to use left atrial volume indexed for body surface area (LAVI) for quantification of left atrial size, a variety of methods are used in clinical practice. Our objectives were to evaluate the accuracy of M-mode and two-dimensional (2D) echocardiographic LA size estimates to LAVI and to determine their ability to predict left ventricular diastolic dysfunction. In 150 consecutive patients, LA diameter (LAD), LA diameter indexed for body surface area (LADI), LA area in the apical two- and four-chamber views (LAA 2c and LAA 4c), biplane area-length LA volume (LAV), and LAVI were obtained. The accuracy of these methods to quantify LA enlargement by LAVI, correlation with clinical parameters, and ability to act as a surrogate for diastolic dysfunction were determined using Pearson correlation coefficients along with univariate and multiple logistic analysis. The true degree of LA size (with LAVI as standard) was identified by LAD in 45%, LADI in 42%, LAA 4c in 43%, and LAA 2c in 41%. All methods showed positive correlation with age, E/E', mitral regurgitation, and right atrial size and negative correlation with ejection fraction. LAVI was the strongest method to predict any (c = 0.655, P = 0.012) or moderate-severe (P = 0.856 and P < 0.001) diastolic dysfunction. All methods have greater capacity to identify moderate or severe diastolic dysfunction than any degree of diastolic dysfunction alone. One-dimensional and 2D methods inaccurately quantify LA size and are inferior to LAVI to predict diastolic dysfunction.


Benthic harmful microalgae and their impacts in South America.
Public awareness about Benthic Harmful Algal Blooms (BHABs) and their negative impacts has increased substantially over the past few decades. Even so, reports of BHABs remain relatively scarce in South America (SA). This paper provides a comprehensive overview of the current state of knowledge on BHABs in the continent, by integrating data from published articles, books, and technical reports. We recorded ∼300 different occurrences of potentially toxic BHAB species over the Caribbean, Atlantic and Pacific coasts, mostly in marine (>95%) but also in estuarine areas located from 12⁰36' N to 54⁰53' S. Over 70% of the data was published/released within the past 10 years, and ∼85% were concentrated in Brazil, Venezuela, Ecuador and Colombia. Benthic species were mainly associated with macroalgae, seagrass and sediment. Incidental detection in the plankton was also relevant, mainly in places where studies targeting BHAB species are still rare, like Argentina, Uruguay, Chile and Peru. The study listed 31 infrageneric taxa of potentially toxic benthic dinoflagellates and eight of estuarine cyanobacteria occurring in SA, with the greatest species diversity recorded in the equatorial-tropical zone, mainly in northeastern Brazil (Atlantic), Venezuela and Colombia (Caribbean), and the Galapagos Islands, Ecuador (Pacific). Local strains of Amphidinium, Gambierdiscus, Coolia and Prorocentrum spp. produced toxic compounds of emerging concern. Prorocentrum lima species complex was the most common and widely distributed taxon, followed by Ostreopsis cf. ovata. In fact, these two dinoflagellates were associated with most BHAB events in SA. Whereas the former has caused the contamination of multiple marine organisms and cases of Diarrhetic Shellfish Poisoning in subtropical and temperate areas, the latter has been associated with faunal mortalities and is suspected of causing respiratory illness to beach users in tropical places. Ciguatera Poisoning has been reported in Colombia (∼240 cases; no deaths) and Venezuela (60 cases; two deaths), and may be also a risk in other places where Gambierdiscus spp. and Fukuyoa paulensis have been reported, such as the Galapagos Islands and the tropical Brazilian coast. Despite the recent advances, negative impacts from BHABs in SA are intensified by limited research/training funding, as well as the lack of official HAB monitoring and poor analytical capability for species identification and toxin detection in parts of the continent.


Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches. The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing. LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFβ1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN. Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.


The Severity of ICU-Acquired Pneumonia.
Much controversy exists about pneumonia in intensive care-especially, ventilator-associated pneumonia (VAP)-about its diagnosis and its attributable mortality. A better consensus exists about its prevention and its treatment. VAP occurs in already critically ill patients, and the relationship between preexisting organ dysfunction or failures and the severity of VAP has been recently highlighted. The role of the underlying disease should be considered as dominant, and this fact explains the paradox that exists between the high mortality of VAP and the relative minor effect of prevention measures on mortality.


Phencyclidine (PCP)-induced disruption in cognitive performance is gender-specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain.
Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub-chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub-chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration.


The prevalence of incidental finding of gynecomastia on thoracic computed tomography in the pediatric age group.
This study aimed to determine the prevalence rate of gynecomastia, determine mean glandular breast tissue sizes, and evaluate whether there is any difference in the prevalence rate of gynecomastia according to age using three different reference values of glandular breast tissue size (≥5, ≥10, ≥20 mm) in the pediatric age group. Glandular breast tissue sizes were measured retrospectively from thoracic computed tomography (CT) images taken for other reasons in 961 boys aged 1-18 years. When each breast was evaluated separately (1,922 breasts), gynecomastia was observed in 1,001 (52.1%), 719 (37.4%), and 216 (11.2%) breasts with ≥5, ≥10, and ≥20 mm considered as reference values, respectively. A significant difference was found in terms of gynecomastia (p<0.001) and mean glandular breast tissue size (p<0.001) with respect to age. New studies are currently needed to determine the glandular breast tissue size and the prevalence rate of gynecomastia in boys, and thoracic CT images can be used for this purpose.


c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis.
The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c-Abl is an important effector of c-Src for PDGF- and serum-induced DNA synthesis. Inactivation of cytoplasmic c-Abl by the kinase-inactive Abl-PP-K(-) (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase-inactive SrcK295M induced a G(1) block that was overcome by the constitutively active Abl-PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl-PP-K(-) was not compensated by Src. c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. Finally, we found that p53 inactivation and c-myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c-Abl: c-Abl function was dispensable in cells deficient in active p53 and inhibition of c-Abl reduced mitogen-induced c-myc expression. These data identify a novel function of cytoplasmic c-Abl in the signalling pathways regulating growth factor-induced c-myc expression and we propose the existence of a tyrosine kinase signalling cascade (PDGFR/c-Src/c-Abl) important for mitogenesis.


Platelet Pharmacytes for the Hierarchical Amplification of Antitumor Immunity in Response to Self-Generated Immune Signals.
Systemic immunosuppression mediated by tumor-derived exosomes is an important cause for the resistance of immune checkpoint blockade (ICB) therapy. Herein, self-adaptive platelet (PLT) pharmacytes are engineered to mediate cascaded delivery of exosome-inhibiting siRNA and anti-PD-L1 (aPDL1) toward synergized antitumor immunity. In the pharmacytes, polycationic nanocomplexes (NCs) assembled from Rab27 siRNA (siRab) and a membrane-penetrating polypeptide are encapsulated inside the open canalicular system of PLTs, and cytotoxic T lymphocytes (CTLs)-responsive aPDL1 nanogels (NGs) are covalently backpacked on the PLT surface. Upon systemic administration, the pharmacytes enable prolonged blood circulation and active accumulation to tumors, wherein PLTs are activated to liberate siRab NCs, which efficiently transfect tumor cells, silence Rab27a, and inhibit exosome secretion. The immunosuppression is thus relieved, leading to the activation, proliferation, and tumoral infiltration of cytotoxic T cells, which trigger latent aPDL1 release. As such, the competitive aPDL1 exhaustion by PD-L1-expressing exosomes is minimized to sensitize ICB. Synergistically, siRab and aPDL1 induce strong antitumor immunological response and memory against syngeneic murine melanoma. This study reports a bioinspired mechanism to resolve the blood circulation/cell internalization contradiction of polycationic siRNA delivery systems, and renders an enlightened approach for the spatiotemporal enhancement of antitumor immunity.


Unhealthy herds: Some epidemiological consequences of host heterogeneity in predator-host-parasite systems.
Models in which all hosts respond in the same fashion to challenge by disease make a number of clear predictions regarding the ameliorating effect of predation on disease burden in prey populations. However, natural populations are typically exposed to a broad spectrum of stressors, some of which can induce changes in an individual's susceptibility to infection and transmission, as well as vulnerability to mortality once infected. When only a subset of the population is exposed to these other factors, host populations will express some heterogeneity in resistance to disease. Here I investigate the influence that such heterogeneity can have on the predicted beneficial epidemiological effect of predators on certain homogeneous prey populations. Results show that, under some conditions, predation can exacerbate disease burden in the heterogeneous prey population. I conclude that such a possibility might have implications for wild and domesticated animal management programs.


Superhydrophobic Pseudosupertetrahedral Sulfido Metalate Clusters for Constructing Liquid Marbles.
One pseudopentasupertetrahedral chalcogenidometalate cluster, [(BuSn)3SnCd4S13(OH)]·6(H+DMP) (PPS-1; H+DMP = protonated 3,5-dimethylpiperidine), has been isolated by use of an organotin precursor. They are arranged to generate two types of tetrahedrally patterned cages, which further interconnect to form a diamond network. Owing to the covalent attachment of abundant alkyl groups, PPS-1 exhibits excellent hydrophobicity and could be used as an assembly substance for building liquid marbles.


Hemodynamic findings in patients with left bundle branch block after myectomy in hypertrophic obstructive cardiomyopathy (HOCM)
To determine the hemodynamic effects of postoperative left bundle branch block (LBBB) in patients with hypertrophic obstructive cardiomyopathy (HOCM), we investigated 28 patients using Swan-Ganz pulmonary artery catheterization at rest and on exercise. Fourteen patients had postoperative LBBB (group A) and 14 had undisturbed intraventricular conduction (group B). All patients were examined by clinical investigation, electrocardiogram and bicycle ergometer exercise preoperatively and postoperatively (mean 6 months). Pulmonary artery pressure and pulmonary capillary wedge pressure were continuously measured, stroke volume index and cardiac index were obtained by the thermodilution method. All patients showed an improvement of their clinical symptoms (NYHA class: 2.8 +/- 0.45 before and 1.7 +/- 0.22 after operation) (P < 0.05). The postoperative exercise capacity (Watt) increased significantly (P < 0.05) in group A by 38% and in group B by 30%. The maximum mean pulmonary artery pressure on physical exercise decreased in group A from 40.7 +/- 9.1 to 32.5 +/- 8.7 mmHg and in group B from 42.8 +/- 12.4 to 32.4 +/- 9.2 mmHg (P < 0.05). The maximal stroke volume index and cardiac index improved significantly in 9 of 14 patients in each group. Thus, patients with HOCM and LBBB after myectomy have a marked improvement in postoperative hemodynamics, the results equaling those of patients with undisturbed intraventricular conduction.


Evolutionary hypothesis for Chiari type I malformation.
Chiari I malformation (CM-I) is classically defined as a cerebellar tonsillar herniation (≥5 mm) through the foramen magnum. A decreased posterior fossa volume, mainly due to basioccipital hypoplasia and sometimes platybasia, leads to posterior fossa overcrowding and consequently cerebellar herniation. Regardless of radiological findings, embryological genetic hypothesis or any other postulations, the real cause behind this malformation is yet not well-elucidated and remains largely unknown. The aim of this paper is to approach CM-I under a broader and new perspective, conjoining anthropology, genetics and neurosurgery, with special focus on the substantial changes that have occurred in the posterior cranial base through human evolution. Important evolutionary allometric changes occurred during brain expansion and genetics studies of human evolution demonstrated an unexpected high rate of gene flow interchange and possibly interbreeding during this process. Based upon this review we hypothesize that CM-I may be the result of an evolutionary anthropological imprint, caused by evolving species populations that eventually met each other and mingled in the last 1.7 million years.


Mycotic aneurysm of the aorta.
The radiographic and pathologic features of 13 cases of mycotic aneurysm of the aorta were reviewed retrospectively. In four cases the mycotic aneurysm was associated with bacterial endocarditis following aortic valve replacement, and in nine cases it was associated with spontaneous bacterial endocarditis. Postmortem examination revealed that the mycotic aneurysm was most frequently found in cases with bicuspid aortic valves. In all cases the chest radiograph revealed cardiomegally, usually with pulmonary vascular congestion. In the six patients in whom the diagnosis was established angiographically, the aneurysm was manifested by an irregular saccular collection of contrast medium under one of the coronary arteries. Mycotic aneurysms must be differentiated from other lesions with similar angiographic findings, such as a congenital aneurysm of the sinus of Valsalva, prolapse of an aortic cusp through a membranous ventricular septal defect, and a congenital aortic-left ventricular tunnel.


Comparison of several groups.
Techniques for the comparison of several samples are described. If the response is quantitative, comparison of the sample means is achieved by one-way analysis of variance. If the response is qualitative, comparison of several proportions is achieved by chi 2 tests.


Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy.
Brain-dead organ donors are depleted of circulating triiodothyronine (T3) and show features suggestive generally of anaerobic metabolism at the tissue level, accompanied by deteriorating hemodynamic function. The principle of single-bolus kinetics with labeled carbon compounds (14C-R), with subsequent measurement of both plasma activity and of exhaled 14C O2 has therefore been used to study glucose, pyruvate, and palmitate utilization under conditions of (1) sedation, (2) brain death, and (3) brain death with T3 therapy in the baboon. Serum lactate and plasma-free fatty acid concentrations were also measured. There was a major change in metabolic oxidative processes following brain death. The rate of glucose, pyruvate, and palmitate utilization was markedly reduced, and there was an accumulation of lactate and free fatty acids in the plasma, indicating a general change from aerobic to anaerobic metabolism. The administration of T3 to the brain-dead baboon resulted in a dramatic increase in the rate of metabolite utilization, and a reduction in the plasma concentrations of plasma lactate and free fatty acids, indicating an apparent reversal from tissue anaerobic to aerobic metabolism. We suggest that T3 should be administered to all brain-dead potential organ donors to correct and maintain a more physiologic metabolic status and thus to improve organ function.


Influence of convergence angle of tooth preparation on the fracture resistance of Y-TZP-based all-ceramic restorations.
To investigate the influence of the convergence angle of tooth preparation on the fracture load of Y-TZP-based ceramic (YZ - Vita YZ) substructure (SB) veneered with a feldspathic porcelain (VM9 - Vita VM9). Finite element stress analysis (FEA) was performed to examine the stress distribution of the system. Eighty YZ SB were fabricated using a CAD-CAM system and divided into four groups (n=20), according to the total occlusal convergence (TOC) angle: G6 - 6° TOC; G12 - 12° TOC; G20 - 20° TOC; and G20MOD - 20° TOC with modified SB. All SB were veneered with VM9, cemented in a fiber reinforced epoxy resin die, and loaded to failure. Half of the specimens from each group (n=10) were cyclic fatigued (10(6) cycles) before testing. Failure analysis was performed to determine the fracture origin. Data were statistically analyzed using Anova and Tukey's tests (α=0.05). The greatest mean load to fracture value was found for the G20MOD, which was predicted by the FEA. Cyclic fatigue did not significantly affect the load of fracture. Catastrophic failure originating from the internal occlusal surface of the SB was the predominant failure mode, except for G20MOD. The YZ-VM9 restorations resisted greater compression load than the usual physiological occlusal load, regardless of the TOC angle of preparations. Yet, the G20MOD design produced the best performance among the experimental conditions evaluated.


Effects of external saccharides on cell wall properties and ion transport inHydrodictyon reticulatum.
Various saccharides, when present at osmotically insignificant concentrations in growth media, were tested as to their effects on the cell walls of the green algaHydrodictyon reticulatum, manifesting themselves in differences in cell water and ion contents. BothD: -xylose andD: -mannose reduce the cell water content andD: -galactose does occasionally the same but onlyD: -xylose reduces significantly the intracellular sodium concentration, presumably by forming steric hindrances at the outlets of the sodium pumps at the outer surface of the cell membrane. No significant effects of eitherL: -arabinose orD: -arabinose on the cell water and ion contents were found.


Satisfying regulatory and accreditation requirements for quality control.
The Clinical Laboratory Improvement Amendments of 1988 (CLIA) requires all US clinical laboratories that test "materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease..." to be regulated. The CLIA mandates are site neutral; based on test complexity; and focus on the three phases of the testing process (preanalytical, analytical, and postanalytical). Many testing sites choose to meet the CLIA requirements by following the testing standards of a professional accreditation organization deemed by the Centers for Medicare and Medicaid Services. The three principal organizations are The Joint Commission, the College of American Pathologists, and COLA.


Low-to-moderate atmospheric ozone levels are negatively correlated with hospital visits by asthma patients.
Asthma is a chronic illness of the airways that affects approximately 300 million individuals worldwide. While it is commonly accepted that high ozone levels exacerbate asthma symptoms, the impact of low to moderate ozone levels on asthma symptoms has received little attention. The purpose of this research was to determine the relationship between hospital visits by asthma patients showing the severity of their symptoms and moderate ozone levels. Statistical analyses were performed on hospital visit big data for asthma patients in Seoul, Korea, collected between 2013 and 2017. The data set includes outpatient hospital visits (n = 17,787,982), hospital admissions (n = 215,696), and emergency department visits (n = 85,482). The frequency of hospital visits by asthma patients was evaluated in relation to low ozone levels (< 0.03 ppm) and moderate ozone levels (0.03-0.06 ppm) in the Seoul environment. In comparison to low ozone levels, moderate ozone levels resulted in a reduction in outpatient hospital visits (t = 7.052, P < .001). When ozone levels were low to moderate, there was a negative correlation between ozone levels and outpatient visits (r = -0.281, 95% CI: -0.331 to -0.228). Negative associations were also identified between ozone levels and new hospital admissions (t = 2.909, P < .01; r = -0.125, 95% CI: -0.179 to -0.070) and emergency treatments (t = 2.679, P < .01; r = -0.132, 95% CI: -0.186 to -0.076). Additionally, it was verified that moderate ozone levels one day before the visits resulted in a reduction in outpatient visits (t = 5.614, P < .001; r = -0.207, 95% CI: -0.259 to -0.153). A strong relationship was identified between moderate atmospheric ozone levels and a reduction in asthma patient hospital visits.


Adult childhood cancer survivors' perceptions of factors that influence their ability to be physically active.
Studies indicate that adult childhood cancer survivors do not achieve recommended physical activity levels. A deeper understanding of factors that influence their ability to be physically active is essential to identify individuals in need of support. The aim was to explore factors that influence adult childhood cancer survivor's ability to be physically active. Semi-structured interviews were conducted from June to October 2020 with 20 adult childhood cancer survivors with a median age of 31 (min-max 20-47) years. Interviews were transcribed verbatim and analyzed with qualitative content analysis. Four main categories: "The impact of environmental factors," "Personal factors of importance," "Consequences of the treatment or disease," and "The impact of support from healthcare" and 10 sub-categories, were identified. Participants described how family habits and encouragement from others influenced their present ability to be physically active. Experienced benefits of physical activity were described as a facilitator for current physical activity while suffering from late complications was identified as a barrier. Participants highlighted the importance of specific and individualized physical activity recommendations. This study includes adult childhood cancer survivors several years after completion of treatment, hence highlighting the importance for support both during treatment and follow-up to sustain their physical activity. Healthcare providers need to identify individuals suffering from late complications, even several years after treatment; provide individualized physical activity recommendations; and educate families and schools about the importance of physical activity in childhood cancer survivorship. This research project was registered in the Swedish National Database of Research and Development, identifier 273320, December 6, 2019 ( https://www.researchweb.org/is/vgr/project/273320 ).


Additional prognostic value of toe-brachial index beyond ankle-brachial index in hemodialysis patients.
Ankle-brachial index (ABI), the first-line diagnostic test for peripheral artery disease, can be falsely elevated when ankle arteries are incompressible, showing a J-shaped association with mortality. In this situation, toe-brachial index (TBI) is the recommended test. However, whether TBI provides additional prognostic information beyond ABI in patients on hemodialysis is unknown. In this retrospective cohort study of 247 Japanese prevalent hemodialysis patients (mean age 66.8 [SD 11.6] years), we evaluated mortality (116 deaths over a median follow-up of 5.2 years) related to quartiles of ABI and TBI, as well as three categories of low ABI (≤0.9), normal/high ABI (> 0.9) + low TBI (≤0.6), and normal/high ABI + normal TBI (> 0.6) using multivariable Cox models. ABI showed a J-shaped association with mortality (adjusted hazard ratio 2.72 [95% CI, 1.52-4.88] in the lowest quartile and 1.59 [95% CI, 0.87-2.90] in the highest quartile vs. the second highest). Lower TBI showed a potentially dose-response association with mortality (e.g., adjusted hazard ratios 2.63 [95% CI, 1.36-5.12] and 2.89 [95% CI, 1.49-5.61] in the lowest two quartiles vs. the highest). When three categories by both ABI and TBI were analyzed, those with low ABI (≤0.9) experienced the highest risk followed by normal/high ABI (> 0.9) + low TBI (≤0.6). Among patients with normal/high ABI (> 0.9), the increased mortality risk in individuals with low TBI (≤0.6) compared to those with normal TBI (> 0.6) were significant (adjusted hazard ratio 1.84 [95% CI, 1.12-3.02]). Lower TBI was independently associated with mortality in patients on hemodialysis and has the potential to classify mortality risk in patients with normal/high ABI. Our results support the importance of evaluating TBI in addition to ABI in this clinical population.


Neurodegeneration with brain iron accumulation.
Neurodegeneration with brain iron accumulation (NBIA) describes a heterogeneous group of inherited rare clinical and genetic entities. Clinical core symptoms comprise a combination of early-onset dystonia, pyramidal and extrapyramidal signs with ataxia, cognitive decline, behavioral abnormalities, and retinal and axonal neuropathy variably accompanying these core features. Increased nonphysiologic, nonaging-associated brain iron, most pronounced in the basal ganglia, is often termed the unifying characteristic of these clinically variable disorders, though occurrence and extent can be fluctuating or even absent. Neuropathologically, NBIA disorders usually are associated with widespread axonal spheroids and local iron accumulation in the basal ganglia. Postmortem, Lewy body, TDP-43, or tau pathology has been observed. Genetics have fostered ongoing progress in elucidating underlying pathophysiologic mechanisms of NBIA disorders. Ten associated genes have been established, with many more being suggested as new technologies and data emerge. Clinically, certain symptom combinations can suggest a specific genetic defect. Genetic tests, combined with postmortem neuropathology, usually make for the final disease confirmation. Despite these advances, treatment to date remains mainly symptomatic. This chapter reviews the established genetic defects leading to different NBIA subtypes, highlights phenotypic presentations to direct genetic testing, and briefly discusses the scarce available treatment options and upcoming challenges and future hopes of the field.


Biocatalytic conversion of cycloalkanes to lactones using an in-vivo cascade in Pseudomonas taiwanensis VLB120.
Chemical synthesis of lactones from cycloalkanes is a multi-step process challenged by limitations in reaction efficiency (conversion and yield), atom economy (by-products) and environmental performance. A heterologous pathway comprising novel enzymes with compatible kinetics was designed in Pseudomonas taiwanensis VLB120 enabling in-vivo cascade for synthesizing lactones from cycloalkanes. The respective pathway included cytochrome P450 monooxygenase (CHX), cyclohexanol dehydrogenase (CDH), and cyclohexanone monooxygenase (CHXON) from Acidovorax sp. CHX100. Resting (non-growing) cells of the recombinant host P. taiwanensis VLB120 converted cyclohexane, cyclohexanol, and cyclohexanone to ϵ-caprolactone at 22, 80-100, and 170 U gCDW-1 , respectively. Cyclohexane (5 mM) was completely converted with a selectivity of 65% for ϵ-caprolactone formation in 2 hr without accumulation of intermediate products. Promiscuity of the whole-cell biocatalyst gave access to analogous lactones from cyclooctane and cyclodecane. A total product concentration of 2.3 g L-1 and a total turnover number of 36,720 was achieved over 5 hr with a biocatalyst concentration of 6.8 gCDW L-1 .


Tuberculosis genes expressed during persistence and reactivation in the resistant rabbit model.
As previously published, after aerosol infection with Mycobacterium tuberculosis H37Rv, New Zealand white rabbits established infection with active bacillary replication, but later contained disease to a paucibacillary state through an effective adaptive response consistent with latency. Despite the heterogeneity among outbred rabbits, the resistant response was uniform. Immunosuppression resulted in reactivation with increased lung bacillary burden. Using this rabbit model, we isolated bacillary RNA from infected rabbit lungs and assessed transcriptional profiles of bacillary genes using RT-PCR to examine genes differentially regulated during active replication, persistence, steroid-induced reactivation, and post-steroid immune reconstitution. Genes involved in hypoxia response (fdxA), resuscitation promoting factors (rpfB), and DNA repair pathways (Rv2191) may be important in bacillary persistence. Further investigation into these gene pathways is warranted.


The immediate effect of lumbopelvic manipulation on knee pain, knee position sense, and balance in patients with patellofemoral pain: A randomized controlled trial.
Patellofemoral pain (PFP) is a common musculoskeletal disorder. Quadriceps and core muscle neuromuscular control impairments are frequently associated with PFP. Lumbopelvic manipulation (LPM) has been shown to improve quadriceps and core muscle activation and decrease their inhibition, but changes in balance and knee joint position sense (JPS) after this intervention remain unknown. To determine whether LPM decreases knee pain and JPS error and increases balance performance in patients with PFP. Randomized controlled trial. Biomechanics laboratory at a rehabilitation science research center. Forty-four patients with PFP participated in this study that randomly divided into two equal groups. One group received LPM and the other received sham LPM (positioning with no thrust) in a single session. At baseline and immediately after the intervention, the outcomes of pain using a visual analog scale, balance using the modified star excursion balance test (mSEBT), and JPS at 20° and 60° of knee flexion using a Biodex dynamometer. There was a statistically significant improvement in pain, balance control (anterior direction) and JPS in the LPM group immediately after the intervention. In addition, we observed significant differences between groups in pain, balance control (anterior direction) and JPS at 60° of knee flexion immediately after the intervention. A single session of LPM immediately improved balance control, knee JPS, and pain in patients diagnosed with PFP. Findings suggest that LPM may be used as a therapeutic tool for immediate improvement of symptoms of PFP. However, more research is needed to determine long term results.


Efficacy of current regular follow-up policy after treatment for head and neck cancer: Need for individualized and obligatory follow-up strategy.
The purpose of this study was to report the efficacy of routine follow-up after head and neck cancer treatment. Data for 520 patients with head and neck cancer registered with between 2002 and 2008 were reviewed retrospectively. The mean ± SD follow-up period taken into account was 34.7 ± 22.8 months. The pickup rate for recurrence using our follow-up protocol in this cohort was 1 in every 79 visits (1.26%). High pickup rates were observed in patients older than 70 years and patients with advanced T classification, whereas low pickup rates were observed in patients who had received treatment including surgery. The only factor on multivariate analysis to influence follow-up visits was surgical treatment (p = .043). Individualized and obligatory follow-up policy is desirable considering various factors, especially age, T classification, and whether treatment modality includes surgery or not.


Mechanically interlocked 3D multi-material micromachines.
Metals and polymers are dissimilar materials in terms of their physicochemical properties, but complementary in terms of functionality. As a result, metal-organic structures can introduce a wealth of novel applications in small-scale robotics. However, current fabrication techniques are unable to process three-dimensional metallic and polymeric components. Here, we show that hybrid microstructures can be interlocked by combining 3D lithography, mold casting, and electrodeposition. Our method can be used to achieve complex multi-material microdevices with unprecedented resolution and topological complexity. We show that metallic components can be combined with structures made of different classes of polymers. Properties of both metals and polymers can be exploited in parallel, resulting in structures with high magnetic responsiveness, elevated drug loading capacity, on-demand shape transformation, and elastic behavior. We showcase the advantages of our approach by demonstrating new microrobotic locomotion modes and controlled agglomeration of swarms.


Molecular morphology of fibrin monomers and early oligomers during fibrin polymerization.
The structural features of early fibrin oligomers produced during the initial stages of polymerization were investigated by rotatory shadowing after cryotechnical preparation. The building blocks of polymerization, namely fibrin monomer units (in analogy to fibrinogen itself), were found to exhibit a high degree of flexibility which is independent of fibrinopeptide A and B removal. Early polymers exhibited directed longitudinal growth and were frequently branched. Along the main oligomer axis, fibrin monomer units were randomly orientated. Within early oligomers, a given fibrin monomer unit was found to establish a single contact with each of its two neighbors, suggesting that during the early stages of polymerization, only one polymerization and one binding site are activated per fibrinogen molecule (becoming an AB2 fibrin monomer unit). This morphological feature was corroborated by the finding that early oligomer fractions are deficient in only 50% of releasable fibrinopeptide A. Early associations between AB2 fibrin monomer units were demonstrated to be reversible and to occur in the absence of direct domainal contact; interactions thus presumably occur via fine molecular protrusions on either D or E domains. The arrangement of AB2 fibrin monomer units within early oligomers suggests that, with respect to their structural organization, fibrinogen molecules are radially symmetrical through the E domain (implying an antiparallel organization of polymerization and binding sites). This pattern is inconsistent with a "top-bottom" model, and thus with "half-staggered double-stranded" polymer growth. The methodological problems responsible for the apparent conflict with previous morphological findings are discussed.


Immunophenotypical characterization of canine mesenchymal stem cells from perivisceral and subcutaneous adipose tissue by a species-specific panel of antibodies.
Immunophenotypical characterization of mesenchymal stem cells is fundamental for the design and execution of sound experimental and clinical studies. The scarce availability of species-specific antibodies for canine antigens has hampered the immunophenotypical characterization of canine mesenchymal stem cells (MSC). The aim of this study was to select a panel of species-specific direct antibodies readily useful for canine mesenchymal stem cells characterization. They were isolated from perivisceral and subcutaneous adipose tissue samples collected during regular surgeries from 8 dogs. Single color flow cytometric analysis of mesenchymal stem cells (P3) deriving from subcutaneous and perivisceral adipose tissue with a panel of 7 direct anti-canine antibodies revealed two largely homogenous cell populations with a similar pattern: CD29+, CD44+, CD73+, CD90+, CD34-, CD45- and MHC-II- with no statistically significant differences among them. Antibody reactivity was demonstrated on canine peripheral blood mononuclear cells. The similarities are reinforced by their in vitro cell morphology, trilineage differentiation ability and RT-PCR analysis (CD90+, CD73+, CD105+, CD44+, CD13+, CD29+, Oct-4+ gene and CD31- and CD45- expression). Our results report for the first time a comparison between the immunophenotypic profile of canine MSC deriving from perivisceral and subcutaneous adipose tissue. The substantial equivalence between the two populations has practical implication on clinical applications, giving the opportunity to choose the source depending on the patient needs. The results contribute to routine characterization of MSC populations grown in vitro, a mandatory process for the definition of solid and reproducible laboratory and therapeutic procedures.


Nitrogen and sulfur co-doped carbon dots with bright fluorescence for intracellular detection of iron ion and thiol.
Carbon dots (CDs) have been widely used in recent years because of their excellent water solubility and abundant surface functional groups. However, compared with quantum dots or biological probes, the quantum yield of CDs is lower, and the fluorescence mainly concentrated in the blue-green range, which significantly limits the biological applications of CDs. Heteroatoms doping is the most common method to improve the luminescence of CDs. In this work, nitrogen and sulfur co-doped luminescent CDs were successfully synthesized by microwave assisted method using glutathione (GSH) and p-phenylenediamine (PPD) as raw materials. It can emit bright green fluorescence in ethanol solution, and the maximum emission wavelength is 535 nm when excited at 374 nm, and the absolute quantum yield is as high as 63%. Iron ion (Fe3+) can interact with the functional groups on the surface of the CDs to form CDs/Fe3+, which is a non-fluorescence complex, and Fe3+ can be reduced to ferrous ion (Fe2+). In other words, the reaction mechanism of CDs and Fe3+ is a combination of dynamic quenching and static quenching. The fluorescence of CDs quenched by Fe3+ can be restored by thiol, because there is a stronger binding force between sulfhydryl (-SH) on the surface of thiol and Fe3+, which enables CDs to be released. In addition, the CDs has good biocompatibility and stability, indicating that it has excellent potential in bioimaging. This discovery will expand the application of CDs in the fields of biosensing and imaging.


Influences of gastro-intestinal polypeptides and glucose on glucagon secretion induced by cholinergic stimulation.
Glucagon secretion from the endocrine pancreas is known to be enhanced by cholinergic stimulation. It has previously been described that vasoactive intestinal polypeptide (VIP) is a potent potentiator of this cholinergically induced glucagon secretion. In the present study, the effects of several gastro-entero-pancreatic polypeptides and glucose on glucagon secretion induced by the cholinergic agonist carbachol were investigated in vivo in the mouse. Carbachol was injected i.v. and it stimulated glucagon secretion. The polypeptides neurotensin and gastric inhibitory polypeptide (GIP) were both found to potentiate the carbachol-induced glucagon secretion, whereas substance P, pancreatic polypeptide, and two different molecular variants of cholecystokinin, CCK-8 and CCK-39, were without effect on cholinergically induced glucagon secretion. Neither of these polypeptides had any influence on basal glucagon secretion when tested over a wide dose range. Somatostatin and glucose both markedly inhibited carbachol-induced glucagon secretion. carbachol is a potent stimulator of glucagon secretion. This cholinergically induced glucagon secretion can be modified by several gastro-entero-pancreatic hormones influencing the release process both in potentiating and inhibiting direction. The physiological relevance of these interactions remains to be further investigated.


Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro.
Extracellular field potentials and [K+]o were recorded in slices of human epileptogenic neocortex maintained in vitro during perfusion with Mg(2+)-free artificial cerebrospinal fluid (ACSF). The human neocortex was obtained during neurosurgical procedures for the relief of seizures that were resistant to medical treatment. Spontaneous epileptiform activity and episodes of spreading depression appeared within 1.5 to 2 hours of perfusion with Mg(2+)-free ACSF. The epileptiform discharges consisted of negative field potential shifts (amplitude, 0.8-10 mV) that lasted 2.5 to 80 seconds and recurred at intervals ranging between 4 and 160 seconds. Both duration and frequency of occurrence of epileptiform events were not significantly different when measured in slices obtained from spiking tissue compared with those gathered from nonspiking neocortical areas. Transient increases in [K+]o of up to 10.5 mM were associated with each epileptiform discharge; these changes were maximal and fastest in the middle neocortical layers. Spreading depression episodes were characterized by 20 to 30-mV negative shifts that lasted up to 200 seconds and were accompanied by increases in [K+]o of approximately 100 mM. Epileptiform discharges and spreading depressions did not occur during perfusion with Mg(2+)-free ACSF that contained either competitive or noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor subtype. In contrast, pharmacological blockade of non-NMDA receptors did not influence the epileptiform activity observed in Mg(2+)-free ACSF. These findings demonstrate that decreasing [Mg2+]o leads to the appearance of both spontaneous epileptiform discharges and spreading depression in the human epileptogenic neocortex.(ABSTRACT TRUNCATED AT 250 WORDS)


Production of [14C]rubratoxin B.
[14C]rubratoxin B was produced by culturing Penicillium rubrum Stoll for 13 days at 22 degrees C in medium containing [14C]glucose. The most efficient incorporation of glucose into rubratoxin occurred when Raulin-Thom medium enriched with 2.5% malt extract was supplemented with 2.5% added glucose. The presence of 1.0 mCi of radioactivity in 50 ml of medium with 2.5% added glucose resulted in the production of 38 mg of labeled, chromatographically pure rubratoxin with a specific activity of 0.47 Ci/mole.


Preventive factors related to brucellosis among rural population using the PRECEDE model: an application of path analysis.
The purpose of this model-based study was to identify behavioral and environmental prevention factors for brucellosis and to determine the causal linkage among these factors in a rural area with high prevalence of the disease. A multi-stage random sampling method was used to select villages in Ahar County, located in East Azerbaijan Province, Iran. Participants (n = 400) were recruited from these villages. Data was collected in accordance with the PRECEDE model established in March 2016. This model consists of four phases intended to assess each participant's health and quality of life. Standardized, structured questionnaires exploring different aspects of brucellosis prevention (predisposing, reinforcing, enabling, environmental, and behavioral factors) were used. Path analysis was applied to assess the pathway structure of the PRECEDE model. Overall, the model fitted the data well (χ2/df = 1.10; RMSEA = .016 (CI 95%: 0.00-0.07), SRMR = .02, CFI = .99). Significant positive associations were found among predisposing, reinforcing, and enabling factors on the one hand, and behavior, on the other hand. The predisposing factors showed significant positive associations with general health, and the reinforcing factors and general health showed significant positive associations with health-related quality of life (HRQOL). The results of this study support the use of the PRECEDE model for brucellosis prevention, and suggest that a high level of general health, in combination with reinforcing factors can increase HRQOL in an area with a high prevalence of brucellosis.


Adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate phosphodiesterase activities in 1,2-dimethylhydrazine induced colon adenocarcinoma.
The intracellular concentrations of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in 1,2-dimethylhydrazine (DMH) induced rat colon tumors were previously reported to be one-half and twice, respectively, that measured in normal rat colon tissue. The results of this present study indicate that the total amount of cyclic nucleotide hydrolysis by the phosphodiesterase enzymes (PDE) could account for the lower cAMP and elevated cGMP noted in cancer tissue. PDE activities in homogenates prepared from normal and neoplastic tissue showed general similarities in both their hydrogen and metal ion dependencies with optimum degradation of nucleotides occurring at pH 7.2-7.8 in the presence of either Mg2+ or Mn2+ ions. The enzymes from both tissue types were inhibited to a similar extent by papaverine and theophylline. Distribution studies indicated PDE activities were similar throughout the entire length of the normal colon; consequently, the anomalous activities measured in the tumors were attributable to the specific cell population and not to the particular site at which malignancy arose. Thus, the findings of this study suggest that one cause for lowered cAMP and elevated cGMP levels in DMH induced colon adenocarcinomas was the amount of cyclic nucleotide hydrolysis by PDE in the malignant tissue.


Effect of Sodium Dodecyl Sulfate on Stability of MXene Aqueous Dispersion.
MXenes suffer from severe oxidation and progressive degradation in aqueous media due to its poor chemical stability. Herein, sodium dodecyl sulfate (SDS) is employed as an efficient protectant for long-term storage of Ti3 C2 Tx -MXene aqueous dispersion. Experimental data support SDS's capability to protect oxidation-prone sites on Ti3 C2 Tx nanosheets, providing extended colloidal stability of up to 213 days. Concentration-dependent anti-oxidation effect articulates that 1.5 mg mL-1 is deemed as an ideal SDS dose for Ti3 C2 Tx to achieve optimal oxidation-resistance in aqueous solution. Additionally, a chroma strategy is developed to instantly and precisely measure the oxidation degree of Ti3 C2 Tx . Adsorption-driven anti-oxidation efficacy of SDS is further confirmed by optimized conformations with interaction energies of SDS on termination-free and surface-defective Ti3 C2 Tx through multiscale simulations. This proposed route is a step forward in broadening the horizons of experimental and theoretical investigations of MXenes with promising implications for long-term storage and reliable applications.


Has botulinum toxin type A a place in the treatment of spasticity in spinal cord injury patients?
To present and discuss treatment of severe spasms related to spinal cord injury with botulinum toxin type A. A 2-year follow-up study of an incomplete T12 paraplegic patient, who was reluctant to undergo intrathecal baclofen therapy, presenting severe painful spasms in his lower limbs treated with intramuscular injections of botulinum toxin type A. Department of Physical Medicine and Rehabilitation, Hôpital de Gravelone, Sion, Switzerland. Single patient case report. Spasticity, spasms and pain measured with the modified Ashworth scale, spasm frequency score and visual analogue scale. Treatment of spasticity with selective intramuscular injections of botulinum toxin type A resulted in subjective and objective improvement. Botulinum toxin type A has its place in the treatment of spasticity in spinal cord injury patients. This treatment is expensive and its effect is reversible. It can complement intrathecal baclofen in treating upper limb spasticity in tetraplegic patients. Tolerance does occur to the toxin. Although high doses of the product are well tolerated, the quantity should be tailored to the patient's need. The minimal amount necessary to reach clinical effects should be adhered to and booster doses at short period intervals should be avoided.


Usefulness of the codification of multiple causes of death in mortality statistics.
The codification of multiple causes of death began in the US in 1917 and systematic publication of this data started in 1984. In Spain this began in 1988, and the data from this year have been taken as the basis for investigation. They have also been studied for regional differences. A representative sample (595) of Spanish Standard Death Certificates (DC) was collected in Asturias for the year 1988. All were coded according to the International Classification of Diseases and a separate coding was made for each nosological entity included in the certificate (coding of multiple causes). The median, mode and the multiple cause/underlying cause ratio were also calculated. More than 80% of the certificates studied contained more than one cause of death. Chronic diseases are those which are accompanied by a greater number of causes and acute diseases those which appear alone. The highest ratios appear for diseases which are ill defined and also in those which are chronic. Our data show that information is lost in the production of the statistics of mortality and there are repercussions for the usefulness of these statistics.


Anti-vascular endothelial growth factor in the treatment of macular edema in epidemic retinitis.
To study efficacy of anti-vascular endothelial growth factor (anti-VEGF) in resolution of macular edema in epidemic retinitis (ER). In this retrospective, comparative study, patients diagnosed as ER with central macular thickness (CMT) ≥ 600 μm on SD-OCT at presentation were studied. Eyes which did not receive intravitreal anti-VEGF formed group A and eyes receiving additional anti-VEGF formed group B. Eyes receiving anti-VEGF monotherapy were studied separately. Cases with subsequent OCT scans with interval of more than 20 days and cases without OCT scan at the resolution were excluded. Treatment details, visual outcome, and days to resolution of macular edema were studied. Mean CMT in group A (n = 8) was 820.1 μm (range 607-1004 μm) and in Group B (n = 4) was 756.0 μm (range 603-1000 μm). Macular edema resolved in 34.8 days (range: 16-65) and 39.0 days (range: 21-45) in group A and B, respectively. Two eyes with anti-VEGF monotherapy recovered in 45 and 18 days, respectively. Mean corrected distance visual acuity (CDVA) at presentation in group A was 19.1 (range: 0-61) ETDRS letters and in group B was 14.3 (range: 0-35) ETDRS letters. Mean CDVA improved to 65.7 (range: 0-85) and 50.8 (range: 20-76) ETDRS letters in group A and B, respectively. Anti-VEGF monotherapy eyes improved from 35 and 46 ETDRS letters to 70 and 85 ETDRS letters, respectively. Additional anti-VEGF therapy has no added advantage in speed of resolution of macular edema due to ER. A randomized controlled trial with steroids sparing "anti-VEGF monotherapy" may verify our observations.


A pneumotoxin, O,O,S-trimethyl phosphorothioate, induces hemorheological alteration in rats.
O,O,S-trimethyl phosphorothioate (OOS-TMP), an impurity present in widely used organophosphorus insecticides, has been shown to induce lung injury after oral administration. To date, very little is known about the hemorheological changes which may occur during the inflammation of lung caused by OOS-TMP. The present study has demonstrated that oral administration of OOS-TMP (10 mg/kg, 20 mg/kg) to rats produced an increase in whole blood apparent viscosity at 24, 48 and 72 h following the treatment in rats. Concomitantly, the plasma fibrinogen level and red blood cell (RBC) aggregation were increased at 24 and 48 h. There was no change in RBC filterability. Thus, OOS-TMP, a pneumotoxin, was capable of causing a systemic hemorheological alteration, probably via increase in fibrinogen content, an acute-phase protein, in rats.


Psoriatic or cystic fibrosis arthropathy? Difficulty with diagnosis and management.
A 19-year-old man with cystic fibrosis developed arthritis at the age of 12 years. He also suffered from psoriasis, and was found to be HLA-B27 positive. His disease was episodic in nature for the first 5 years, but he later developed an unremitting erosive arthropathy which proved difficult to treat.


Natural causes of programmed death of yeast Saccharomyces cerevisiae.
The existence of cell death program in unicellular organisms has been reported for a number of species. Nevertheless, the question why the ability to commit suicide has been maintained throughout evolution is far from being solved. While it is believed that altruistic death of individual yeast cells could be beneficial for the population, it is generally not known (i) what is wrong with the individuals destined for elimination, (ii) what is the critical value of the parameter that makes a cell unfit and (iii) how the cell monitors this parameter. Studies performed on yeast Saccharomyces cerevisiae allow us to hypothesize on ways of possible solutions of these problems. Here we argue that (a) the main parameter for life-or-death decision measured by the cell is the degree of damage to the genetic material, (b) its critical value is dictated by quorum sensing machinery, and (c) it is measured by monitoring delays in cell division.


Real-World Efficacy and Safety of Extended-Release Methylphenidate (PRC-063) in the Treatment of ADHD in Pediatric and Adult Subjects: Results of a Phase IV Multicenter Comparison With Lisdexamfetamine Dimesylate.
To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a phase IV, open-label study. The primary endpoint was the change in the ADHD-DSM-5 Rating Scale (ADHD-5-RS) total score from baseline to Month 4. Secondary endpoints included a non-inferiority comparison between PRC-063 and LDX and measures of functioning and evening behavior. One hundred forty-three pediatric and 112 adult subjects were enrolled. Mean ADHD-5-RS scores (standard deviation) were reduced in pediatric (-16.6 [10.4]) and adult (-14.8 [10.6]) subjects treated with PRC-063 (p < .001). PRC-063 was non-inferior to LDX in the pediatric population but not in the adult population. Significant improvements were demonstrated in quality of life and functionality. Both medications were well-tolerated; more adverse events led to study discontinuation in pediatric subjects treated with LDX versus PRC-063. PRC-063 and LDX significantly improved ADHD symptomatology and functioning and were well-tolerated.


Re-expression of differentiated properties in SV40-infected human epidermal keratinocytes induced by 5-azacytidine.
Infection of human epidermal keratinocytes by the oncogenic virus SV40 leads to progressive inhibition of the normal differentiation process in vitro. Treatment of infected cells with 5-azacytidine (5-aza-CR) over a 24-h period produced a striking enlargement and pronounced flattening of cells within 5-7 days following removal of the agent. This morphological change was accompanied by a several-fold increase in the number of cells staining positively for the cell envelope precursor protein, involucrin, and in the exfoliation of cornified envelope bearing cells from the monolayer. The drug-treated cultures at high passage levels were stained by immunofluorescence using monoclonal antibodies to keratin classes associated with different epidermal layers. These experiments revealed that 5-aza-CR caused the re-expression of two keratin classes (suprabasal and stratum corneum-associated), whose synthesis had been suppressed during the transformation process. 5-Aza-CR also brought about re-expression of 58 and 56 kD keratin markers of epithelial keratinization and stratification, as well as of 40 and 49-52 kD keratin markers of viral transformation. However, the responsiveness to the drug was gradually lost over time following infection.


Association of Renal Function and Menopausal Status with Bone Mineral Density in Middle-aged Women.
The association between mild renal dysfunction and bone mineral density (BMD) has not been fully explored. It is also unclear how menopausal status and the use of Chinese herb affect this association. This is a cross-sectional study that included a total of 1,419 women aged 40 to 55 years old who were recruited from the MJ Health Management Institution in Taiwan between 2009 and 2010. Spinal BMD was assessed by dual-energy X-ray absorptiometry. Renal function was assessed using estimated glomerular filtration rate (eGFR) and creatinine clearance rate (CCr). The multivariable logistic regression and general linear models were employed to assess the association between renal function and BMD. Stratification analyses were performed by menopausal status and use of Chinese herbs. Low CCr levels were significantly associated with low BMD [adjusted odds ratio (AOR) = 1.48, 95% confidence interval (CI) = 1.15-1.90]. This association was observed in premenopausal women (AOR = 1.43, 95% CI = 1.07-1.92) and in women not taking Chinese herbs (AOR = 1.48, 95% CI = 1.14-1.94). CCr is a better predictor for low BMD in middle-aged women. Menopausal status and the use of Chinese herbs also affected this association.


[STEMI network Essen--results after 1 year].
The myocardial infarction network "Herzinfarktverbund Essen" was initiated on September 1, 2004 in order to establish a standardized strategy and therapy for patients with ST elevation myocardial infarction (STEMI) in the city of Essen. The primary goal is the immediate reopening of the infarcted vessel by direct transfer of the patient to a hospital with 24-h stand-by catheter laboratory. The first 1-year follow-up, completed on August 31, 2006, showed a low 1-year mortality rate (11.2%), whereby 7.6% of the patients died in hospital. There was a significant dependency of mortality on age, the prehospital stability of cardiovascular circulation, the amount of left ventricular damage, the TIMI flow after intervention, and the duration of interventional therapy ("puncture-to-balloon" time). The coronary status, anticoagulation therapy as well as diabetes mellitus were also dependent variables, whereas the type of stent showed no influence. The rate of restenosis was greater with bare-metal stents (BMS) compared to the use of drug-eluting stents (DES). There was a low rate of repeated STEMI or NSTEMI (non-ST elevation myocardial infarction; 1.8%, 1.7%). These first long-term data confirm the successful implementation of treatment guidelines for STEMI patients within a standardized strategy in an urban environment.


Axial giant cell tumor - current standard of practice.
Giant cell tumors of bone are relatively rare in the axial skeleton, accounting for approximately 6.7% of all cases. Due to their anatomical complexity, difficult access and proximity to vital neurovascular structures, management of these tumors poses a huge challenge on the treating surgeon. Several data series reported on axial GCTB involve short series of limited cases with varied methods used in their local control due to which, proper guidelines are unavailable for the management of such difficult cases. Though the present data support the use of denosumab for effective management of these lesions but there is varied consensus on dosage and duration of treatment. This review article summarizes the basic features and treatment modalities related to axial GCTB stressing on multidisciplinary approach to achieve optimum outcomes.


Arthroscopic treatment of osteochondral lesions of the talar dome.
Nine osteochondral lesions of the talar dome were treated arthroscopically. Two patients (a 16-year-old boy) had two recent osteochondral fractures, anterior and superior lateral, with a free fragment detached in the joint. The lesions were treated with simple ablation of the loose body. Seven old lesions were found in four men and three women, aged 18-32 years, with an osteocartilaginous, partially loose body with necrosis of the underlying bone. The lesion was posterior medial in these seven cases. Technically, arthroscopy is usually performed using an anterior approach. However, it is sometimes necessary to place the foot in the talipes equinus position to achieve articular distraction for diagnosis and treatment of posterior lesions. Treatment consisted of removal of the loose body, with curettage of the necrotic bone. The nine patients were clinically and radiologically reviewed with a follow-up period of 10-24 months. For the two osteochondral fractures, clinical results following the removal of free loose bodies in the joint were spectacular, with complete pain relief and osseous rehabilitation almost radiologically complete after 2 years. In the seven patients with an old necrotic lesion, the result was very good or good in six cases, and poor in one case. Radiologically, osseous rehabilitation occurred progressively, but remained incomplete at 2 years. This technique provides multiple advantages: minimal morbidity, 48-h hospitalization, and rapid functional recuperation without immobilization. Our results confirm the recent data in the literature (1-4).


Effect of human interferon beta gene transfer upon human glioma, transplanted into nude mouse brain, involves induced natural killer cells.
We investigated the immunological responses induced by human interferon beta (IFNbeta) gene transfer in human gliomas produced in the brains of nude mice. A suspension of human glioma U251-SP cells was injected into the brains of nude mice. The IFNbeta gene was transferred by intratumoral injection with cationic liposomes or cationic liposomes associated with anti-glioma monoclonal antibody (immunoliposomes). When intratumoral injection of liposomes or immunoliposomes containing the human IFNbeta gene was performed every second day for a total of six injections, starting 7 days after tumor transplantation, complete disappearance of the tumor was observed in six of seven mice that had received liposomes and in all seven mice receiving immunoliposomes. In addition, experimental gliomas injected with immunoliposomes were much smaller than those injected with ordinary liposomes following delayed injections beginning 14 days after transplantation. An immunohistochemical study of the treated nude mouse brains revealed a remarkable induction of natural killer (NK) cells expressing asialoGM1 antigen. To investigate the significance of NK cells in the antitumor effect, we injected liposomes or immunoliposomes containing the human IFNbeta gene into tumors in nude mice depleted of NK cells by irradiation and anti-asialoGM1 antibody administration. The antitumor effect of the liposomes or immunoliposomes was abolished. Subsequent subcutaneous glioma challenge of the nude mice after intracerebral tumor implantation and gene transfer resulted in no subcutaneous tumor growth. These results suggest that the induction of NK cells is important in the cytocidal effect of liposomes or immunoliposomes containing the human IFNbeta gene upon experimental gliomas.


Collection and analysis of peritoneal fluid from healthy llamas and alpacas.
To describe a technique for abdominocentesis in camelids and report peritoneal fluid biochemical and cytologic findings from healthy llamas and alpacas. Prospective study. Animals-17 adult llamas and 5 adult alpacas. Right paracostal abdominocentesis was performed. Peritoneal fluid was collected by gravity flow into tubes containing potassium-EDTA for cell count and cytologic evaluation and lithium heparin for biochemical analysis. Blood samples were collected via jugular venipuncture into heparinized tubes at the same time. Cytologic components were quantified. Fluid pH and concentrations of total carbon dioxide, sodium, potassium, chloride, lactate, and glucose were compared between peritoneal fluid and venous blood. All but 3 camelids had peritoneal fluid cell counts of < 3,000 nucleated cells/microL, with < 2,000 neutrophils/microL and < 1,040 large mononuclear cells/microL. All but 1 had peritoneal fluid protein concentrations of > or = 2.5 g/dL. Peritoneal fluid of camelids generally contained slightly less glucose, lactate, and sodium and roughly equal concentrations of potassium and chloride as venous blood. Peritoneal fluid was collected safely from healthy camelids. Compared with blood, peritoneal fluid usually had a low cell count and protein concentration, but some individuals had higher values. Electrolyte concentrations resembled those found in blood. High cell counts and protein concentrations found in peritoneal fluid of some healthy camelids may overlap with values found in diseased camelids, complicating interpretation of peritoneal fluid values.


Thalamic stroke secondary to straight sinus thrombosis in a nephrotic child.
A 7-year-old Chinese boy with steroid-resistant nephrotic syndrome developed thalamic stroke secondary to straight sinus thrombosis. He was hospitalized due to status epilepticus and coma. The child recovered after treatment by low-molecular-weight heparin (LMWH) and warfarin. This case highlights the importance of magnetic resonance imaging with venography in the early diagnosis of cerebral sinus thrombosis (CST) in nephrotic children and the effectiveness of anticoagulation therapy in improving the neurological outcome.


Utilization and patterns of community healthcare services for senior residents in long-term care facilities in Taiwan: a nationwide study.
Community healthcare is one of the many important services used to care for the disabled elderly in aging societies. The aim of this study was to evaluate the utilization and patterns of community healthcare services used by senior residents in long-term care facilities (LTCFs) in Taiwan. Secondary data analyses were conducted of the Taiwan National Health Insurance Research Database for 9338 LTCF senior residents receiving community healthcare services throughout the 2004 calendar year. The community healthcare services used by male and female LTCF senior residents were also compared by Chi-square testing. Descriptive statistics are used to present the patterns of professional visits and services by contracted healthcare facilities. About one-third of those senior residents living in LTCFs in Taiwan in 2004 received community healthcare services. Female residents received a higher percentage of community healthcare services than males in all age groups (p<0.001). Community home nursing care institutions provided 67% of healthcare visits and professional visits. Of those services provided to patients, the majority of the skilled nursing services were attributable to replacement of nasogastric tube (55%) and urinary catheter (38%). Whether or not the replacement of nasogastric tubes and urinary catheters among the LTCF senior resident population is an appropriate use of time and targeted medical resources needs further investigation. When addressing concerns about the community healthcare needs of senior residents of LTCFs, policymakers should carefully consider the current shortage of professional healthcare workers as they assess strategies to best meet the needs of the elderly in Taiwan.


Leather waste--potential threat to human health, and a new technology of its treatment.
In this paper, the authors deal with the problem of processing various types of waste generated by leather industry, with special emphasis to chrome-tanned waste. The agent that makes this waste potentially hazardous is hexavalent chromium. Its compounds can have negative effects on human health and some CrVI salts are considered carcinogens. The authors present the risks of spontaneous oxidization of CrIII to CrVI in the open-air dumps as well as the possible risks of wearing bad quality shoes, in which the chromium content is not controlled. There are several ways of handling primary leather waste, but no satisfactory technology has been developed for the secondary waste (manipulation waste, e.g. leather scraps and used leather products). In this contribution, a new three-step hybrid technology of processing manipulation waste is presented and tested under laboratory, pilot-scale and industrial conditions. The filtrate can be used as a good quality NPK fertilizer. The solid product, titanium-chromium sludge, can serve as an inorganic pigment in glass and ceramic industry. Further, the authors propose selective collection of used leather products (e.g. old shoes), the hydrolysable parts of which can be also processed by the new hybrid technology.


Membranoproliferative glomerulonephritis in a patient with congenital deficiency of the third component of complement: effect of treatment with plasma.
A 21-year-old woman with a known congenital complement component 3 (C3) deficiency developed membranoproliferative glomerulonephritis. The kidney biopsy exhibited deposits of immunoglobulins and complement components despite the C3 deficiency. The administration of fresh frozen plasma was without therapeutic benefit. Corticosteroid treatment was followed by an improvement in kidney function.


An older rural widow's transition from home care to assisted living.
Designed to foster appreciation of comprehensive evaluation of home care outcomes, this case study of an older rural widow is part of a longitudinal phenomenological study of home care. Over 14 months, while her home care agency reacted to the Balanced Budget Act, nine interviews were done with a 95-year-old woman who lived alone until she moved to an assisted living facility. Data analysis yielded structures of her changing experience of home care. Although primarily supportive services may have been inconsistent with Medicare regulations, such services may have influenced the favorable outcomes of sustaining elders at home and undergirding the rural economy.


Late sequelae of penetrating cardiac wounds.
Physiological and psychological parameters of 20 survivors of penetrating wounds of the heart were examined 7 to 52 months after recovery. All survivors had cardiac complaints. The psychological parameters for hypochondriasis, compulsiveness, and internalization were much greater in the patients than in control subjects but were similar to those in victims of violent major abdominal trauma. Physiological abnormalities were present in 19, although no particular pattern or abnormality could be related with certainty to the type of wound, operative procedure, or postoperative course. One recovered and re-employed victim required late surgical repair of a traumatic ventricular septal defect and ventricular diverticulum. Although functional work capacity measured by stress testing was normal in 90 percent, only eight survivors resumed employment. Complete rehabilitation was impaired by a residual traumatic neurosis. Management goals for patients with penetrating cardiac wounds should be broadened to include prevention of psychological disabilities.


Acquired microcephaly in blepharophimosis-ptosis-epicanthus inversus syndrome because of an interstitial 3q22.3q23 deletion.
Blepharophimosis-ptosis-epicanthus inversus syndrome is an autosomal dominant condition because of mutations or deletions of the FOXL2 gene. Microcephaly is not associated with FOXL2 mutations but has been reported in individuals with chromosome 3q deletions, which include the FOXL2 gene and other contiguous genes. The ATR gene has been reported as a candidate gene for microcephaly in individuals with contiguous deletion of chromosome 3q involving the FOXL2 gene. We describe a girl with blepharophimosis-ptosis-epicanthus inversus syndrome along with acquired microcephaly and intellectual disability. Our patient had a deletion of chromosome 3q22.2q23, which does not include the ATR gene but does include the PIK3CB gene as a candidate gene for microcephaly. We propose that the PIK3CB gene included in our patient's chromosome 3q deletion may be the gene responsible for microcephaly and other patients with blepharophimosis-ptosis-epicanthus inversus syndrome because of a chromosome 3q deletion.


Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin.
In mammals, many daily cycles are driven by a central circadian clock, which is based on the cell-autonomous rhythmic expression of clock genes. It is not clear, however, how peripheral cells are able to interpret the rhythmic signals disseminated from this central oscillator. Here we show that cycling expression of the clock gene Period1 in rodent pituitary cells depends on the heterologous sensitization of the adenosine A2b receptor, which occurs through the nocturnal activation of melatonin mt1 receptors. Eliminating the impact of the neurohormone melatonin simultaneously suppresses the expression of Period1 and evokes an increase in the release of pituitary prolactin. Our findings expose a mechanism by which two convergent signals interact within a temporal dimension to establish high-amplitude, precise and robust cycles of gene expression.


DALI-the first human whole-blood low-density lipoprotein and lipoprotein (a) apheresis system in clinical use: procedure and clinical results.
The DALI low-density lipoprotein (LDL) apheresis system is the first whole-blood apheresis system in regular clinical use. DALI stands for direct adsorption of lipoproteins, which describes the basic principle of operation of this newly developed LDL apheresis procedure. The selective removal of LDLs and lipoprotein (a) [Lp(a)] is performed in human whole blood by adsorption onto polyacrylate-coated polyacrylamide beads in an adsorber. This article describes the results of the first open multicentre clinical trial in 14 patients in whom the safety and the efficacy of the system were tested. All patients were treated on average 17 times on a weekly basis. In total, 238 sessions were carried out during the study without severe side-effects. On average, 7675 mL of the patients' whole blood was processed in about 2 h. Anticoagulation in the extracorporeal system was carried out by first giving a heparin bolus followed by continuous addition of an acid citrate dextrose (ACD-A) infusion during the treatment. The processing of nearly 1.6 times the patient blood volumes resulted in a reduction in the median LDL-cholesterol level by 66-77% (dependent on the system configuration). The Lp(a) concentrations were reduced by 59-73% (dependent on the system configuration). HDL-cholesterol, blood cell count and the other clinical parameters were not significantly affected. Based on this short-term evaluation, the DALI apheresis system is a well-tolerated, effective and simple way of reducing LDL and Lp(a) in human whole blood. The system has been introduced to clinical practice. However, to use the DALI apheresis system in clinical routine, further evaluation of long-term effects is required.


Immunosuppression in renal transplantation: viral diseases and chronic allograft nephropathy.
Chronic allograft dysfunction after renal transplantation can be ascribed to different causes, among which are viral infections. The aim of this work was to show the various ways by which different kinds of viruses affect transplant structure and function. Polyoma virus is an example of viruses directly affecting the kidney because of a specific tropism to the uroepitelial cells. Cytomegalovirus (CMV) has been chosen both because of the frequency of this infection and because CMV (as other viruses) can produce transplant vascular sclerosis. Finally, we describe hepatitis C virus (HCV) because of its capacity to induce renal lesions independently from chronic allograft nephropathy. Indeed HCV is likely to determine immunologically mediated nephritis in the transplanted kidney as well in the native one.


Nabumetone. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in rheumatic diseases.
Nabumetone is a new non-steroidal anti-inflammatory drug advocated for use in the symptomatic treatment of rheumatic and inflammatory conditions. Unlike most other drugs of its class it is non-acidic and a prodrug, which after absorption forms an active metabolite. Published data suggest that nabumetone 1 to 2g daily is comparable with therapeutic dosages of aspirin, diclofenac, ibuprofen, indomethacin, naproxen and sulindac for the treatment of pain and inflammation associated with rheumatoid arthritis, osteoarthritis and acute soft tissue injuries. While nabumetone produced fewer side effects than aspirin, results have generally shown tolerability to be similar to that of other nonsteroidal anti-inflammatory drugs. If further definition of its efficacy and tolerability relative to other non-steroidal anti-inflammatory drugs confirms these initially favourable results, then nabumetone would appear to offer a useful alternative in the treatment of painful rheumatic and inflammatory conditions.


Lipid topogenesis--35years on.
Glycerophospholipids are the principal fabric of cellular membranes. The pathways by which these lipids are synthesized were elucidated mainly through the work of Kennedy and colleagues in the late 1950s and early 1960s. Subsequently, attention turned to cell biological aspects of lipids: Where in the cell are lipids synthesized? How are lipids integrated into membranes to form a bilayer? How are they sorted and transported from their site of synthesis to other cellular destinations? These topics, collectively termed 'lipid topogenesis', were the subject of a review article in 1981 by Bell, Ballas and Coleman. We now assess what has been learned about early events of lipid topogenesis, i.e. "lipid synthesis, the integration of lipids into membranes, and lipid translocation across membranes", in the 35 years since the publication of this important review. We highlight the recent elucidation of the X-ray structures of key membrane enzymes of glycerophospholipid synthesis, progress on identifying lipid scramblase proteins needed to equilibrate lipids across membranes, and new complexities in the subcellular location and membrane topology of phosphatidylinositol synthesis revealed through a comparison of two unicellular model eukaryotes. This article is part of a Special Issue entitled: The cellular lipid landscape edited by Tim P. Levine and Anant K. Menon.


ACOG committee opinion. Number 319, October 2005. The role of obstetrician-gynecologist in the assessment and management of obesity.
Approximately one third of all women in the United States are obese. Obstetrician-gynecologists should evaluate all women for obesity by calculating body mass index (BMI) measurement and should offer appropriate interventions or referrals to promote a health weight and lifestyle.


Comparison of three enzyme-linked immunosorbant assays with the indirect immunofluorescent antibody test for the diagnosis of canine infection with Ehrlichia canis.
The aim of this study was to compare three different enzyme-linked immunosorbant assays (recombinant major antigenic protein 2 (rMAP2)-ELISA, the Immunocomb (Biogal, Israel) and the Snap 3Dx assay (IDEXX Laboratories Inc., USA)) with the indirect immunofluorescent antibody test in detecting anti-Ehrlichia canis immunoglobulin-G (IgG) antibodies. Samples tested were collected from dogs suspected to be naturally infected with E. canis and from experimentally infected dogs. When qualitative results (positive/negative) were compared, there was an overall agreement of 81% (54/67) between the indirect immunofluorescence antibody (IFA) test and the rMAP2-ELISA. An overall agreement of 94% (63/67) was found between the IFA test and the Immunocomb, and an overall agreement of 91% (61/67) was found between the IFA test and the Snap 3Dx assay. In 50 of 67 (74.6%) samples tested, complete agreement in the qualitative results was found in all four tests. Sixteen of 17 samples with disagreement in the qualitative results were found to have IFA titers of 1:320 or less. The sensitivities and specificities of the tests were found to be 0.71 and 0.85 for the rMAP2-ELISA, 0.86 and 0.98 for the Immunocomb, and 0.71 and 1.00 for the Snap 3Dx assay. The tests performed in this study were found to be highly specific in detecting E. canis antibodies. Their sensitivity was found to be low with sera having IFA titers of < or =1:320, while high with sera having titers greater than 1:320. Repeating the serological tests 1-2 weeks after the first antibody assay may overcome the sensitivity problem with titers of < or =1:320.


Preoperative Nutritional Status and Enhanced Recovery after Surgery (ERAS) Prior to Radical Cystectomy: A Review of the Literature.
Preoperative nutritional status is an important and modifiable risk factor of a patient's recovery and outcome after radical cystectomy. There are multiple malnutrition screening tools and treatment options. In this review, we discuss the best indicators of this condition and how to optimize nutrition status prior to radical cystectomy.


Recent advances in the epidemiology of primary biliary cirrhosis.
Since initial reports in the mid-1970s provided epidemiology data on primary biliary cirrhosis (PBC), many studies have characterized the variable frequency of this disease in diverse populations worldwide and sought to identify associated risk factors. Recent research confirms earlier work suggesting that the incidence and prevalence of PBC are on the rise, although geographic variation persists. Analysis of familial and geographic clustering supports the hypothesis that development and progression of the disease hinge on a complex interplay between genetic and environmental risk factors. International clinical data systems are needed to advance PBC epidemiologic research. Given this complexity, international clinical data systems are needed to advance PBC epidemiologic research.


Evaluation of serum zonulin for use as an early predictor for gestational diabetes.
Diet has an important role in regulating intestinal permeability and subsequently the risk for metabolic disorders. In this observational study, we examined whether serum intestinal permeability marker zonulin, could be used as a predictor for gestational diabetes mellitus (GDM). Serum zonulin concentration was measured in early pregnancy in overweight or obese pregnant women (n=88) at risk for developing GDM. Serum zonulin was associated with higher odds of GDM (adjusted OR for 1 ng ml-1 increase in zonulin: 1.08, 95% CI: 1.02-1.15; P=0.009), diagnosed by a 2-h 75-g oral glucose tolerance test at late pregnancy. The optimal cutoff value was 43.3 ng ml-1, with sensitivity of 88% (95% CI: 71-100%) and specificity of 47% (95% CI: 33-58%). The area under the ROC-curve was 0.67 (95% CI: 0.54-0.81). Our results show an association between increased early-pregnancy serum zonulin concentration and GDM, suggesting zonulin as a possible predictor for GDM.


Steroid synthesis by Taenia crassiceps WFU cysticerci is regulated by enzyme inhibitors.
Cysticerci and tapeworms from Taenia crassiceps WFU, ORF and Taenia solium synthesize sex-steroid hormones in vitro. Corticosteroids increase the 17β-estradiol synthesis by T. crassiceps cysticerci. T. crassiceps WFU cysticerci synthesize corticosteroids, mainly 11-deoxycorticosterone (DOC). The aim of this work was to investigate whether classical steroidogenic inhibitors modify the capacity of T. crassiceps WFU cysticerci to synthesize corticosteroids and sex steroid hormones. For this purpose, T. crassiceps WFU cysticerci were obtained from the abdominal cavity of mice, pre-cultured for 24h in DMEM+antibiotics/antimycotics and cultured in the presence of tritiated progesterone ((3)H-P4), androstendione ((3)H-A4), or dehydroepiandrosterone ((3)H-DHEA) plus different doses of the corresponding inhibitors, for different periods. Blanks with the culture media adding the tritiated precursors were simultaneously incubated. At the end of the incubation period, parasites were separated and media extracted with ether. The resulting steroids were separated by thin layer chromatography (TLC). Data were expressed as percent transformation of the tritiated precursors. Results showed that after 2h of exposure of the cysticerci to 100 μM formestane, the (3)H-17β-estradiol synthesis from tritiated androstenedione was significantly inhibited. The incubation of cysticerci in the presence of (3)H-DHEA and danazol (100 nM) resulted in (3)H-androstenediol accumulation and a significant reduction of the 17β-estradiol synthesis. The cysticerci (3)H-DOC synthesis was significantly inhibited when the parasites were cultured in the presence of different ketoconazole dosis. The drug treatments did not affect parasite's viability. The results of this study showed that corticosteroid and sex steroid synthesis in T. crassiceps WFU cysticerci can be modified by steroidogenic enzyme inhibitors. As was shown previously by our laboratory and others, parasite survival and development depends on sex steroids, therefore the inhibition of their synthesis is a good starting point exploited in situations where the inhibition of steroidogenesis could help to control the infection for the development of new treatments, or replacement of the usual therapy in resistant parasite infections. We raise the possibility that these drug actions may be beneficially.


Spatially distinct production of reactive oxygen species regulates platelet activation.
Platelets play a key role in hemostasis and changes in redox balance are known to alter platelet activation and aggregation. Interestingly, activation of platelets leads to production of reactive oxygen species (ROS), but the role(s) of these ROS remain unclear. Using flow cytometry and chemiluminescence, agonist-induced ROS generation was found to be spatially distinct with stimulation through the major collagen receptor GPVI inducing only intraplatelet ROS while thrombin induced production of extracellular ROS. Platelet activation by either the GPVI-selective agonist convulxin or thrombin was differentially regulated by ROS generation. Thus, surface expression of CD62P, CD40L, or activated integrin alphaIIbbeta3 was abrogated by pharmacologic antioxidants but externalization of phosphatidylserine was not inhibited. Furthermore, extracellular antioxidants SOD/catalase markedly inhibited thrombin-, but not convulxin-, induced CD62P expression and alphaIIbbeta3 activation. The data suggest that ROS selectively regulate biochemical steps in platelet activation and that distinct source(s) of ROS and discrete redox-sensitive pathway(s) may control platelet activation in response to GPVI or thrombin stimulation. Thus, targeting ROS with site-specific antioxidants may differentially regulate platelet activation via thrombin or collagen.


Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer: data from a randomised trial with long-term follow-up.
Tumour-infiltrating lymphocytes (TILs) are of important prognostic and predictive value in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC), but their clinical relevance in oestrogen receptor-positive/HER2-negative (ER+/HER2-) remains unknown. The primary study aim was to analyse the prognostic effect of TILs on the BC-free interval (BCFi) in premenopausal patients stratified by BC subtypes. The secondary aim was to investigate if TILs are predictive of tamoxifen (TAM) benefit. Archival tissues from primary breast tumours were collected from patients from the SBII:2pre trial, in which 564 premenopausal women were randomised to 2 years of adjuvant TAM or no systemic treatment, regardless of hormone receptor status. TILs were scored on whole tissue sections from 447 patients with available ER status. Tumours were divided into ER+/HER2-, HER2+ and TNBC subtypes by immunohistochemistry and in situ hybridisation. The prognostic value of TILs was analysed in systemically untreated patients (n = 221); the predictive information was investigated in the ER+ subgroup (n = 321) by cumulative incidence curves and Cox regression analyses. The median follow-up was 28 years. High (≥ 50%) infiltration of TILs was a favourable prognostic factor in terms of BCFi (univariable analysis: hazard ratioBCFi (HRBCFi) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002). Similar effects were observed across all BC subtypes. The effect of adjuvant TAM was stronger in patients with ER+ tumours and TILs < 50% (HRBCFi 0.63; 95% CI 0.47-0.84; P = 0.002) than in patients with high immune infiltration (≥ 50%) (HRBCFi 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effects of TAM in categories of TILs, i.e. interaction, was weak. We demonstrate a long-term favourable prognostic value of high infiltration of TILs in a cohort of premenopausal BC patients and the positive prognostic effect was extended to the ER+/HER2- subgroup. A beneficial effect of TAM in ER+ patients was observed in patients with tumours of low TIL infiltration, but evidence for a treatment predictive effect was weak. This trial is registered in the ISRCTN database, trial ID: ISRCTN12474687 .


Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies.
Maternal lupus anticoagulants and anticardiolipin antibodies are associated with a syndrome of recurrent pregnancy loss or preterm birth in live-borns, fetal growth retardation, and placental infarction. Fourteen women with one or more abnormal pregnancy outcomes (total 28 losses, one severely growth-retarded premature live-born) and no normal outcomes were treated with full-dose, subcutaneous, twice-daily heparin therapy in subsequent pregnancies. Treatment was started at an estimated gestational age of 10.3 +/- 4.0 (mean +/- SD) weeks (range 6-18), in a mean total daily dosage of 24,700 +/- 7400 units (range 10,000-36,000). Fourteen of 15 pregnancies resulted in live births at 36.1 +/- 1.7 weeks (range 33-39). The mean birth weight percentile was 57 +/- 21 (range 10-90), and Apgar scores were good to excellent. The number of placental infarcts was fewer in treated cases than in previous deliveries. Five fetuses had third-trimester or perinatal problems with no sequelae, four discovered by close maternal-fetal monitoring. There was an increased rate of preterm and cesarean deliveries. Maternal complications of treatment were few and minor, with no hypertension, preeclampsia, or serious drug-related complications. Heparin appears suitable for further investigation in the treatment of this obstetric syndrome.


The International Classification of Functioning, Disability and Health environmental factors as facilitators or barriers used in describing personal and social networks: a pilot study of adults with cerebral palsy.
Using the environmental factors of the International Classification of Functioning, Disability and Health (ICF), the aim of the study was to describe the social networks involved in the everyday lives of adults with cerebral palsy (CP). A further aim was to use the ICF generic scale to describe how far these adults experienced the contacts within these networks as facilitators or barriers. Sixteen adults with CP, including nine women, with a mean age of 32 years were interviewed. The interviews were performed using a guide based on the component environmental factors of the ICF. The participants described (ICF codes e310-e360) 85 contacts in the domain of 'support and relationships' as substantial facilitators (md=3.5), and 45 as both moderate-to-substantial facilitators and barriers (md=2.5). Four contacts were considered as barriers. The participants described (ICF codes e410-e455) 88 contacts in the domain of 'attitudes' as substantial facilitators (md=3) and 36 contacts as both moderate barriers and facilitators (md=2). Another four contacts were considered as moderate-to-severe barriers (md=2.5). Within the domain 'services, systems and policies' (e535-e590), the participants described 123 facilitators, the majority considered as substantial, 37 considered as both moderate facilitators and barriers and one considered as a complete barrier. The result of this pilot study contributes new information concerning the contact networks of adults with CP. It indicates new possibilities for using the ICF environmental factors and the 1-4 scale of facilitators and barriers in clinical work. The participants felt the majority of the contacts in their networks to be supportive, whereas some were felt to be both facilitators and barriers.


In vivo dynamics of anti-viral CD8 T cell responses to different epitopes. An evaluation of bystander activation in primary and secondary responses to viral infection.
Viral infections induce extensive T cell proliferation in vivo. However, only a small fraction (1-5%) of the activated T cells have been shown to be virus specific leading to the prevailing notion that most of the T cell expansion represents cytokine-mediated by-stander activation and/or cross reactive stimulation of non specific cells. To re-examine this issue we quantitated antigen specific CD8 T cells during acute LCMV infection of mice using three sensitive techniques: (i) intracellular cytokine production, (ii) single cell ELISPOT and (iii) direct visualization of antigen specific CD8 T cells by staining with MHC class I tetramers + peptide. In contrast to previous estimates, we found that 50-70% of the activated CD8 T cells were LCMV specific. This represented > or = 10,000-fold increase (approximately 2 x 10(7) virus specific cells/spleen) in 8 days with the peak expansion occurring between day 3 and 5 during which period virus specific CD8 T cells had an estimated division time of approximately 8 hours. Following viral clearance, the number of antigen specific CD8 T cells dropped to 1 x 10(6) per spleen and were maintained at this level for the life of the mouse. Upon rechallenge with LCMV, memory CD8 T cells rapidly proliferated and again comprised > 50% of the total CD8 T cells. In contrast, upon challenge with a heterologous virus such as vaccinia, there was no change in the number of LCMV specific memory CTL, despite a substantial increase in the number of activated CD8 T cells. Taken together, these results show that much of the CD8 T cell expansion seen during viral infection represents antigen specific cells.


Screening for esophageal luminal narrowing--a magnetic disc tablet as a bolus challenge: preliminary report.
Narrowing of the esophageal lumen often exists for months before being noted by the patient. Screening tests for such lesions would be useful, if applicable to office use. A magnetic disc tablet (14 mm in diameter and 5 mm thick) was fashioned by hand using dental acrylic material to enclose the magnet with a smooth watertight sheath. A magnetic detector was held on the anterior abdominal wall 2.5 cm below the xiphoid cartilage and 2.5 cm to its left. A significant change in reading indicated that the tablet had reached the cardia of the stomach. The magnetic tablet was readily detected in 11 patients without organic narrowing. Our method attempts to detect narrowing of the esophageal lumen by use of a magnetic disc tablet. Perhaps this will be of clinical usefulness in detecting esophageal disease before symptoms become apparent.