Targeting tumor cell senescence and polyploidy as potential therapeutic strategies.
Senescence is a unique state of growth arrest that develops in response to a plethora of cellular stresses, including replicative exhaustion, oxidative injury, and genotoxic insults. Senescence has been implicated in the pathogenesis of multiple aging-related pathologies, including cancer. In cancer, senescence plays a dual role, initially acting as a barrier against tumor progression by enforcing a durable growth arrest in premalignant cells, but potentially promoting malignant transformation in neighboring cells through the secretion of pro-tumorigenic drivers. Moreover, senescence is induced in tumor cells upon exposure to a wide variety of conventional and targeted anticancer drugs (termed Therapy-Induced Senescence-TIS), representing a critical contributing factor to therapeutic outcomes. As with replicative or oxidative senescence, TIS manifests as a complex phenotype of macromolecular damage, energetic dysregulation, and altered gene expression. Senescent cells are also frequently polyploid. In vitro studies have suggested that polyploidy may confer upon senescent tumor cells the ability to escape from growth arrest, thereby providing an additional avenue whereby tumor cells escape the lethality of anticancer treatment. Polyploidy in tumor cells is also associated with persistent energy production, chromatin remodeling, self-renewal, stemness and drug resistance - features that are also associated with escape from senescence and conversion to a more malignant phenotype. However, senescent cells are highly heterogenous and can present with variable phenotypes, where polyploidy is one component of a complex reversion process. Lastly, emerging efforts to pharmacologically target polyploid tumor cells might pave the way towards the identification of novel targets for the elimination of senescent tumor cells by the incorporation of senolytic agents into cancer therapeutic strategies.


Fatigue research in 2011: from the bench to practice.
Over the last 20 years, academic, industry and community stakeholders have been meeting at a biennial scientific conference to discuss fatigue-related research and policy in the transportation, resources and health sectors. During this period, the research conducted around the world has progressed substantially: we now better understand the basic processes of sleep and circadian physiology that underpin performance; we better understand that fatigue risk management in the absence of any discussion about sleep is fruitless at worst and inadequate at best; and we are improving the capacity of models and other technologies to assist us to predict, monitor, identify, minimise and mitigate fatigue-related risk. At the same time however, the relationship between performance on simple cognitive tasks in laboratory settings and performance on complex tasks required to operate efficiently and safely in the workplace, remains a stumbling block. This special issue brings together fifteen papers that cover the range of areas in the field of fatigue research and challenges us as researchers, regulators, industry representatives and community members to continue the work of managing the risk of fatigue.


Isolated pontine progressive multifocal leukoencephalopathy: unusual magnetic resonance imaging features.
Progressive multifocal leukoencephalopathy (PML) is an uncommon opportunistic infection that causes focal or multifocal demyelination predominantly in the subcortical white matter. The authors describe the clinical and radiographic features in 2 unusual cases of PML that were initially isolated to the pons. One patient presented clinically with only an isolated sixth cranial nerve palsy.


Pain responsivity in major depression and bipolar disorder.
Signal detection theory measures of thermal pain responsivity were examined in patients with major depression and bipolar disorder and in control subjects. Patients with major depression had significantly poorer sensory discrimination of painful thermal stimuli than control subjects, but they did not differ from the control subjects in their sensory discrimination of warm thermal stimuli of lower intensity. Patients with bipolar disorder did not differ significantly in sensory discrimination from either the patients with major depression or the control subjects. Patients with major depression had significantly higher (i.e., more stoical) response criteria than the control subjects for the painful thermal stimuli and also for the lower intensity stimuli; patients with bipolar disorder had significantly higher criteria than control subjects for only the lower intensity stimuli. The results suggest that reduced responsivity to pain in major depression may reflect sensory as well as affective abnormalities. Complaints of pain are very common in mood disorders, and continued examination of experimental pain in individuals with these disorders has the potential to enhance our understanding of this phenomenon.


Uveoscleritis after excessive neodymium:YAG laser posterior capsulotomy.
A 66-year-old woman developed severe and recurrent scleritis and uveitis after neodymium:YAG capsulotomy performed 18 months after cataract extraction. Four cracks on the intraocular lens and plastic splinters in the vitreous indicated that excessive laser energy had been used. Inflammation was treated successfully only when a combination of dexamethasone acetate 0.1% drops (Maxidex), drops of diclofenac sodium 0.1% (Voltaren Ophtha), and systemic diclofenac sodium (Voltaren) was used. Inflammation might be explained by chronic irritation of the ciliary body by a displaced haptic or by an immune reaction triggered by damage to the ciliary body at the time of excessive posterior capsulotomy.


Rapid plasticity of visual responses in the adult lateral geniculate nucleus.
Compared to the developing visual system, where neuronal plasticity has been well characterized at multiple levels, little is known about plasticity in the adult, particularly within subcortical structures. We made intraocular injections of 2-amino-4-phosphonobutyric acid (APB) in adult cats to block visual responses in On-center retinal ganglion cells and examined the consequences on visual responses in the lateral geniculate nucleus (LGN) of the thalamus. In contrast to current views of retinogeniculate organization, which hold that On-center LGN neurons should become silent with APB, we find that ∼50% of On-center neurons rapidly develop Off-center responses. The time course of these emergent responses and the actions of APB in the retina indicate the plasticity occurs within the LGN. These results suggest there is greater divergence of retinogeniculate connections than previously recognized and that functionally silent, nonspecific retinal inputs can serve as a substrate for rapid plasticity in the adult.


The wedding proposal.
In this narrative essay, the author, a medical student, describes a patient who was nearing the end of her life and who feared passing away before she could witness her daughter's wedding. This story describes the lengths to which the medical team went to in order to address this concern, illustrating a particularly humanistic instance of what end-of-life care can mean.


Treatment of early-stage HER2+ breast cancer-an evolving field.
The evolving field of HER2-targeted therapy has significantly improved the outcome of women diagnosed with HER2-positive invasive breast cancer. In this review, we sought to summarise the efficacy of trastuzumab-based regimens in the adjuvant and neoadjuvant setting with a special emphasis on relevant clinical questions: treatment duration, sequence of trastuzumab administration, toxicity, the role of anthracycline-based regimens, and optimal management of small HER2+ tumours. Controversial topics are discussed taking into consideration the development of modern anti-HER2 agents.


Evolution: Assembling the deuterostome body plan.
Starfish, graptolites and humans look as different as can be, yet are more closely related to each other than to any other phylum. Disc-shaped Cambrian fossils join the dots between these disparate body plans to plot out their evolutionary origins.


Misconceptions predict dropout and poor adherence prospectively among newly admitted first-time methadone maintenance treatment clients in Guangzhou, China.
To investigate the incidence of dropout and the prevalence of poor adherence among newly admitted first-time clients of methadone maintenance treatment (MMT) clinics, and the associations between MMT-related misconceptions and these two treatment outcomes. A cohort study (maximum follow-up period = 17.6 months) was conducted. Three of the nine MMT clinics in Guangzhou, China participated in the study. The sample included 158 newly admitted first-time MMT clients. Information collected included background characteristics, history of drug use, MMT-related misconceptions, dropout during the entire study period and poor adherence within the first 6 months since admission to MMT. Of all newly admitted MMT clients, 98.2% possessed at least one and 50.6% possessed all four types of MMT-related misconception; 51.3% had dropped out before the completion of the study [95% confidence interval (CI): 43.5-59.1%] and 62% exhibited poor adherence within the first 6 months since admission (95% CI: 54.2-69.6%). Adjusting for significant background variables, the number of misconceived responses predicted significantly both dropout [hazard ratio (HR) = 3.80 for two to three misconceived items, HR = 7.13 for four misconceived items, with zero to one misconceived item being the reference] and poor adherence within the first 6 months [relative risk (RR) = 4.13 for two to three misconceived items; RR = 4.40 for four misconceived items, with zero to one misconceived item being the reference. Among opiate addicts in China prescribed methadone maintenance therapy for the first time, misconceptions about this medication are prevalent and are associated with poor adherence to the medication regimen and a high a rate of dropout from the treatment programme.


Lifecourse socioeconomic predictors of midlife drinking patterns, problems and abstention: findings from the 1958 British Birth Cohort Study.
Research suggests that outcomes associated with drinking may differ depending upon patterns of consumption, drinking related symptoms and social problems. This paper investigated socioeconomic predictors (measuring multiple indices, period and consistency of disadvantage) of midlife drinking patterns. Socioeconomic information from the 1958 British Birth Cohort Study (n=9146) included: manual socioeconomic position and owner/buyer residential tenure (7, 11, 16, 33 and 42 y), and educational attainment (33 y). At 45 y, the overlap between drinking patterns was explored using the Alcohol Use Disorders Identification Test. Patterns included: 'Moderate-binge' (binge drinkers with low-problem scores, consuming within UK sensible drinking weekly guidelines); Low-Problem Heavy (LPH) drinkers (regardless of binge); 'Problem' (and heavy or binge) and 'Non-/occasional' (< or =monthly) drinkers. These categories were compared to 'Low-risk' drinkers. Socioeconomic disadvantage was consistently associated with moderate-binge, non-/occasional and problem but not LPH drinking. The highest risk was associated with multiple and persistent disadvantage across childhood and adulthood; this risk was partially accounted for education. Non-/occasional and moderate-binge drinking was predicted by disadvantage during childhood alone. The socioeconomic disadvantage of non-/occasional drinkers was not explained by past problem or heavy drinking. Socioeconomic disadvantage across the lifecourse was consistently linked to specific drinking patterns. Furthermore, associations linking socioeconomic disadvantage with drinking patterns will typically be underestimated if multiple and persistent disadvantage is not investigated. The role of persistent socioeconomic disadvantage in the poor health of non-drinkers and moderate-binge drinkers needs investigation. The findings support current initiatives targeting the reduction of social and individual costs associated with specific drinking patterns.


Simultaneous measurement of membrane potential changes in multiple pattern generating neurons using voltage sensitive dye imaging.
Optical imaging using voltage-sensitive dyes (VSDs) is a promising technique for the simultaneous activity recording of many individual neurons. While such simultaneous recordings are critical for the understanding of the integral functionality of neural systems, functional interpretations on a single neuron level are difficult without knowledge of the connectivity of the underlying circuit. Central pattern generating circuits, such as the pyloric and gastric mill circuits in the stomatogastric ganglion (STG) of crustaceans, allow such investigations due to their well-known connectivities and have already contributed much to our understanding of general neuronal mechanisms. Here we present for the first time simultaneous optical recordings of the pattern generating neurons in the STG of two crustacean species using bulk loading of the VSD di-4-ANEPPS. We demonstrate the recording of firing activities and synaptic interactions of the circuit neurons as well as inter-circuit interactions in their functional context, i.e. without artificial stimulation. Neurons could be uniquely identified using simple event-triggered averaging. We tested this technique in two different species of crustaceans (lobsters and crabs), since several crustacean species are used for studying motor pattern generation. The signal-to-noise ratio of the optical signal was high enough in both species to derive phase-relationship between the network neurons, as well as action potentials and excitatory and inhibitory postsynaptic potentials. We argue that imaging of neural networks with identifiable neurons with well-known connectivity, like in the STG, is crucial for the understanding of emergence of network functionality.


O-POSSUM and P-POSSUM as predictors of morbidity and mortality in older patients after hip fracture surgery: a meta-analysis.
The POSSUM model has been widely used to predict morbidity and mortality after general surgery. Modified versions known as O-POSSUM and P-POSSUM have been used extensively in orthopedic surgery, but their accuracy is unclear. This systematic review evaluated the predictive value of these models in older patients with hip fractures. This study was performed and reported based on the "Preferred reporting items for systematic reviews and meta-analyses" guidelines. PubMed, Cochrane, EMBASE, and Web of Science were comprehensively searched for relevant studies, whose methodological quality was evaluated according to the "Methodological index for non-randomized studies" scale. Revman 5 was used to calculate weighted ratios of observed to expected morbidity or mortality. The meta-analysis included 10 studies, of which nine (2549 patients) assessed the ability of O-POSSUM to predict postoperative morbidity, nine (3649 patients) assessed the ability of O-POSSUM to predict postoperative mortality, and four (1794 patients) assessed the ability of P-POSSUM to predict postoperative mortality. The corresponding weighted ratios of observed to expected morbidity or mortality were 0.84 (95% CI 0.70-1.00), 0.68 (95% CI 0.49-0.95), and 0.61 (95% CI 0.16-2.38). While O-POSSUM shows reasonable accuracy in predicting postoperative morbidity in older patients with hip fractures, both P-POSSUM and O-POSSUM substantially overestimate postoperative mortality. The POSSUM model should be optimized further for this patient population.


Effect of seating forces on cement-ceramic adhesion in microtensile bond tests.
The aim of this study was to evaluate the effect of different seating forces during cementation in cement-ceramic microtensile bond strength (μTBS). Forty-five blocks (5 × 5 × 4 mm(3)) of a glass-infiltrated alumina-based ceramic (In-Ceram Alumina) were fabricated according to the manufacturer's instructions and duplicated in resin composite. Ceramic surfaces were polished, cleaned for 10 min in an ultrasonic bath, silica coated using a laboratory type of air abrasion device, and silanized. Each treated ceramic block was then randomly assigned to five groups (n = 9) and cemented to a composite block under five seating forces (10 g, 50 g, 100 g, 500 g, and 750 g) using a dual-cured resin cement (Panavia F). The ceramic-cement-composite assemblies were cut under coolant water to obtain bar specimens (1 mm × 0.8 mm(2)). The μTBS tests were performed in a universal testing machine (1 mm/min). The mean bond strengths values were statistically analyzed using one-way ANOVA (α ≤ 0.05). Different seating forces resulted in no significant difference in the μTBS results ranging between 13.1 ± 4.7 and 18.8 ± 2.1 MPa (p = 0.13) and no significant differences among cement thickness. Excessive seating forces during cementation seem not to affect the μTBS results. Excessive forces during the seating of single all-ceramic restorations cementation seem to display the same tensile bond strength to the resin cement.


Near-peer question writing and teaching programme.
Near-peer assisted learning (NPAL) is an increasingly important tool in medical education; however, although numerous published papers discuss its merits, the evidence on the effectiveness and student perception of NPAL is limited. We describe a novel near-peer question writing and teaching programme to assess whether it improves the confidence of first-year medical students for their first In-Course Assessment (ICA) in medical school. The evidence on the effectiveness and student perception of NPAL is limited METHODS: A team of medical students designed a question development procedure and a structured teaching programme. A total of 280 first-year medical students were invited to appraise the questions. A questionnaire assessing confidence and student perception was sent to participants at different time points leading up to and after their first ICA at the medical school. Statistical analysis was performed using spss 20. One hundred and seventy one students attempted the questions. Students felt more confident with short-answer questions (SAQs; 95% CI 1.5-2.0, p < 0.05) and multiple-choice questions (MCQs; 95% CI 1.0-1.5, p < 0.05), as assessed using the Wilcoxon signed-rank test. Overall, students were satisfied with the NPAL questions and teaching programme following their university examinations (p > 0.01). The NPAL project highlighted a trend towards improving students' confidence. Furthermore, the question writing and teaching programme can be used as a guide to confidently hold teaching sessions in the future. The NPAL project further reinforces existing published papers that have shown NPAL to be a powerful adjunct to existing undergraduate medical education.


Specialized peptidoglycan of the bacterial endospore: the inner wall of the lockbox.
A modified peptidoglycan (PG) wall is required for maintenance of spore core dehydration and the accompanying metabolic dormancy and heat resistance. Production of the spore PG depends on the cooperative expression of gene products within both the mother cell and forespore compartments of the sporangium. Structural elements that differentiate spore PG from vegetative cell PG include the presence of the modified sugar muramic-delta-lactam and a low level of peptide cross-links between the glycan strands. Detailed analyses of PG structure in dormant spores and in developing forespores of wild-type and mutant strains are providing data on factors required for introduction of these modifications and the importance of these structural elements in determining spore properties. Muramic-delta-lactam is not required for spore core dehydration but serves as a specificity factor for spore germination lytic enzymes. Cross-linking of spore PG can vary over a relatively wide range without significantly effecting spore core dehydration but does have an influence on the rate of spore germination and outgrowth. Future studies will examine how the two cells within the sporangium coordinate the production of this unique structure between themselves and how specific spore PG structural modifications are produced and participate in determining spore resistance properties.


Sodium dodecyl sulfate-glycerol polyacrylamide slab gel electrophoresis for the resolution of apolipoproteins.
We describe the resolution of the plasma apolipoproteins with molecular weights from 8,800 to greater than 550,000, using a 3.5% sodium dodecyl sulfate-glycerol polyacrylamide slab gel system. The simplicity of this system and the resolution of proteins over a broad range of molecular weights will make it particularly useful in investigations of apolipoprotein composition of plasma lipoproteins.


Ornithine decarboxylase as an early indicator of in vitro hepatocyte DNA synthesis.
The enzyme ornithine decarboxylase, one of the key enzymes involved in polyamine biosynthesis, catalyzes the decarboxylation of ornithine to give putrescine. The activity of this enzyme in an in vitro hepatocyte culture assay system was measured because it is known that ornithine decarboxylase levels increase in instances where active protein synthesis, DNA synthesis, and cell growth is initiated. A good correlation was found between ornithine decarboxylase activity and the rate of tritiated thymidine incorporation into hepatocyte DNA. The increase in enzyme activity precedes the incorporation of tritiated thymidine into DNA (enzyme activity increases 2-3 hr following stimulation of cell growth; whereas the tritiated thymidine uptake increases at about 14-18 hr). Experimental results obtained with this assay system, suggest that hepatocytes from the regenerating liver remnant, grown in vitro, secrete a factor(s) into the culture medium which stimulates DNA synthesis of normal hepatocytes. Use of the increase in ornithine decarboxylase activity in this hepatocyte monolayer culture system confirmed the observation made by several investigators: that the serum of rats which underwent partial hepatectomy contains a factor(s) which stimulates hepatocyte DNA synthesis in vitro. In conclusion, these results suggest that ornithine decarboxylase activity can be used as a sensitive, early indicator of the degree of stimulation of hepatocyte DNA synthesis and thus be of use in determining the effect of various trophic factors on hepatocyte DNA synthesis in vitro.


Biodegradation of nicosulfuron by a novel Alcaligenes faecalis strain ZWS11.
A bacterial strain ZWS11 was isolated from sulfonylurea herbicide-contaminated farmland soil and identified as a potential nicosulfuron-degrading bacterium. Based on morphological and physicochemical characterization of the bacterium and phylogenetic analysis of the 16S rRNA sequence, strain ZWS11 was identified as Alcaligenes faecalis. The effects of the initial concentration of nicosulfuron, inoculation volume, and medium pH on degradation of nicosulfuron were investigated. Strain ZWS11 could degrade 80.56% of the initial nicosulfuron supplemented at 500.0mg/L under the conditions of pH7.0, 180r/min and 30°C after incubation for 6days. Strain ZWS11 was also capable of degrading rimsulfuron, tribenuron-methyl and thifensulfuron-methyl. Four metabolites from biodegradation of nicosulfuron were identified, which were 2-aminosulfonyl-N, N-dimethylnicotinamide (M1), 4, 6-dihydroxypyrimidine (M2), 2-amino-4, 6-dimethoxypyrimidine (M3) and 2-(1-(4,6-dimethoxy-pyrimidin-2-yl)-ureido)-N,N-dimethyl-nicotinamide (M4). Among the metabolites detected, M2 was reported for the first time. Possible biodegradation pathways of nicosulfuron by strain ZWS11 were proposed. The degradation proceeded mainly via cleavage of the sulfonylurea bridge, O-dealkylation, and contraction of the sulfonylurea bridge by elimination of a sulfur dioxide group. The results provide valuable information for degradation of nicosulfuron in contaminated environments.


Anthocyanic pigments from elicited in vitro grown shoot cultures of Vaccinium corymbosum L., cv. Brigitta Blue, as photosensitizer in natural dye-sensitized solar cells (NDSSC).
We investigated the effect on anthocyanins and total phenols content and antioxidant capacity of in vitro shoot cultures of Vaccinium corymbosum L., cv. Brigitta Blue, grown on an eliciting medium supplied with 10 μM naphthalene acetic acid, in combination with reduced content of salts and organics in respect to the basal medium. After 45 days, higher content of total phenols and anthocyanins was obtained from extracts of shoots grown on the elicitation medium. Anthocyanin molecules, absent in control shoots, were identified by HPLC-MS as delphinidine-glycoside, cyanidine-glycoside, delphinidine-arabinoside, cyanidine- arabinoside and cyanidine-acetylglycoside. Chlorogenic acid, present in control shoots, was nearly absent in elicited shoots. We exploited the anthocyanin - based raw extracts of "Brigitta Blue" shoots grown on the elicitation medium as a source of natural dye photosensitizers for Dye Sensitized Solar Cells, taking into account that such raw extracts showed antioxidant properties and photostability features. A purified dye was also prepared and the comparison of the latter with the raw one has been analysed by spectrophotometric, chromatographic and power conversion efficiency determination. The power conversion efficiencies from the raw and the purified dye were not different and they were comparable to the data obtained by other authors with anthocyanin-based dyes from in vivo grown plants.


Security Perspective Analysis of Industrial Cyber Physical Systems (I-CPS): A Decade-wide Survey.
Considering the exceptional growth of Cyber Physical Systems (CPSs), multiple and potentially grave security challenges have emerged in this field. Different vulnerabilities and attacks are present in front of new generation CPSs, such as Industrial CPS (I-CPS). The underlying non-uniform standards, device heterogeneity, network complexity, etc., make it difficult to offer a systematized coverage on CPS security in an industrial environment. This work considers the security perspective of I-CPSs, and offers a decade-wide survey including different vulnerabilities, attacks, CPS components, and various other aspects. The comparative year-wise analysis of the existing works w.r.t objective, approach referred, testbed used and derived inference, is also presented over a decade. Additionally, the work details different security issues and research challenges present in I-CPS. This work attempts to offer a concise and precise literature study focused on the state-of-the-art I-CPS security. This work also encourages the young researchers to explore the wide possibilities present in this emerging field.


Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both.
The neurotransmitter dopamine on its own increased significantly TNFalpha and IL-10 secretion by resting normal-human T-cells, and induced approximately 5-fold elevation of the corresponding mRNA's, without affecting IFNgamma and IL-4. Using seven highly selective dopamine-receptor (DR) agonists and antagonists we found that TNFalpha-upregulation, evident after 24 h, was mediated by D3R and D1/D5R while IL-10-upregulation, evident after 72 h, was mediated by D2R and D1/D5R. We confirmed the expression of D2R and D3R in these human T cells. Dopamine's unique ability to trigger a selective secretion of either TNFalpha only (via D3R) or IL-10 only (via D2R) or both (via D1/D5R), differs from the robust and non-selective cytokine-secretion induced by 'classical' TCR-activation, and as such may have important beneficial or detrimental implications in various immunological and neurological diseases/injuries/cancers.


Lipid-lowering agents that cause drug-induced hepatotoxicity.
The effort to reduce cardiovascular risk factors, including hyperlipidemia, has led to the increased use of lipid-lowering agents. Hyperlipidemic patients often have underlying fatty liver disease, however, and thus may have elevated and fluctuating liver biochemistries. Therefore, caution should be applied before attributing elevated liver tests to lipid-lowering agents. Data indicate that patients who have chronic liver disease and compensated cirrhosis should not be precluded from receiving statins to treat hyperlipidemia. Several recent studies and expert opinion currently fully endorse statin use in patients who have nonalcoholic fatty liver disease and other chronic liver disease if clinically indicated.


[Cardiovascular rehabilitation].
Cardiovascular rehabilitation encompasses the optimization of secondary prevention to reduce morbidity and mortality, the improvement of physical fitness and quality of life as well as the reintegration into social life and employment. This requires a multifactorial intervention on the physical, psychological, educative and social level by a multidisciplinary team. In Germany, cardiac rehabilitation started early after an index event, could demonstrate a significant reduction of total mortality, myocardial infarction and hospitalization during a follow-up of 1-2 years in 4 cohort studies including 10,758 patients with myocardial infarction and bypass surgery. This reduction of clinical events was obtained in addition to rapid revascularization therapy during the acute coronary event and on top of an evidence based secondary preventive medication. By national and international medical societies, cardiac rehabilitation is recommended as well in patients with congestive heart failure, after valve replacement or valve repair, after heart transplantation and cardioverter/defibrillator implantation. In the future, cardiac rehabilitation in Germany should be evaluated by a randomized controlled trial and multifactorial interventions should be tailored individually to specific patient subgroups and medical conditions.


Influence of chronic Cd intoxication on the alkaline phosphatase activity of liver and kidney; biochemical, histochemical and histological investigations.
To distinguish between: (a) the decrease of activity of alkaline phosphatase due to inhibition by cadmium; and (b) the decline of enzyme activity due to cell destruction, 20 adult female Wistar rats were treated 3 times/week with 0.5 mg/kg CdCl2 (by subcutaneous injection) during 28 weeks. Controls received the same volume of 0.9% NaCl solution. The animals were killed at different intervals. The liver and kidneys were investigated with biochemical, histochemical, light and electron microscopical techniques. The liver homogenates show an increase of alkaline phosphatase activity after about 12-13 weeks, whereas the activity of this enzyme in the kidney decreases. This activity could not be restored by the administration of Zn ions to the medium of the enzyme assay. However, in previous in vitro experiments the Cd inhibited alkaline phosphatase activity could be totally restored by such a Zn administration. By histochemical assay of alkaline phosphatase in the renal cortex a decrease of enzyme activity was demonstrated. By evaluation of the results obtained with light and electron microscopy, in combination with the biochemical results, the decrease of alkaline phosphatase activity in the kidney should be considered as a real decrease in the amount of this enzyme due to cell degeneration.


Immunogold labeling of carbonic anhydrase isozyme (CA-VI) in secretory granules of human parotid glands.
Serous granules in the human parotid gland have a well-defined substructure, consisting of a dense spherule suspended in a moderately dense matrix. Immunogold labeling with an antibody against carbonic anhydrase VI revealed that this enzyme is localized within the matrix and is absent from the spherule. This location matches that of a number of other salivary gland proteins. Cell organelles involved in the secretory pathway are devoid of label. Labeling was not observed in any ductular component of the gland.


Glomerular filtration rate determination in diabetic patients using iohexol clearance--comparison of single and multiple plasma sampling methods.
Use of iohexol clearance has been described as the gold standard for the measurement of glomerular filtration rate (GFR). It is suggested that multiple plasma sampling following iohexol injection is required to accurately determine GFR by area under plasma clearance curve. The aim of this study was to determine whether single plasma sampling 4 h after injection of iohexol could accurately determine GFR in diabetic patients with mild to moderate renal failure, compared to multiple plasma sampling. A total of 120 GFR determinations in 36 patients with non-insulin dependent diabetic renal disease were done over 1 year. No acute deterioration was seen in renal function following injection of contrast in any patient. Strong correlation in GFR measurement was observed between the multiple plasma sampling method and the single plasma sampling method (r2 = 0.975). Single plasma sampling 4 h after bolus injection of iohexol is a safe and accurate method of determining GFR and change in GFR in diabetic subjects with mild to moderate renal impairment.


Adaptive responses of geographically distinct strains of the benthic dinoflagellate, Prorocentrum lima (Dinophyceae), to varying light intensity and photoperiod.
The toxic Prorocentrum lima complex can potentially cause serious harm to the benthos and entire food chain. Studies have revealed physiological differences in strains from different regions related to local environment, while differences in the adaptive responses of P. lima complex should be urgently assessed. Hence, this study explored the adaptive responses to varying light intensities and photoperiods of two P. lima complex strains SHG101 and 3XS34, isolated from the Bohai Sea and the South China Sea, respectively. We found the highest cell density of 7.49 × 104 cells mL-1 recorded in the 3XS strain in the stationary phase with high light intensity exposure. No significant difference was observed in growth rate among SHG groups, however, significant differences were found among 3XS groups ranging from 0.176 to 0.311 d-1. Three key pigments Chl a, Peri, and Fuco accounted for up to 60% of the total pigments. Production and concentrations of pigments and Fv/Fm values exhibit a significant negative correlation with high light intensity and growth. Conversely, total diarrhetic shellfish toxin content and the proportion of diol esters increased to varying degrees after high intensity light exposure, with 3XS strain under high light intensity and a photoperiod of light and darkness (12L:12D) consistently exhibiting the highest levels, finally reaching a maximum (21.6 pg cell-1) at day 28. A shortened photoperiod of high light intensity (8L:16D) resulted in impaired recovery compared with 12L:12D. Furthermore, 3XS showed more delayed and intense adaptive responses, indicating a stronger tolerance compared to SHG. Collectively, these results directly characterized variation in the adaptive responses of geographically distinct strains of P. lima complex, highlighting the previously ignored potential risk diversity of this species.


Maximum urinary flow rate by uroflowmetry: automatic or visual interpretation.
We measured the maximum urinary flow rate monthly for 1 year by uroflowmetry in 1,645 patients in a double-blind, placebo-controlled study of finasteride therapy for benign prostatic hyperplasia. Patients were randomized to receive placebo (555) or finasteride (1,090). A total of 23,857 flow measurements was obtained. Because of the presence of artifacts on many uroflow curves, we read the maximum urinary flow rate values manually and compared them to the values provided electronically by the uroflowmeter. On average, the manually read values were 1.5 ml. per second lower than the machine read values. Artifacts causing a difference of 2 ml. per second or more between the 2 methods were found in 20% and of more than 3 ml. per second in 9% of the tracings. The difference between treatment groups in mean maximum urinary flow rate change at the end of the study was the same with both reading methods. However, confidence intervals were 15 to 25% larger for the machine read compared to the manually read values. This larger variability in machine read maximum urinary flow rate has a marked negative impact on the power of statistical tests to assess any given difference in maximum urinary flow rate between treatment groups. Furthermore, it increases sample size requirements by 50% to achieve any given statistical power. We conclude that maximum urinary flow rate artifacts contribute significantly to the variability of maximum urinary flow rate measurement by uroflowmetry. Manual reading of the maximum urinary flow rate eliminates an important fraction of such variability.


Hyperpigmentation and melanocytic hyperplasia in transgenic mice expressing the human T24 Ha-ras gene regulated by a mouse tyrosinase promoter.
The tyrosinase promoter has been used to target expression of the mutated human T24 Ha-ras oncogene in pigment-producing cells of transgenic mice. Two independent founder mice carrying the transgene survived and showed the same distinct phenotype of mutated coat color, deeply pigmented skin with multiple nevi, and twirling behavior. The offspring of one of these founders were developed into a line that stably expressed the same phenotype. Histopathological analysis of the tissues revealed hyperpigmentation and/or melanocytic hyperplasia in the skin, eyes, inner ear, and meningeal membranes in the brain. Reverse transcriptase-polymerase chain reaction analysis revealed expression of the transgene in skin, brain, and spleen. We propose that these transgenic mice will be a model for studying the process of multistage melanoma carcinogenesis and a system for evaluating potential chemopreventive agents.


Caste differences in dopamine-related substances and dopamine supply in the brains of honeybees (Apis mellifera L.).
We determined the mechanisms underlying caste differences in the brain levels of dopamine-related substances in adult honeybees (Apis mellifera L.). Brain levels of dopamine, DOPA (a dopamine precursor), and N-acetyldopamine (a dopamine metabolite, NADA) were significantly higher in three-day-old virgin queens than same-aged workers. Caste differences in dopamine and NADA levels were also found in the hemolymph. The in vitro enzymatic activities of DOPA decarboxylase (DDC) during dopamine synthesis in brains were not significantly different between castes. The DDC activity in adult queens was mainly found in the brain, but with lower levels of activity detected in the mandibular glands, salivary glands and ovaries. Oral application of DOPA to workers led to DOPA uptake in the brain and significantly higher dopamine and NADA levels in the brain, suggesting that dopamine synthesis could be controlled by the amount of DDC substrate. Royal jelly samples taken from queen cells had a >25-fold higher concentration of dopamine compared with honey samples collected from honey cells. However, oral application of the same concentration of dopamine did not significantly enhance the brain levels of dopamine and NADA. These results suggest that the higher levels of brain dopamine in queens compared with workers can be explained by the higher level of DDC substrate, rather than DDC activity in the brain and other tissues of queens as well as exogenous dopamine in the royal jelly.


[Changes in the breast in Hodgkin's and non-Hodgkin's lymphoma].
The results of mammography, infrared thermography, cytology and histology are compared for 13 patients with secondary Hodgkin's disease and for 4 patients with primary and 9 with secondary Non-Hodgkin lymphoma. It was found, that an accurate diagnosis can be achieved only by cytology and histology


Is daily walking distance affected in adolescent idiopathic scoliosis? An original prospective study using the pedometer on smartphones.
Little is known about daily walking distance levels, which accounts for approximately 80% of overall physical activity per day, in adolescents with idiopathic scoliosis (AIS). The aim of this study was to assess the level of walking distance in AIS treated by bracing or not, comparing this activity with that of a control group. We used an original method based on smartphone pedometers for studying walking distance in everyday life. Nineteen AIS patients, aged 14.1 (13-17) years, and 25 asymptomatic patients, aged 12.9 (12-14) years were included prospectively. The 19 AIS cases comprised 9 untreated individuals and 10 with ongoing night brace treatment. The mean walking distance per day as estimated by the pedometer application on smartphones for 2 months was assessed. Weekly sports activities (hours per week) were also reported. During the first month, the mean walking distance was 2.58±0.65 km/day for control patients, 2.31±1.38 km/day for untreated AIS, and 3.65±0.72 km/day for AIS patients treated with a night brace. During the second month, the mean walking distance was 2.60±0.73 km/day for control patients, 2.40±1.41 km/day for untreated AIS, and 3.70±0.72 km/day for AIS patients treated with a night brace. Statistical analysis between groups showed a statistically significant difference with a higher level of daily walking distance in adolescents treated with a night brace compared with other groups. The pedometer on smartphones is a cost-effective and friendly tool to assess adolescents' level of walking distance. Our results indicate no restriction in terms of daily walking distance between adolescents without scoliosis and those with idiopathic scoliosis. Level II.


Thermodynamic computational approach to capture molecular recognition in the binding of different inhibitors to the DNA gyrase B subunit from Escherichia coli.
DNA gyrase subunit B, that catalyzes the hydrolysis of ATP, is an attractive target for the development of antibacterial drugs. This work is intended to rationalize molecular recognition at DNA gyrase B enzyme - inhibitor binding interface through the evaluation of different scoring functions in finding the correct pose and scoring properly 50 Escherichia coli DNA Gyrase B inhibitors belonging to five different classes. Improving the binding free energy calculation accuracy is further attempted by using rescoring schemes after short molecular dynamic simulations of the obtained docked complexes. These data are then compared with the corresponding experimental enzyme activity data. The results are analyzed from a structural point of view emphasizing the strengths and limitations of the techniques applied in the study.


Measurement of body surface area in atopic dermatitis using specific PC software (ScoradCard).
In skin diseases, evaluation of involved surface area is a crucial factor in grading the degree of severity. We examined the reliability of body surface area assessment and relative inter-observer and intra-observer variability using new software (ScoraCard), specifically designed to evaluate automatically the extension of the involved area in the SCORAD index. Twenty pediatricians, untrained in the evaluation of skin disease, estimated the percentage of surface area involved in photo-tests of two children with artificial well-delimited lesions, at first by sight and then through software. As "gold standard" the exact amount of pixels was counted for the whole body surface of the children, for the different body zones and for the painted artificial lesions, expressed as percentage of the respective zone. For photo 1, gold standard was 38.06% and median percentage was 43.44% (95% CI 40.7-46.21) by sight (p = 0.002) and 37.99% (95% CI 36.04-39.94) by ScoradCard (p = 0.79). For photo 2, gold standard was 27.84%, median percentage was 30.44% (95% CI 28.25-32.63) by sight (p = 0.047) and 27.8% (95% CI 26.55-29.04) by ScoradCard (p = 0.79). The level of agreement (kappa statistic), cumulative for the two photo tests, was 0.38 (fair agreement) by sight method and 0.67 (good agreement) by ScoradCard. Among the 10 pediatricians who repeated the computer aided evaluation 3 months apart, the intra-observer variability was not significantly different: the median percentage was 31.5% (95% CI 27.0-49.4) at time 0 and 29.0% (95% CI 26.7-47.2) 3 months later (p = 0.76). This new software could be a useful tool in evaluating skin lesions extension, minimizing inter- and intra-observer variability, which is an important goal in multi-centre studies.


Diagnostic imaging of fracture complications.
Fracture complications as discussed in this article are those abnormalities occurring as a direct result of or in association with a fracture or dislocation. Complications with radiographic findings are stressed, although those without definite radiographic manifestations are mentioned for the sake of completeness.


CT fluoroscopy-guided postmyelographic transthecal radiofrequency ablation of a posterior vertebral body osteoid osteoma.
The present case report describes a unique case of radiofrequency (RF) ablation of an osteoid osteoma in the inferoposterior paramedian region of the L5 vertebral body. After computed tomographic (CT) myelography, CT fluoroscopy was used to guide the transthecal approach of the RF ablation procedure.


shRNA-Induced Gene Knockdown In Vivo to Investigate Neutrophil Function.
To silence genes in neutrophils efficiently, we exploited the RNA interference and developed an shRNA-based gene knockdown technique. This method involves transfection of mouse bone marrow-derived hematopoietic stem cells with retroviral vector carrying shRNA directed at a specific gene. Transfected stem cells are then transplanted into irradiated wild-type mice. After engraftment of stem cells, the transplanted mice have two sets of circulating neutrophils. One set has a gene of interest knocked down while the other set has full complement of expressed genes. This efficient technique provides a unique way to directly compare the response of neutrophils with a knocked-down gene to that of neutrophils with the full complement of expressed genes in the same environment.


Correcting tumour SUV for enhanced bone marrow uptake: retrospective 18F-FDG PET/CT studies.
The concentration of F-FDG in the bone marrow is usually low. One common cause of high uptake is due to bone marrow stimulating drugs administered in conjunction with chemotherapy or radiation therapy. It has been hypothesized that the sequestration of F-FDG to the bone marrow may reduce the standardized uptake value (SUV) of a tumour. We tested this hypothesis by quantifying total F-FDG uptake in the bone marrow of patients with visibly enhanced bone marrow uptake and computing its effect on tumour SUV. Total F-FDG in bone marrow was measured in two groups of PET/CT studies: one (n=19) with visibly enhanced bone marrow, the other (n=5), a baseline group with 'normal' levels of uptake. To measure the F-FDG in bone marrow, the entire skeleton in the CT was segmented from surrounding tissue, and the resulting volume applied to the PET image. Using kinetic analysis we show that the predicted correction factor to tumour SUV is given by (1-q0/Q)/(1-q/Q), where Q is the injected dose, and q and q0 are enhanced and baseline bone marrow uptake (MBq). The enhanced bone marrow uptake averaged 8.9+/-3.2% of injected dose (15.2% max) vs. 4.2+/-0.4% (4.6% max) at baseline. This resulted in a predicted artificial decrease in tumour SUV of up to 11.5% (4.9+/-4.3%, on average). Enhanced bone marrow uptake is predicted to reduce tumour SUVs by as much as 11.5% in our patient group and is a potential confounding factor in using SUV for monitoring tumour response to therapy.


The challenge of differentiating tuberculous meningitis from bacterial meningitis.
Tuberculous meningitis (TBM) is a rare but important differential diagnosis in patients with impaired consciousness. Here, we describe a case of TBM in an 83-year-old Japanese woman who presented to a local hospital with fever and decreased consciousness of 20 days' duration (from day -40). She was started on treatment for bacterial meningitis due to an increased cerebrospinal fluid cell count, but her condition did not improve. She was transferred to a second hospital on suspicion for cholecystitis, then to a university hospital when consciousness did not improve and finally to us at a fourth hospital. On day -2, diffuse granulation was seen in both lung fields on chest computed tomography, sputum Mycobacterium test was positive and adenosine deaminase was elevated in spinal fluid. We diagnosed TBM secondary to miliary tuberculosis and started treatment with steroids and anti-tuberculous drugs (day 0). However, her level of consciousness did not improve and she died at a sanatorium on day 178. Delayed treatment of TBM has a prognostic impact and should be kept in mind as a differential diagnosis for impaired consciousness.


Expression, purification and characterization of the Hepatitis B virus entire envelope large protein in Pichia pastoris.
The current HBsAg vaccine has performed a vital role in preventing the transmission of HBV during the past 20 years. However, a number of individuals still show no response or a low response to the vaccine. In the present study, the HBV envelope large protein gene was cloned into the eukaryotic expression vector pPIC9k and was subsequently expressed in the yeast Pichia pastoris. The HBV large protein (L protein) was produced and secreted into the medium, where some of the L protein formed particles. The soluble L protein and particles were purified by column chromatography and sucrose density gradient centrifugation. Western blot analysis demonstrated that the particle was composed of both HBV L and S protein. To compare the antigenicity of the L protein and HBsAg, rabbits were immunized with the soluble L protein and the commercially available HBV vaccine and the increasing level of antibodies was determined by ELISA. The results showed that the anti-HBsAg antibody, from rabbits injected with the L protein at a dose of 2 and 10microg, was detected on day 14, whereas rabbits vaccinated with 10 and 2microg HBsAg did not develop antibodies until day 21 and 28, respectively. The antibody level in groups inoculated with the L protein was approximately 50% higher than in the group injected with HBsAg using the same dose. Furthermore, 2microg L protein induced a significant and rapid anti-HBsAg antibody response than 10microg HBsAg. Therefore, we suggest that the L protein is an ideal candidate for a new generation HB vaccine to protect people from HBV infection.


Etiology and prognostic implications of a large pericardial effusion in men.
To assess the etiology and prognosis of a large pericardial effusion, we reviewed 25 consecutive patients who presented with a large pericardial effusion and underwent a drainage procedure. Large pericardial effusion was defined as: (1) an echo-free space greater than or equal to 10 mm anteriorly and posteriorly by M-mode echocardiography and (2) removal of greater than or equal to 350 ml of fluid at pericardial drainage. The etiologies of large pericardial effusion were: neoplastic (36%), idiopathic (32%), uremic (20%), postmyocardial infarction (8%), and acute rheumatic fever (4%). Of our patients, 44% presented with cardiac tamponade, while 25% of patients with idiopathic pericarditis had hemorrhage effusion and cardiac tamponade. At follow-up, 37 +/- 17 months after pericardial drainage, 68% had died from complications of their underlying disease. There were no deaths attributed to pericardial disease. While 88% of patients with idiopathic large pericardial effusion were alive at follow-up, none of the neoplastic large pericardial effusion patients survived longer than 5 months after initial pericardial drainage (p less than 0.001). Additionally, the survival of patients with uremic large pericardial effusion was better than patients with neoplastic large pericardial effusion (p less than 0.05). We conclude: (1) neoplastic, idiopathic, and uremic pericarditis are the most common causes of large pericardial effusion in men, (2) idiopathic pericarditis can be hemorrhagic and cause cardiac tamponade, and (3) the prognosis of large pericardial effusion is related to patients' underlying disease.


Hepatitis TT virus infection in high-risk groups.
The novel hepatitis TT virus first described by a Japanese group has been reported to be parenterally transmitted and furthermore, to have been detected in patients with hepatitis of unknown etiology. Hence, in the present study its prevalence was investigated within groups at high risk for contracting blood-borne viruses, such as individuals with chronic liver disease, intravenous drug users and recipients of blood and blood products, as compared to voluntary blood donors and pregnant women. To that end, DNA was extracted from sera obtained from the respective patients and subjected to PCR using semi-nested primers. The frequency of TTV DNA detected within high risk groups, such as nine out of 50 patients with chronic non-A-to-G liver disease (18%), nine out of 98 hepatocellular carcinoma cases (9.2%), 17 out of 52 intravenous drug users (32.7%), 15 out of 80 thalassemia patients with multiple blood transfusions (18.8%) and three out of 31 prostitutes (9.7%) exceeded that among voluntary blood donors and pregnant women, which amounted to 14 out of 200 (7%) and seven out of 103 (6.8%), respectively. Additional molecular research should be performed in order to determine its short-, as well as long-term clinical significance.


Tetrapyrrole synthesis of photosynthetic chromerids is likely homologous to the unusual pathway of apicomplexan parasites.
Most photosynthetic eukaryotes synthesize both heme and chlorophyll via a common tetrapyrrole biosynthetic pathway starting from glutamate. This pathway was derived mainly from cyanobacterial predecessor of the plastid and differs from the heme synthesis of the plastid-lacking eukaryotes. Here, we show that the coral-associated alveolate Chromera velia, the closest known photosynthetic relative to Apicomplexa, possesses a tetrapyrrole pathway that is homologous to the unusual pathway of apicomplexan parasites. We also demonstrate that, unlike other eukaryotic phototrophs, Chromera synthesizes chlorophyll from glycine and succinyl-CoA rather than glutamate. Our data shed light on the evolution of the heme biosynthesis in parasitic Apicomplexa and photosynthesis-related biochemical processes in their ancestors.


Malignant change in cysts of the skin.
The concept that squamous carcinoma arises with any frequency from common skin cysts is examined. We believe this to be extremely rare and suggest that many of the previously reported cases are pilar tumors or proliferating trichilemmal cysts, a benign but clinically impressive lesion occurring most commonly in the scalps of older women. An illustrative case is presented.


Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2 months to 2 years of age with urea cycle disorders.
Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2 months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN). Pharmacokinetics (PK) of GPB were examined to see if hydrolysis is impaired in very young patients who may lack lipase activity. Patients 2 months to <2 years of age with UCDs from two open label studies (n = 17, median age 10 months) predominantly on stable doses of nitrogen scavengers (n = 14) were switched to GPB. Primary assessments included traditional plasma PK analyses of PBA, PAA, and PAGN, using noncompartmental methods with WinNonlin™. UPAGN was collected periodically throughout the study up to 12 months. PBA, PAA and PAGN rapidly appeared in plasma after GPB dosing, demonstrating evidence of GPB cleavage with subsequent PBA absorption. Median concentrations of PBA, PAA and PAGN did not increase over time and were similar to or lower than the values observed in older UCD patients. The median PAA/PAGN ratio was well below one over time, demonstrating that conjugation of PAA with glutamine to form PAGN did not reach saturation. Covariate analyses indicated that age did not influence the PK parameters, with body surface area (BSA) being the most significant covariate, reinforcing current BSA based dosing recommendations as seen in older patients. These observations demonstrate that UCD patients aged 2 months to <2 years have sufficient lipase activity to adequately convert the pre-prodrug GPB to PBA. PBA is then converted to its active moiety (PAA) providing successful nitrogen scavenging even in very young children.


(E)-6-(Furan-2-yl-methyl-idene)-6,7,8,9-tetra-hydro-pyrido[2,1-b]quinazoline-11-thione.
A quinazolinthione, C17H14N2OS, was synthesized by the condensation reaction of 6,7,8,9-tetra-hydro-11H-pyrido[2,1-b]quinazolin-11-thione with furfural. The mol-ecule crystallizes in the monoclinic system (Cc space group) and has an E configuration with respect to the exocyclic C=C bond. In the crystal, mol-ecules are linked through C-H⋯π(furan) inter-actions, forming zigzag chains propagating along the [001] direction.


Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop.
The epidermal growth factor receptor (EGFR) and its ligand amphiregulin (AR) have been shown to be co-over expressed in breast cancer. We have previously shown that an AR/EGFR autocrine loop is required for SUM149 human breast cancer cell proliferation, motility and invasion. We also demonstrated that AR can induce these altered phenotypes when expressed in the normal mammary epithelial cell line MCF10A, or by exposure of these cells to AR in the medium. In the present studies, we demonstrate that SUM149 cells and immortalized human mammary epithelial MCF10A cells that over express AR (MCF10A AR) or are cultured in the presence of exogenous AR, express higher levels of EGFR protein than MCF10A cells cultured in EGF. Pulse-chase analysis showed that EGFR protein remained stable in the presence of AR, yet was degraded in the presence of EGF. Consistent with this observation, tyrosine 1045 on the EGFR, the c-cbl binding site, exhibited less phosphorylation following stimulation with AR than following stimulation with EGF. Ubiquitination of the receptor was also dramatically less following stimulation with AR than following stimulation with EGF. Flow cytometry analysis showed that EGFR remained on the cell surface following stimulation with AR but was rapidly internalized following stimulation with EGF. Immunofluorescence and confocal microscopy confirmed the flow cytometry results. EGFR in MCF10A cells cultured in the presence of EGF exhibited a predominantly intracellular, punctate localization. In stark contrast, SUM149 cells and MCF10A cells growing in the presence of AR expressed EGFR predominantly on the membrane and at cell-cell junctions. We propose that AR alters EGFR internalization and degradation in a way that favors accumulation of EGFR at the cell surface and ultimately leads to changes in EGFR signaling.


[Acroloxus lacustris (fam. Ancylidae) as a new intermediate trematode host in the USSR].
585 specimens of the mollusk Acroloxus lacustris were parasitologically investigated in the Divichin Bay of the Caspian Sea. 3 species of cercarians (Echinostoma sp., Echinoparyphium recurvatum, Asymphylodora sp.), 2 species of parthenites (Echinostomatidae gen. sp. Redia I, Echinostomatidae gen. sp. Redia II) and 4 species of metacercarians (Metacercaria gen. sp. I, Metacercaria gen. sp. II. Metacercaria gen. sp. III, Tetracotyle sp.) were found in the specimens examined. A. lacustris is first reported as an intermediate host of trematodes.


En block C-terminal charge cluster reversals in prestin (SLC26A5): effects on voltage-dependent electromechanical activity.
Prestin, the transmembrane motor protein is a novel protein underlying the motility of the outer hair cells. Nonlinear capacitance (NLC) or gating charge current, which can be observed in both auditory and transfected non-auditory cells, is the electrical signature of prestin's electromechanical activity. To test the functional role of the C-terminus of prestin, several charged residue clusters were reversed en-block by site-directed mutagenesis. They are D/E to K at 516, 518, 522, 524, 527, 528 and 531 (cluster a); R/K to D at 571, 572, 573, 576, 577 and 580 (cluster b); R to D at 571; and E/D to K at 608, 609, 610, 611, 612 and 613 (cluster c). These constructs were transfected into Chinese hamster ovary cells (CHO) and NLC recordings were performed to evaluate the effects of these charge substitutions. All of the mutants showed NLC. Charge cluster a reversal significantly reduced the maximum charge movement (Qmax). All but one mutation (charge cluster c reversal) shifted V(h), indicative of the operating voltage range, in the depolarizing direction. None of the mutations affected unitary charge movement (z). These data suggest that the C-terminus of prestin lies outside the membrane voltage field, and may play an important role in controlling the operating voltage range through control of the protein's conformational energy profile via allosteric means.


Rana cascadae tadpoles aggregate with siblings: an experimental field study.
Previous laboratory studies have shown that Rana cascadae larvae preferentially associated with siblings over non-siblings in choice tests. This study, conducted during three consecutive summers, tests the hypothesis that R. cascadae larvae aggregate nonrandomly with respect to sibship in natural ponds. Pairs of sibships were reared in separate tanks or together in the same tank in the laboratory. Each sibship within a pair was then stained with neutral red or methylene blue dye and released together in a natural pond. Over a period of several days, aggregations of tadpoles within test ponds were repeatedly captured, censused for sibship composition, and released. In control tests, two groups of tadpoles from the same sibship were dyed different colors and released together. In total, 25 different tests were conducted using tadpoles from 31 sibships and 456 aggregations were sampled. The distribution of color compositions of aggregations in control tests did not differ from an expected random distribution. Color compositions of aggregations in experimental tests differed from controls and from an expected random distribution. Aggregations in these tests tended to be dominated by one of the two colors (sibships). We conclude that R. cascadae tadpoles recognize and prefer to aggregate with siblings in natural field conditions. Circumstances of early rearing (i.e., whether tadpoles were reared with siblings or in mixed sibling/non-sibling groups) had no influence on preferences to associate with siblings, but there was an inverse correlation between group size and sibling association.


Distribution of corrosive microbial communities in rust layers of steel immersed in seawater.
In this paper, high-throughput sequencing technology was adopted to visualize the microbial communities on the surfaces of two types of carbon steel immersed in Sea Area Ⅰ. The results showed that different microbial communities were formed on different carbon steel surfaces, in which the genus with the highest abundance on the surface of Q235 was Escherichia-Shigella, while anaerobic Desulfovibrio on the surface of 921a was the most abundant, and the dominant genus varied with the depth of the rust layer. In addition, the distribution of sulfate-reducing bacteria (SRB) on the surface of Q235 submerged in Sea Area Ⅱ was compared with the sulfate-reducing bacteria's distribution in Sea Area Ⅰ, using the environmental factors correlation analysis. The results showed that the concentrations of Ca2+, Na+, K+, Mg2+, and Al3+ were positively correlated with the distribution of SRB, while the concentrations of Cu2+, Zn2+, SO4 2-, Cl-, NO3 -, and organic carbon were negatively correlated with it. Furthermore, there was a highly significant correlation between each geochemical factor and Desulfotomaculum (p < 0.01).


Sex and Prediction Error, Part 1: The Metapsychology of Jouissance.
Jouissance is one of Jacques Lacan's most impenetrable concepts. Yet it is essential to Lacan's view of sex. The term is sometimes translated as "enjoyment," but this misses key features of the concept, notably its "traumatic," excessive character. This excess points to a structural negativity within the subject (i.e., the real), an original split that cannot be remedied. In this first of a series of three papers, it is proposed that "surplus prediction error"-as understood within contemporary neuropsychoanalysis-is a neural correlate for jouissance. In part 1, jouissance is explicated within Lacanian metapsychology, primarily in reference to Lacan's real and symbolic registers. Jouissance is an excess enjoyment, outside of the binding, representational capacities of language. The real is the negativity or antagonism within the symbolic, the limit of language and meaning, the point where jouissance emerges. To clarify the relationships among these terms, their positions are traced in some of Freud's major concepts, including drive, infantile sexuality, repetition, and the unconscious. A basic understanding of jouissance is necessary for the rest of this Lacanian neuropsychoanalytic project.


Ethanol inhibition of rabbit reticulocyte haem synthesis at the level of delta-aminolaevulinic acid synthetase.
Ethanol inhibition of rabbit reticulocyte synthesis occurs as a result of a decrease in haem synthesis. The present study therefore was undertaken in order to localize the inhibitory site of ethanol on the haem biosynthetic pathway. Ethanol (0.05--0.15 M) inhibition of reticulocyte protein synthesis was prevented by simultaneous incubation with 0.025--1 mM delta-aminolaevulinic acid (ALA). Ethanol inhibited both 14C-glycine and 14C-ALA incorporation into haem. However, the extent of haem formation with 14C-ALA as substrate in the presence of ethanol was still equal to that when 14C-glycine was used. These data suggest that ethanol inhibits the haem synthetic pathway at several loci, but that the decrease in haem synthesis, responsible for the decrease in protein synthesis, is due to the inhibition at the rate-limiting enzyme, delta-aminolaevulinic acid synthetase (ALA-S). To confirm this, ALA-S activity was then directly measured in intact reticulocytes, and it was shown that ethanol indeed inhibited its activity. The inhibition of ALA-S was prevented by 10(-4) M dibutyryl cyclic AMP (db cAMP) or theophylline, agents which elevate intracellular cAMP and which have previously been shown to prevent and reverse ethanol inhibition of haem and protein synthesis. Thus, it appears that cAMP protects against ethanol toxicity by preventing inhibition of ALA-S.


Studying the Symphonizing Effect of NLO Properties in Hydrated and Non-hydrated Donor Acceptor Complexes Formed Via Charge Transfer.
The present work intended to report the synthesis of newly designed donor-acceptor complexes of the pyrimidine-based system namely TAPHIA 1 and TAPHIA 2, which are symphonized to give the NLO properties. The methodologies adopted for both complexes were different and hence influenced their geometrical properties. The synthesized complexes were characterized using different techniques including SCXRD, FTIR, UV, PXRD, and TGA to confirm their formation. The SCXRD analysis revealed that TAPHIA 1 was crystallized in the Pca21 space group in an orthorhombic system while TAPHIA 2 was crystallized in the P21/c space group in a monoclinic system. The third-order NLO properties of both complexes were explored using the Z-Scan technique by employing a continuous wave (CW) diode laser of 520 nm. The third-order NLO parameters including nonlinear refractive index (n2), nonlinear absorption coefficient (β) and nonlinear optical susceptibility (χ (3)) were calculated at different powers; 40, 50 and 60 mW at fixed solution concentration (10 mM) for both the complexes. Moreover, the experimental properties including NLO, FTIR, and UV were well corroborated with theoretical results obtained at the B3LYP-D3/6-31++G(d,p) level of theory. The analysis of the theoretical and experimental properties of both complexes suggests that TAPHIA 2 is a better applicant to be employed in optical devices than TAPHIA 1 due to the enhanced ability of internal charge transfer. Symphonizing effect of NLO properties exhibited by two newly synthesized donor acceptor complexes namely TAPHIA 1 and TAPHIA 2. The NLO potential of the two newly reported organic complexes were influenced by their structural properties and charge transfer ability, made them good applicants to be employed in optoelectronic field.


Banana Peel Powder Biosorbent for Removal of Hazardous Organic Pollutants from Wastewater.
Disposing of pollutants in water sources poses risks to human health and the environment, but biosorption has emerged as an eco-friendly, cost-effective, and green alternative for wastewater treatment. This work shows the ability of banana peel powder (BPP) biosorbents for efficient sorption of methylene blue (MB), atrazine, and glyphosate pollutants. The biosorbent highlights several surface chemical functional groups and morphologies containing agglomerated microsized particles and microporous structures. BPP showed a 66% elimination of MB in 60 min, with an adsorption capacity (qe) of ~33 mg g-1, and a combination of film diffusion and chemisorption governed the sorption process. The biosorbent removed 91% and 97% of atrazine and glyphosate pesticides after 120 min, with qe of 3.26 and 3.02 mg g-1, respectively. The glyphosate and atrazine uptake best followed the Elovich and the pseudo-first-order kinetic, respectively, revealing different sorption mechanisms. Our results suggest that BPP is a low-cost biomaterial for green and environmentally friendly wastewater treatment.


Active ingredients targeting Nrf2 in the Mongolian medicine Qiwei Putao powder: Systematic pharmacological prediction and validation for chronic obstructive pulmonary disease treatment.
Qiwei Putao powder (Uzhumu-7 in Mongolian) is a traditional Mongolian medicine, which has been widely used for alleviating cough and dyspnea, especially in aged individuals in both Inner Mongolia Autonomous Region and Xinjiang Uygur Autonomous Region of China. However, the active ingredients and exact pharmacological mechanism remain unclear. The protective effect of Qiwei Putao powder (QPP) on mice with cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced chronic obstructive pulmonary disease (COPD) was assessed by histopathological hematoxylin and eosin staining, lung coefficient determination and measurement of cytokine levels. The bioactive ingredients and potential targets of the QPP were screened and detected with network pharmacology method and ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS). The mechanism and efficacy of active ingredients were further validated in COPD mice with immunohistochemistry tests, cytokine level measurement and RT-PCR. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus, interleukin (IL)-1β, superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA) kits to evaluate oxidative stress and inflammatory conditions in vivo after treatment. The expression of Nrf2 and downstream genes was detected by RT-PCR. QPP can alleviate pathological changes in the lung during COPD progression. Sixty-one bioactive molecules were identified in QPP, 42 candidate compounds present in UPLC-Q/TOF-MS and 30 predicted COPD-related targets were generated by in silico analysis. A therapeutic network was constructed with all potential targets to predict the preventive effects of the targets on respiratory disease as well as cardiovascular diseases, nervous system diseases, musculoskeletal diseases and bacterial infections. Targets related to inflammation, immunity and oxidative stress (prostaglandin-endoperoxide synthase 2, PTGS2; Nrf2; heat shock protein 90 alpha class A1, HSP90AA1; nitric oxide synthase, NOS2A; etc.) influenced COPD progression the most. We found that Nrf2 promotes a cell antioxidant response and is a key common target in the response to treatment with isoliquiritigenin (ISL), pterostilbene (PTE) and quercetin (QUE), the highly absorbed active ingredients in the formula. The data showed a strong synergistic protective role of these three molecules against the death of human type II alveolar adenocarcinoma (A549) cells through Nrf2 activation following H2O2 exposure and provide pharmacological mechanism of QPP in COPD treatment.


How much and how fast: rapid processing of spoken language in later adulthood.
Speech processing involves rapid decoding and construction of meaning from a transitory acoustic signal. Because older adults have been found to be slower in performing many cognitive tasks, we hypothesized that they may have difficulty in immediate recall for speech of increasing input rate. Two experiments are reported in which both older and younger participants listened to and immediately recalled sentences that were systematically varied in speech rate and number of propositions. Although recall performance of the older adults showed a disproportionate decline when speech rate was increased, older adults, as well as the younger adults, were able to recall sentences of increasing propositional densities. We also found that the tendency to recall a greater proportion of main ideas than details (the levels effect) was enhanced by increased propositional density, and depressed by increased speech rate and increased age. These results are discussed in terms of an age-related change in the rate at which information can be processed in working memory.


A Blueprint for Medium-Fidelity Postpartum Hemorrhage Simulations.
Many pregnancy-related deaths remain preventable, particularly those associated with postpartum hemorrhage (PPH). The use of bundles for care of women during the perinatal period has been shown to improve maternal and neonatal outcomes. Drills or simulation-based learning are an integral part of a broader implementation of postpartum hemorrhage bundles. In addition, The Joint Commission has cited drills as one of the required performance elements of accreditation. It is therefore incumbent upon perinatal clinical teams to conduct PPH simulations as a readiness tool. This article is intended to help nurses and other clinicians enhance the realism of low- and medium-fidelity PPH simulations.


Human multidrug resistance-1 gene transfer to long-term repopulating human mobilized peripheral blood progenitor cells.
Mobilized peripheral blood progenitor cells (PBPC) are an attractive target for the retrovirus-mediated transfer of cytostatic drug resistance genes. We analyzed NOD/SCID mouse repopulating CD34+ PBPC from cancer patients following retroviral Transwell transduction in various cytokine combinations with the FMEV-based (Friend-mink cell focus forming/murine embryonic stem cell virus) hybrid vector SF-MDR carrying the human multidrug resistance-1 (MDR1) gene. Five to 10 weeks following transplantation of 2.0 x 10(6) CD34+ PBPC into NOD/SCID mice we observed medium to high levels of human cell engraftment with up to 33%. The extent of vector-marked human cells was assessed by a quantitative real-time polymerase chain reaction (PCR). SF-MDR gene transfer into long-term in vivo repopulating human hematopoietic cells was optimal in the presence of either IL-3/IL-6/SCF/FL or FL/TPO/SCF resulting in three-fold (12.4% +/- 1.7%) or four-fold (16.5% +/- 6.8%) higher average proportions of gene-marked human cells in NOD/SCID mice as compared to IL-3 alone (P < 0.01). In conclusion, we could optimize the engraftment capacity and the retroviral gene transfer to CD34+ PBPC using cocktails of early acting cytokines in combination with the recombinant fibronectin fragment CH-296. Our data suggest that the NOD/SCID model provides a valid assay to estimate the gene transfer efficiency to repopulating human PBPC that may be achievable in clinical autologous transplantation settings.


Enzymeless voltammetric sensor for simultaneous determination of parathion and paraoxon based on Nd-based metal-organic framework.
The aim of this work is to fabricate a sensitive and novel enzymeless electrochemical sensor for the simultaneous determination of parathion and paraoxon using the Nd-UiO-66@MWCNT nanocomposite. For this purpose, Neodymium (Nd) was introduced into a Universitetet i Oslo (UiO-66) structure to construct Nd-UiO-66 and then, adding multi-walled carbon nanotubes to the Nd-UiO-66 to increase the electrocatalytic activity and surface area of the obtained composite. The Nd-UiO-66@MWCNT has numerous advantages like excellent conductivity, tunable texture, and large surface area and can be used as a distinctive structure for the construction of modified glassy carbon electrode (GCE) to enhance the charge-transfer and the efficiency of electrochemical sensors. This modified electrode showed sensitive and selective determination of paraoxon and parathion over the linear ranges of 0.7-100 and 1-120 nM, with detection limits of 0.04 and 0.07 nM, respectively. The proposed Nd-UiO-66@MWCNT/GCE sensor in this study can be applied in environmental and toxicological laboratories and field tests to detect parathion and paraoxon levels.


Dopamine transporter concentration is reduced in asymptomatic Machado-Joseph disease gene carriers.
Dopamine transporter (DAT) binding is decreased in Machado-Joseph disease (MJD) patients. To further investigate the DAT activity in asymptomatic MJD (aMJD) gene carriers, we performed this prospective study using (99m)Tc-TRODAT-1 ([(99m)Tc][2[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3,2,1]oct-2-yl]-methyl](2-mercaptoethyl)amino]ethyl]amino]ethane-thiolato(3-)-N2,N2',S2,S2]oxo-[1R-(exo-exo)])) brain SPECT on 5 aMJD gene carriers, 10 age-matched MJD patients, and 10 age-matched healthy control subjects. Brain SPECT images were acquired 4 h after intravenous injection of 925 MBq (25 mCi) (99m)Tc-T RODAT-1, which is known to bind specifically to the DAT on the nigrostriatal terminals. By fusing these SPECT images with a striatal atlas, obtained from MRI, binding of this tracer in the entire striatum was measured and the uptake values in bilateral striatal areas were compared between these 3 groups. The uptake values of the aMJD gene carriers (P < 0.001) and MJD patients (P < 0.001) displayed a significant reduction compared with those of the control subjects. The reduction was more severe in the MJD patient group (P < 0.05). Bilateral putamen-to-caudate ratios were significantly lower in the aMJD gene carrier and MJD patient groups (P < 0.001). The dopamine neuronal activity, as represented by the tracer binding, was more prominently affected in the putamen in these patients and gene carriers. (99m)Tc-TRODAT-1 brain SPECT is capable of detecting early alteration of dopamine neurons in the striatal region. Significantly, the results suggest that this impairment of presynaptic dopamine function actually occurs at an early stage, which was previously unrecognized in these aMJD gene carriers.


Conservative operation for mitral stenosis with densely fibrosed or partially calcified valves. An eight-year evaluation.
Of 284 patients undergoing open mitral commissurotomy for mitral stenosis from January 1978 to December 1985, 81 patients had a densely scarred or partly calcified valve. In this study, we evaluated the postoperative results in these 81 patients. There were no operative or late deaths. Seventy-seven patients (95%) are in Functional Class I or II. Three patients required reoperation 3, 30, and 50 months after the initial procedure because of moderate or severe residual mitral regurgitation. After valvotomy there were four episodes of embolism. The actuarial rate of freedom from any complication (mortality, reoperation, congestive heart failure, and thromboembolic events) was 89.3% +/- 3.9% (mean +/- standard error of the mean) 8 years after operation. We conclude that for a follow-up period of 8 years, the stenotic mitral valve with anatomical deformities can be salvaged with satisfactory results. Therefore, we believe that this approach, at present, is a better alternative than prosthetic replacement with any type of valve presently available.


The alternative approach of low temperature-long time cooking on bovine semitendinosus meat quality.
This study aimed to elucidate whether innovative sous vide treatment has a significant influence on the beef semitendinosus muscle as compared to common sous vide treatment and traditional cooking. The innovative sous vide treatments were cooked at 45°C and 65°C for 6 h (SV45-65), common sous vide treatment at 45°C and 65°C for 3 h (SV45 and SV65) and traditional cooking at 75°C for 30 min (CON75). Water loss and cooking loss, as well as the physical properties (color and shear force) and chemical properties (protein and collagen solubility) of the treated meat, were investigated. The results obtained indicated that the innovative sous vide with double thermal treatment (SV45-65) and cooked with air presence (CON75) resulted to lower a* and higher b* values, respectively. The water loss and cooking loss increased when temperature increased from 45°C to 65°C, and lower water loss was recorded in SV45 and CON75. These samples presented higher water content and revealed strong correlation to protein solubility. Warner-Bratzler shear force (SF) analysis showed the marked interaction between cooking temperature and time. Sample cooked at a high temperature (CON75) and a long period (SV45-65) showed a significantly lower value of SF than sample SV65 (p<0.05). Interestingly, there was no difference in SF values between SV45-65 and CON75. The innovative sous vide treatment with double thermal effect appears an attractive cooking method as compared to common sous vide and traditional cooking method, as it has a potential for improving tenderness values of cooked beef semitendinosus muscle.


Transactivation of the human MDR1 gene by hepatitis B virus X gene product.
Persistent hepatitis B virus (HBV) infection may cause hepatocellular carcinoma. Patients with hepatocellular carcinoma are characterized by nonresponsiveness to chemotherapeutic agents. While many studies have been devoted to understanding the hepatocarcinogenesis mechanism of HBV, the possible relationship between HBV and the drug sensitivity phenotype of cancer cells has rarely been addressed. The hepatitis B virus X gene encodes a transcription transactivator which has been suggested to be a potential factor in viral hepatocarcinogenesis. The role of HBV pX in mediating the drug resistance phenotype of hepatoma cell lines was examined in this study. Standard transfection and chloramphenicol acetyltransferase assay were utilized to examine the effect of HBV pX transactivator on a reporter gene under the control of the human multidrug resistance (MDR) 1 upstream regulatory elements. Selected Hep G2 clones with or without HBV pX expression were tested for their sensitivity towards various anti-cancer agents by utilization of MTT assay. The expression of HBV pX in both Hep G2 (p53+) and Hep 3B (p53-) cells resulted in transactivation of the reporter gene under control of the human MDR1 upstream regulatory elements. Northern blot analysis indicated that expression of the endogenous MDR1 gene was also elevated in Hep G2 clones with HBV pX expression. Decreased drug sensitivity towards adriamycin, vinblastine, and VP-16 was observed in Hep G2 clones with HBV pX expression. HBV pX can transactivate the MDR1 gene. Drug sensitivity was altered in Hep G2 cells with HBV pX expression.


Malignant melanoma with neuroendocrine differentiation: clinical, histological, immunohistochemical and ultrastructural features of three cases.
To document the clinical, histological, immunohistochemical and ultrastructural features of three malignant melanomas showing neuroendocrine differentiation. Three patients, two with primary cutaneous melanoma and one with nasal mucosal melanoma, subsequently developing or simultaneously presenting with metastatic malignant melanoma, were studied by conventional histological technique, immunohistochemistry of formalin-fixed paraffin-wax embedded tissues, and electron microscopy of epoxy-resin-embedded tumour tissue. Tumours showed either small cell or conventional malignant melanoma cell morphology. One of the three primary melanocytic lesions (the nasal melanoma) exhibited neuroendocrine differentiation immunohistochemically. All three metastatic malignant melanomas showed, in varying combinations, immunohistochemical and ultrastructural evidence for neuroendocrine differentiation: they were positive for the melanocytic markers, S100 protein, HMB-45, Melan-A and tyrosinase, and the neuroendocrine markers chromogranin, synaptophysin and neurofilament protein. Ultrastructural study in two of the metastases revealed neuroendocrine granules but no lattice-bearing melanosomes. The cases described are the most comprehensively investigated malignant melanomas showing neuroendocrine differentiation to date, and the first to document neuroendocrine differentiation ultrastructurally in these tumours. Malignant melanoma with neuroendocrine differentiation therefore needs to be recognized among the other, better known variants of malignant melanoma.


Immunohistochemical localization of chick retinal 24 kdalton protein (visinin) in various vertebrate retinae.
Antiserum against a protein (24,000 daltons, visinin) of chick retina has been provided for immunohistochemical study on the localization of visinin in chick retinae during development, as well as in various vertebrate retinae. The photoreceptor cells were stained with anti-visinin serum from 7th day embryonic retinae and its intensity was gradually increased with embryonic age. In addition, visinin-like immunoreactivity was found in some kinds of amacrine and displaced amacrine cells from 11th-day embryonic retinae. When human, cat, frog and carp retinae which contain both rods and cones were examined, staining of cone cells was clearly observed in the photoreceptor cell layer, but not in the rods. Furthermore visinin-like immunoreactivity was barely detectable in the photoreceptor cells of bovine, rat and mouse retinae containing mostly rod cells. These results suggest that visinin is mainly located in the cone cells in various vertebrate retinae and is a good marker for the cone cells.


Coordinated protein sorting, targeting and distribution in polarized cells.
The polarized distribution of functions in polarized cells requires the coordinated interaction of three machineries that modify the basic mechanisms of intracellular protein trafficking and distribution. First, intrinsic protein-sorting signals and cellular decoding machineries regulate protein trafficking to plasma membrane domains; second, intracellular signalling complexes define the plasma membrane domains to which proteins are delivered; and third, proteins that are involved in cell-cell and cell-substrate adhesion orientate the three-dimensional distribution of intracellular signalling complexes and, accordingly, the direction of membrane traffic. The integration of these mechanisms into a complex and dynamic network is crucial for normal tissue function and is often defective in disease states.


Longitudinal changes in left ventricular architecture and function in peripartum cardiomyopathy.
Left ventricular (LV) function was quantitated in 14 patients with peripartum cardiomyopathy, in 10 using 2-dimensional (2-D) echocardiography and in 4 radionuclide ventriculography, and values were compared with those in 11 normal women in the immediate postpartum period. LV end-diastolic and end-systolic volume indexes, LV wall mass index and ejection fraction were calculated during the acute phase of the illness and serially through long-term follow-up (mean 24 months). During the acute phase of illness there was marked LV dilatation: mean end-diastolic volume index was 95 +/- 22 ml/m2, vs 67 +/- 9 ml/m2 in control subjects (p less than 0.005), and mean end-systolic volume index was 66 +/- 18 ml/m2, compared to 27 +/- 5 ml/m2 in control subjects (p less than 0.001). Mean heart rates and mean systolic pressures in the patients with peripartum cardiomyopathy and the control subjects were similar, 91 +/- 24 vs 79 +/- 14 beats/min and 120 +/- 14 vs 117 +/- 10 mm Hg, respectively. LV wall mass index was higher, 139 +/- 38 vs 96 +/- 8 g/m2 (p less than 0.005), and ejection fraction much lower, 29 +/- 5% vs 67 +/- 5% (p less than 0.001), in control subjects. Five patients underwent endomyocardial biopsy during the acute illness, which showed interstitial fibrosis but no evidence of active inflammation. There was rapid and early improvement in LV function in 13 of 14 patients. Changes in LV volume, mass and ejection fraction all followed an exponential time course during LV remodeling.(ABSTRACT TRUNCATED AT 250 WORDS)


Chromatographic determination of flumequine in food samples by post-column derivatisation with terbium(III).
The potential usefulness of terbium(III) as reagent for the luminescent determination of flumequine residues in food samples has been studied using both fluorescence (FL) and time-resolved (TR) modes and both batch (B) and integrated liquid chromatography (LC)/derivatisation approaches. The system was optimised in each instance to establish the analytical features of the four methods. The dynamic ranges of the calibration graphs, obtained with standard solutions of flumequine, were (ng mL(-1)): B-FL 0.18-600; B-TR 2.4-150; LC-FL 3.7-1000 and LC-TR 52-3000. The detection limits were also obtained giving the following values (ng mL(-1)): B-FL 0.055; B-TR 0.7; LC-FL 1.1 and LC-TR 15. The precision, expressed as the percentage of relative standard deviation, was equal or lower than 5.1% in all instances. The LC methods, which avoid the interference of other quinolone antibiotics, were applied to the analysis of chicken muscle and liver, and whole milk samples. The sample pre-treatment only consisted of a deproteinisation step. The validation procedure for the analysis of samples was carried out using EC recommendations, and the decision limit and detection capability were calculated. The recoveries obtained ranged from 95.0% to 103.8%.


Neurological symptoms and neuropsychological abnormalities in lymphadenopathy syndrome.
This case-control study of 39 homosexual or bisexual men who were human immunodeficiency virus (HIV)-seropositive and had lymphadenopathy syndrome and 38 HIV-seronegative homosexual or bisexual men indicates an association between neurological and neuropsychological abnormalities and HIV infection in patients with lymphadenopathy syndrome.


Identification of essential tremor based on resting-state functional connectivity.
Currently, machine-learning algorithms have been considered the most promising approach to reach a clinical diagnosis at the individual level. This study aimed to investigate whether the whole-brain resting-state functional connectivity (RSFC) metrics combined with machine-learning algorithms could be used to identify essential tremor (ET) patients from healthy controls (HCs) and further revealed ET-related brain network pathogenesis to establish the potential diagnostic biomarkers. The RSFC metrics obtained from 127 ET patients and 120 HCs were used as input features, then the Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) methods were applied to reduce feature dimensionality. Four machine-learning algorithms were adopted to identify ET from HCs. The accuracy, sensitivity, specificity and the area under the curve (AUC) were used to evaluate the classification performances. The support vector machine, gradient boosting decision tree, random forest and Gaussian naïve Bayes algorithms could achieve good classification performances with accuracy at 82.8%, 79.4%, 78.9% and 72.4%, respectively. The most discriminative features were primarily located in the cerebello-thalamo-motor and non-motor circuits. Correlation analysis showed that two RSFC features were positively correlated with tremor frequency and four RSFC features were negatively correlated with tremor severity. The present study demonstrated that combining the RSFC matrices with multiple machine-learning algorithms could not only achieve high classification accuracy for discriminating ET patients from HCs but also help us to reveal the potential brain network pathogenesis in ET.


Paclitaxel and cisplatin as salvage treatment in patients with non-seminomatous germ cell tumour who failed to achieve a complete remission on induction chemotherapy.
The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour markers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m2 as a 3-hour infusion, followed by cisplatin 100 mg/m2, repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine > 130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 50%, and nausea and vomiting in 43%. Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31% in patients with poor prognosis who had not achieved a CR on induction chemotherapy.


Mortality and volume of cases in paediatric cardiac surgery: retrospective study based on routinely collected data.
To determine whether mortality between 1991 and 1995 in hospitals in England carrying out surgery for congenital heart disease in children was associated with the annual volume of cases and to estimate the extent to which an association could explain the apparent divergent mortality at Bristol Royal Infirmary. Retrospective analysis of data from two sources, a register of returns by surgeons to their professional society and an administrative database. 12 hospitals in England carrying out surgery for congenital heart disease over the period April 1991 to March 1995. 30 day mortality. For open heart operations in children under 1 year old, and in particular for arterial switches and repair of atrioventricular septal defect, there is strong and consistent evidence of an inverse association between mortality and volume of cases (not taking into account any data from Bristol). A hospital carrying out 120 open operations per year in 1991-5 on children aged under 1 year would be expected to have a mortality 25% lower than that in a hospital carrying out 40 operations. If the children in the hospitals had the same mix of operations, this reduction is 34%. Stratifying for types of operation or including the results from Bristol strengthens this association. It was also estimated that less than a fifth of the excess mortality at Bristol Royal Infirmary in open operations in children less than 1 year old was due to the hospital's lower volume of surgery. Using appropriate methods, this study showed that mortality in paediatric cardiac surgery was inversely related to the volume of surgery. Considerable caution is needed in interpreting these results, and it does not necessarily follow that concentrating resources in fewer centres would reduce mortality.


Systematic review: microbial manipulation as therapy for primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a progressive liver disease with poor prognosis and no effective therapies to prevent progression. An aetiopathological link between PSC and gastrointestinal microbial dysbiosis has been suggested. To evaluate all potential medical therapies which may exert their effect in PSC by modulation of the gut-liver axis. We conducted a comprehensive scoping review of PubMed and Cochrane Library, including all articles evaluating an intervention aimed at manipulating the gastrointestinal microbiome in PSC. A wide range of therapies proposed altering the gastrointestinal microbiome for the treatment of PSC. In particular, these considered antibiotics including vancomycin, metronidazole, rifaximin, minocycline and azithromycin. However, few therapies have been investigated in randomised, placebo-controlled trials. Vancomycin has been the most widely studied antibiotic, with improvement in alkaline phosphatase reported in two randomised controlled trials, but with no data on disease progression. Unlike antibiotics, strategies such as faecal microbiota transplantation and dietary therapy can improve microbial diversity. However, since these have only been tested in small numbers of patients, robust efficacy data are currently lacking. The gut-liver axis is increasingly considered a potential target for the treatment of PSC. However, no therapies have been demonstrated to improve transplant-free survival. Innovative and well-designed clinical trials of microbiome-targeted therapies with long-term follow-up are required for this orphan disease.


Evaluation and management of stress fractures of the pelvis and sacrum.
Most stress fractures of the pelvis and sacrum can be treated nonoperatively with activity modification and thorough assessment of training activities and nutritional factors.