Retained medullary cord in humans: late arrest of secondary neurulation.
Formation of the caudal spinal cord in vertebrates is by secondary neurulation, which begins with mesenchyme-epithelium transformation within a pluripotential blastema called the tail bud or caudal cell mass, from thence initiating an event sequence proceeding from the condensation of mesenchyme into a solid medullary cord, intrachordal lumen formation, to eventual partial degeneration of the cavitatory medullary cord until, in human and tailless mammals, only the conus and filum remain. We describe a secondary neurulation malformation probably representing an undegenerated medullary cord that causes tethered cord symptoms. We present 7 patients with a robust elongated neural structure continuous from the conus and extending to the dural cul-de-sac, complete with issuing nerve roots, which, except in 2 infants, produced neurological deficits by tethering. Intraoperative motor root and direct cord stimulation indicated that a large portion of this stout neural structure was "redundant" nonfunctional spinal cord below the true conus. Histopathology of the redundant cord resected at surgery showed a glioneuronal core with ependyma-lined lumen, nerve roots, and dorsal root ganglia, corroborating the picture of a blighted spinal cord. We propose that these redundant spinal cords are portions of the medullary cord normally destined to regress but are here retained because of late arrest of secondary neurulation before the degenerative phase. Because programmed cell death almost certainly plays a central role during degeneration, defective apoptosis may be the underlying mechanism.


Sleep stage-related changes in sympathetic sudomotor and vasomotor skin responses in man.
The aim of the study was to evaluate the characteristics of the spontaneous and evoked sympathetic skin responses (SSR) during sleep and wakefulness in comparison with the skin vasomotor responses (SVR). Five healthy subjects underwent a night of videopolysomnographic recording. Spontaneous SSR were recorded via surface electrodes placed on the dorsal and ventral aspect of the hand while SVR were evaluated by means of an infrared photoelectric transducer placed on the index finger. SSR and SVR were evoked via electrical stimuli applied to the left supraorbital nerve. Spontaneous SSR frequency was highest during stage 4 of NREM sleep and lowest during REM phases. On the contrary, spontaneous SVR frequency reached its lowest value during stage 4 and its highest value during stage 2 of NREM sleep, remaining at levels above waking values during REM. SSR could be elicited by stimuli inducing arousal during light sleep but it was absent during deep NREM and REM sleep. SVR could be evoked throughout NREM and REM sleep. Spontaneous SSR and SVR act differently during physiological modifications of vigilance. Evoked SSR is strictly dependent upon the state of vigilance, whereas evoked SVR shows no modifications during the different stages of the wake-sleep cycle.


An alternative approach to reduction mammoplasty.
The female breast can be reduced by a number of operative techniques. Their goal is to transform different deformities into a so-called ideal form. The ideal form is obtained by small changes such as fixing the nipple's position in relation to predetermined anatomical marks. Under certain conditions we have to deviate from the ideal form. In these cases the operative method used is not determined by the deformity but by the desired form. Reduction mammoplasty techniques are just variations of a single method whose principles still need to be defined.


Response to thermal and physical strain during flashover training in Croatian firefighters.
Flashover training (FOT) for firefighters is a simulation of the flashover phenomenon under controlled conditions. This study assessed arterial blood pressure (BP) and its response to thermal and physical strain during FOT in 48 professional and 18 volunteer firefighters. A high prevalence of obesity (27%), basal hypertensive (53%) and prehypertensive (33%) BP values was found. FOT induced mild hyperthermia and physical strain (average increase of 1.1 °C in tympanic temperature and 61% of the maximal heart beat predicted for age). Compared to professional firefighters, FOT in the volunteers induced a higher increase in pulse (P = 0.050) and tympanic temperature (P = 0.025). Systolic BP did not vary significantly, and diastolic BP slightly decreased in both groups. Results confirm that FOT induced only physiological cardiovascular responses to thermal and physical strain in firefighters. High prevalence of obesity and elevated BP values indicate the need for better physical fitness and BP control among firefighters.


In vitro and in vivo interaction between sporocysts of Sarcocystis muris and mouse peritoneal macrophages.
The interaction between the sporocysts of Sarcocystis muris and mouse peritoneal macrophages was studied both in vitro and in vivo in an attempt to determine whether or not resident peritoneal macrophages might effect the excystation of S. muris sporozoites from sporocysts injected intraperitoneally. Sporocysts of S. muris were phagocytosed by peritoneal macrophages both in vitro and in vivo. The addition of either unheated mouse serum or fetal calf serum did not significantly alter the level of phagocytosis. The percentage of phagocytosis in vivo and by thioglycolate-, proteose peptone- and BCG-elicited macrophages in vitro was greater than that shown by unstimulated macrophages in vitro. After 8 h incubation in vivo and in vitro a small proportion of sporocysts (less than 5%) was seen to have collapsed walls and up to 5% to have stained sporozoites, suggesting increased permeability of the sporocyst wall. The significance of increased permeability of the cyst wall in the process of sporozoite excystation is discussed.


Role of cannabinoid receptors in memory storage.
Studies have shown that delta 9-tetrahydrocannabinol, the principal psychoactive ingredient in marijuana, produces memory deficits similar to those produced by neurochemical lesions of the hippocampus. Such lesions impair performance in short-term spatial memory tasks learned prior to the lesion. Animals trained in the behavioral task following the lesion can still perform the task, but learn a different behavioral strategy. Cannabinoid agonists impair behavioral performance in a delay-dependent manner similar to that produced by lesions, but also shift the behavioral response strategy. A possible role for cannabinoid receptors and endogenous cannabinoids may thus be to regulate the storage (i.e., encoding) of information, as well as the means by which that information is retrieved.


Modulation of testicular and whole blood trace element concentrations in conjunction with testosterone release following kisspeptin administration in male rabbits (Oryctolagus cuniculus).
The present study investigated the role of kisspeptin-10 on reproductively significant trace elements in relation to testosterone release in male rabbits, Oryctolagus cuniculus. Groups of rabbits were exposed to single 1 μg kisspeptin dose (i.v., saphenous vein), while simultaneous groups were pretreated with a kisspeptin antagonist, peptide-234 (50 μg) 20 min before administering kisspeptin. Sequential blood sampling was done through marginal ear vein puncture at staggered time intervals: 0, 0.5, 1, 2, 4, and 24 h to determine serum testosterone. Testes and whole blood were collected at 4 and 24 h post dosage to determine trace element concentrations through atomic absorption spectrophotometry. In testes, zinc (Zn), manganese (Mn), and Fe concentrations showed significant increases at 24 h, while copper (Cu) concentration was found elevated at 4 and 24 h both (P < 0.001). In whole blood, Zn and Cu concentrations were significantly elevated at 4 and 24 h, while Mn and cobalt (Co) concentrations showed increases only at 24 h (P < 0.001). Blood iron concentration was not altered in the blood. In contrast, no change occurred in testicular Co, and chromium or nickel concentrations in either testes or blood. Compared to control and predose groups, serum testosterone levels increased gradually and peaked at 2 h (P < 0.001) post kisspeptin treatment but declined thereafter. Pretreatment with antagonist abolished all increases in trace elements and testosterone concentrations. The present study provides first evidence that reproduction- and fertility-related peptide "kisspeptin" modulates testicular and blood trace elements and that this action is likely GPR54-dependent.


Exogenous phospholipase C permeabilizes mammalian cells to proteins.
Mammalian cells treated with low concentrations of phospholipase C become permeable to the protein toxin alpha-sarcin. A similar permeabilization is not induced upon treatment with other lipases such as phospholipase A2, sphingomyelinase, or cholesterol esterase. Concentrations of 10 micrograms/ml alpha-sarcin almost completely blocked translation in HeLa cells treated with 0.3 U/ml phospholipase C (PL-C) for 1 h. In contrast, 200 micrograms/ml of alpha-sarcin had no effect at all on protein synthesis in untreated cells. Other macromolecules such as horseradish peroxidase and luciferase also enter into cells if they are treated with phospholipase C. This permeabilization method is fully reversible. As soon as 5 min after PL-C removal, the cells become impermeable to alpha-sarcin. Other metabolites such as uridine nucleotides are partially released after PL-C incubation, whereas the content of 86Rb+ remains at control levels, probably because the Na+/K+ ATPase activity increases.


Localization or delocalization in the electronic structure of Creutz-Taube-type complexes in aqueous solution.
Creutz-Taube complex, [(NH3)5Ru-pyrazine-Ru(NH3)5]5+ (1), and its analogues, [(NH3)5Os-pyrazine-Os(NH3)5]5+ (2), [(NH3)5Ru(4,4'-bipyridine)Ru(NH3)5]5+ (3), and [(NH3)5Os(4,4'-bipyridine)Os(NH3)5]5+ (4), were theoretically investigated by the combination of a two-state model and the dielectric continuum model. Their electronic structures are very sensitive to the metal, ligand, and solvent. In the gas phase, the electronic structures of 1-4 would be completely delocalized. In aqueous solution, that of 3 becomes localized because the polar solvent stabilizes the localized electronic structure with the large dipole moment. However, 1 and 2 are still delocalized in aqueous solution. In 4, the electronic structure would be localized when the dihedral angle between two pyridyl rings is 80 degrees , while it would become delocalized when the angle is small. The origins of the difference are the smaller overlap integral and larger energy difference between two diabatic states, of which electronic structure is almost localized on each metal center.


Transarterial Therapy for Colorectal Liver Metastases.
Until recently, hepatic arterial therapies (HAT) had been used for colorectal liver metastases after failure of first-, second-, and third-line chemotherapies. HAT has gained greater acceptance in patients with liver-dominant colorectal metastases after failure of surgery or systemic chemotherapy. The current data demonstrate that HAT is a safe and effective option for preoperative downsizing, optimizing the time to surgery, limiting non-tumor-bearing liver toxicity, and improving overall survival after surgery in patients with colorectal liver-only metastases. The aim of this review is to present the current data for HAT in liver-only and liver-dominant colorectal liver metastases.


Outbreaks of Gastrointestinal Diseases on Cruise Ships: Lessons from Three Decades of Progress.
Dramatic improvements in sanitary engineering and, especially, operational procedures aboard cruise ships began in the mid-1970s after several large outbreaks of acute gastroenteritis. The US Centers for Disease Control and Prevention's Vessel Sanitation Program, working with the cruise industry, conducts ship inspections, provides public access to ship sanitation scores, and reports outbreak investigations. The significant increase in median ship sanitation scores over the past decade has been concomitant with a reduction in outbreak frequency to 3.7 per 1000 cruises. Most outbreaks of the past decade were linked to noroviruses (Norwalk-like viruses), enterotoxigenic Escherichia coli, or the residual "unknown" causes. Although norovirus outbreaks may begin as foodborne or waterborne disease, easy person-to-person transmission occurs through fecal- or vomitus-splattered surfaces, other items, clothing, and especially, hands. Control of person-to-person spread of illness among crew and passengers becomes the major objective. Rigorous handwashing, environmental disinfection, and other food service job-related restrictions are required to prevent multiple outbreaks on the same ship. Vigilance by public health and industry officials has prevented many thousands of illnesses and some associated deaths. Clinicians providing pretravel health advice and post-travel diagnoses and care can benefit from and contribute to epidemiologic investigations and thereby enhance the health of cruise passengers individually and collectively.


Electrocyclic ring closure of the enols of vinyl quinones. A 2H-chromene synthesis.
Thermolysis of enolizable vinyl quinones in polar, aprotic media provides 2H-chromenes. Experimental evidence supports a two-step mechanism in which enolization is followed by a thermal 6pi-electrocyclic reaction of an intermediate quinone methide. Application of this method led to the total synthesis of the reputed structure of an Ageratum juvenile hormone. When enolizable vinyl quinones are the products of Stille coupling, the chromene annulation product is obtained directly. [reaction: see text]


Optogenetics and translational medicine.
Optogenetic tools enable light-mediated control of cellular excitability and signaling in vivo. By manipulating biological processes, scientists can determine the roles played by these processes in intact biological systems, such as the brain. Such cellular-level control has greatly affected basic science. Here, we discuss how optogenetic tools might be translated into clinical impact through identification of new molecular and circuit-level targets and provide temporally precise interventions for defined biochemical or cellular events.


Double-color-pumped photorefractive oscillator and image color conversion.
Can two laser beams of different colors interact with each other to initiate a photorefractive oscillation in a slowly responding (~1 sec) crystal? We report on the operation of this new nondegenerate four-wave mixing device, in which two other beams and the gratings are efficiently self-generated. An application for image color conversion is demonstrated. In an experiment, we used for the two pumps combinations of the lines of an argon-ion laser (514.5, 496.5, 488, 476.5, and 457.9 nm) and a He-Ne laser (632.8 nm). The mixing crystal was BaTiO(3) with a photorefractive time constant of the order of 1 sec.


Gene cloning and characterization of L-ribulose 3-epimerase from Mesorhizobium loti and its application to rare sugar production.
A gene encoding L-ribulose 3-epimerase (L-RE) from Mesorhizobium loti, an important enzyme for rare sugar production by the Izumoring strategy, was cloned and overexpressed. The enzyme showed highest activity toward L-ribulose (230 U/mg) among keto-pentoses and keto-hexoses. This is the first report on a ketose 3-epimerase showing highest activity toward keto-pentose. The optimum enzyme reaction conditions for L-RE were determined to be sodium phosphate buffer (pH 8.0) at 60 °C. The enzyme showed of higher maximum reaction a rate (416 U/mg) and catalytic efficiency (43 M(-1) min(-1)) for L-ribulose than other known ketose 3-epimerases. It was able to produce L-xylulose efficiently from ribitol in two-step reactions. In the end, 7.2 g of L-xylulose was obtained from 20 g of ribitol via L-ribulose at a yield of 36%.


High-density lipoprotein-based drug discovery for treatment of atherosclerosis.
Although there has been great progress achieved by the use of intensive statin therapy, the burden of atherosclerotic cardiovascular disease (CVD) remains high. This has initiated the search for novel high-density lipoprotein (HDL)-based therapeutics. Recent years have witnessed a shift from traditional raising HDL-C levels to enhancing HDL functionality, in which the process of reverse cholesterol transport (RCT) has acquired much attention. In this review, the authors describe the key factors involved in RCT process for potential drug targets to reduce the CVD risk. Furthermore, the review provides a summary of the effective screening methods that have been developed to target RCT and their applications. This review also introduces some new strategies currently being clinically developed, which have the potential to improve HDL function in the RCT process. It is rational that the functionality of HDL is more important than the plasma HDL-C level in the evaluation of pharmacological treatment in atherosclerosis. HDL-based strategies designed to promote macrophage RCT are a major area of current drug discovery and development for atherosclerotic diseases. A better understanding of the functionality of HDL and its relationship with atherosclerosis will expand our knowledge of the role of HDL in lipid metabolism, holding promise for a future successful HDL-based therapy.


Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice.
The risk of cognitive decline during Alzheimer's disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice.


Telencephalic transplants in mice: characterization of growth and differentiation patterns.
Telencephalic grafting represents a powerful tool for developmental studies and for the investigation of biological features of transgenic brain tissue. The interpretation of grafting experiments, however, requires detailed knowledge of graft biology. Therefore, we have characterized growth rates, graft size, and differentiation of embryonic telencephalic tissue harvested at various developmental stages and grafted into the caudoputamen and lateral ventricles of histocompatible mice. A total of 164 grafts were analysed up to 500 days after transplantation. Of all transplants, 79.3% resulted in the formation of solid neural grafts. Grafted cells were identified by 3H-thymidine labelling and autoradiography. Proliferation was studied by bromodeoxyuridine incorporation and decreased from an initial 35% at 1-3 d after grafting to less than 1.6% after 40 days. The graft size was measured as a function of the embryonic age of the transplanted tissue. Our data indicate that telencephalic tissue harvested at embryonic day E 12.5 reproducibly yields large, fully differentiated neuroectodermal grafts. The parameters defined in this study will be useful for detailed analysis of neuroectodermal tissue from mice undergoing fatal neurodegeneration, such as knockout mice bearing lethal mutations.


Identification of STAT3 and STAT5 proteins in the rat suprachiasmatic nucleus and the Day/Night difference in astrocytic STAT3 phosphorylation in response to lipopolysaccharide.
Signal transducers and activators of transcription (STAT) proteins regulate many aspects of cellular physiology from growth and differentiations to immune responses. Using immunohistochemistry, we show the daily rhythm of STAT3 protein in the rat suprachiasmatic nucleus (SCN), with low but significant amplitude peaking in the morning. We also reveal the strong expression of STAT5A in astrocytes of the SCN and the STAT5B signal in nonastrocytic cells. Administration of lipopolysaccharide (LPS) acutely induced phosphorylation of STAT3 on Tyr705 during both the day and the night and induced phosphorylation on Ser727 but only after the daytime application. The LPS-induced phospho-STAT3 (Tyr705) remained elevated for 24 hr after the daytime application but declined within 8 hr when LPS was applied at night.


Investigating the dynamic behavior of biochemical networks using model families.
Supporting the evolutionary modeling process of dynamic biochemical networks based on sampled in vivo data requires more than just simulation. In the course of the modeling process, the modeler is typically concerned not only with a single model but also with sequences, alternatives and structural variants of models. Powerful automatic methods are then required to assist the modeler in the organization and the evaluation of alternative models. Moreover, the structure and peculiarities of the data require dedicated tool support. To support all stages of an evolutionary modeling process, a new general formalism for the combinatorial specification of large model families is introduced. It allows for automatic navigation in the space of models and excludes biologically meaningless models on the basis of elementary flux mode analysis. An incremental usage of the measured data is supported by using splined data instead of state variables. With MMT2, a versatile tool has been developed as a computational engine intended to be built into a tool chain. Using automatic code generation, automatic differentiation for sensitivity analysis and grid computing technology, a high performance computing environment is achieved. MMT2 supplies XML model specification and several software interfaces. The performance of MMT2 is illustrated by several examples from ongoing research projects. http://www.simtec.mb.uni-siegen.de/ wiechert@simtec.mb.uni-siegen.de.


Sleep and breathing.
The sleep state is associated with significant changes in respiratory physiology, including ventilatory responses to hypoxia and hypercapnia, upper airway and intercostal muscle tone, and tidal volume and minute ventilation. These changes are further magnified in certain disease states, such as chronic obstructive pulmonary disease, restrictive respiratory disorders, neuromuscular conditions, and cardiac diseases. This article discusses the regulation of breathing during sleep in health and associated comorbid conditions.


Densities and morphology of two co-existing lizard species (Lacerta agilis and Zootoca vivipara) in extensively used farmland in Poland.
The study was carried out in extensive farmland area near the town of Odolanów, Poland. During two breeding seasons (April-May, 2006-2007) lizards were counted on transect routes and captured by hand or by noosing. In total, 123 specimens of L. agilis and 153 specimens of Z. vivipara were captured. The proportion of males to females wasn't differed from the theoretical 1:1 ratio. Almost half of the individuals exhibited tail autotomy at least once in life. In the studied sand lizards significant sex specific differences were found between all morphological traits, i.e. males were shorter, lighter, but had a bigger head. In common lizards significant sex specific differences were detected only in body length, i.e. females were longer. All of the morphological traits were highly inter-correlated.


Copper-Catalyzed Regioselective and Stereoselective Coupling of Grignard Reagents with Pent-1-en-4-yn-3-yl Benzoates: A Shortcut to ( Z) -1,5-Disubstituted Pent-3-en-1-ynes from Accessible Starting Materials.
Copper-catalyzed coupling of Grignard reagents with pent-1-en-4-yn-3-yl benzoates occurs regioselectively at the terminal alkenyl carbon rather than the alkynyl site, leading to the stereoselective formation of unexpected ( Z) -1,5-disubstituted pent-3-en-1-ynes without generation of the initially expected alkenyl allene products. By using easily accessible starting materials, this reaction can provide direct access to thermodynamically unfavorable Z-configured enynes, which widely exist in many bioactive natural products, such as the anti-inflammatory components in henna.


A meta-analysis of the rates of Staphylococcus aureus and methicillin-resistant S aureus contamination on the surfaces of environmental objects that health care workers frequently touch.
Health care workers may potentially spread Staphylococcus aureus and methicillin-resistant S aureus (MRSA) to patients by contaminated high-touch items. We aimed to determine the pooled rates of S aureus and MRSA contamination and influencing factors. A literature search of the PubMed, ScienceDirect, Embase, Ovid, and Scopus databases was performed. Pooled contamination rates were determined using random effect models. Subgroup and meta-regression analyses were conducted to identify factors potentially influencing the rates of S aureus and MRSA contamination. Sensitivity and publication bias analyses were performed. Thirty-eight studies were included in the meta-analysis. The pooled contamination rates were 15.0% (95% confidence interval [CI], 9.8%-21.1%) for S aureus and 5.0% (95% CI, 2.7%-7.7%) for MRSA. The subgroup analyses indicated that the pooled rate of S aureus contamination was significantly higher for studies conducted in South America, in developing countries, and during 2010-2015. The pooled rate of MRSA contamination was significantly higher for studies conducted in Africa. The meta-regression analysis suggested that the pooled rate of S aureus contamination was lower for studies conducted in developed countries (odds ratio, 0.664; 95% CI, 0.509-0.867; P = .004). No bias was found in the publication of the rates of S aureus and MRSA contamination. S aureus and MRSA contamination statuses of high-touch items are worrisome and should be paid greater attention. Developing country status was a risk factor for S aureus contamination.


Laparoscopic Roux-En-Y Gastric Bypass in Elderly Patients (60 Years or Older): A Meta-Analysis of Comparative Studies.
Elderly patient might experience an increased risk of complications after laparoscopic Roux-en-Y gastric bypass. We aimed to perform a meta-analysis of comparative studies on this issue in patients aged 60 years or older. A systematic literature search was performed. Medline, Cochrane Library, Embase, Scopus, and Google Scholar were searched until July 2016 for studies on outcomes of laparoscopic Roux-en-Y gastric bypass in elderly versus younger patients. Primary outcomes were mortality and overall complications. Secondary outcomes were length of hospital stay, excess weight loss percentage, effect on diabetes, hypertension, hyperlipidemia and obstructive sleep apnea. Heterogeneity across the studies was evaluated by the I2 test, and a random effects model was used. Results were expressed as mean difference and risk ratio (RR). Seven studies involving 3128 patients were retrieved and included in this study. A significantly increased risk of mortality and overall complications was observed among patients older than 60 years compared with younger ones (RR, 6.12; 95% confidence interval 1.08-34.83; p = 0.04; RR, 1.51; 95% confidence interval 1.07-2.11; p = 0.02). Particularly, elderly patients experienced 1% increased risk of mortality and 3% increased risk of overall complications. Length of stay, diabetes, and obstructive sleep apnea remission rates were similar among the groups. Excess weight loss percentage was significantly greater among younger patients (mean difference, -3.44; 95% confidence interval -5.20, -1.68; p < 0.001), as were hypertension (RR, 0.57; 95% confidence interval 0.42-0.76; p < 0.001) and hyperlipidemia (RR, 0.61; 95% confidence interval 0.45-0.83; p = 0.002) remission rates. Laparoscopic Roux-en-Y gastric bypass in patients older than 60 years may be a risky bariatric surgery operation due to higher complications and mortality and may not be as effective as in patients younger than 60 years. Thus, older patients should be carefully counseled before this procedure for individual risk-benefit assessment.


CREBRF is a potent tumor suppressor of glioblastoma by blocking hypoxia-induced autophagy via the CREB3/ATG5 pathway.
Hypoxia induces protective autophagy in advanced glioblastoma cells, and targeting this process may improve the outcome for glioblastoma patients. Recent studies have suggested that the autophagic process is upregulated in glioblastoma cells in response to extensive hypoxia. Here, we describe a novel tumor suppressor in glioblastoma cells, whereby hypoxia downregulated CREBRF expression and acts as a potent inhibitor of autophagy in glioblastoma cells via the CREB3/ATG5 pathway. Our results demonstrate that CREBRF expression negatively correlates with autophagic and HIF-1α levels in different grade gliomas. Given that CREBRF is a negative regulator of CREB3, CREB3 knockdown also repressed hypoxia-induced autophagy in glioblastoma cells in vitro. Collectively, our findings provide new insight into the molecular mechanisms underlying hypoxia-induced glioblastoma cell autophagy and indicate that the hypoxia/CREBRF/CREB3/ATG5 pathway plays a central role in malignant glioma progression.


Ultrasound-Based Optimal Parameter Estimation Improves Assessment of Calf Muscle-Tendon Interaction During Walking.
We present and evaluate a new approach to estimate calf muscle-tendon parameters and calculate calf muscle-tendon function during walking. We used motion analysis, ultrasound, and EMG data of the calf muscles collected in six young and six older adults during treadmill walking as inputs to a new optimal estimation algorithm. We used estimated parameters or scaled generic parameters in an existing approach to calculate muscle fiber lengths and activations. We calculated the fit with experimental data in terms of root mean squared differences (RMSD) and coefficients of determination (R2). We also calculated the calf muscle metabolic energy cost. RMSD between measured and calculated fiber lengths and activations decreased and R2 increased when estimating parameters compared to using scaled generic parameters. Moreover, R2 between measured and calculated gastrocnemius medialis fiber length and soleus activations increased by 19 and 70%, and calf muscle metabolic energy decreased by 25% when using estimated parameters compared to using scaled generic parameters at speeds not used for estimation. This new approach estimates calf muscle-tendon parameters in good accordance with values reported in literature. The approach improves calculations of calf muscle-tendon interaction during walking and highlights the importance of individualizing calf muscle-tendon parameters.


Competition for enzymes in metabolic pathways: implications for optimal distributions of enzyme concentrations and for the distribution of flux control.
The structures of biochemical pathways are assumed to be determined by evolutionary optimization processes. In the framework of mathematical models, these structures should be explained by the formulation of optimization principles. In the present work, the principle of minimal total enzyme concentration at fixed steady state fluxes is applied to metabolic networks. According to this principle there exists a competition of the reactions for the available amount of enzymes such that all biological functions are maintained. In states which fulfil these optimization criteria the enzyme concentrations are distributed in a non-uniform manner among the reactions. This result has consequences for the distribution of flux control. It is shown that the flux control matrix c, the elasticity matrix epsilon, and the vector e of enzyme concentrations fulfil in optimal states the relations c(T)e = e and epsilon(T)e = 0. Starting from a well-balanced distribution of enzymes the minimization of total enzyme concentration leads to a lowering of the SD of the flux control coefficients.


Postmortem chemistry update part I.
Postmortem chemistry is becoming increasingly essential in the forensic pathology routine and considerable progress has been made over the past years. Biochemical analyses of vitreous humor, cerebrospinal fluid, blood and urine may provide significant information in determining the cause of death or in elucidating forensic cases. Postmortem chemistry may essentially contribute in the determination of the cause of death when the pathophysiological changes involved in the death process cannot be detected by morphological methods (e.g. diabetes mellitus, alcoholic ketoacidosis and electrolytic disorders). It can also provide significant information and useful support in other forensic situations, including anaphylaxis, hypothermia, sepsis and hormonal disturbances. In this article, we present a review of the literature that covers this vast topic and we report the results of our observations. We have focused our attention on glucose metabolism, renal function and electrolytic disorders.


Experimental animal modeling of depression and anxiety.
Experimental animal models have been introduced to study aspects of psychiatric symptoms of depression and anxiety; however, there is no comprehensive animal model for these conditions. The models introduced may simulate certain symptoms (despair), be used to evaluate behavioral theories (cognitive theory of learned helplessness), allow study of underlying neurochemical mechanisms (CSF metabolites, genetic, neurotransmitter model), be used to evaluate developmental issues, and lead to finding new treatments through preclinical pharmacologic trials. A variety of models are needed, as each one attempts to deal with a particular aspect of a syndrome. Pharmacologic models, the model of uncontrollability, separation models, and genetic approaches have been summarized. Depression is viewed as a complex, multifactorial illness. Anxiety models have focused on pharmacologic treatment of motivational conflict and the elicitation of fear and panic through environmental and drug manipulations. The most recent investigations in this area address separation calls and alarm calls in primates as potential models for separation distress and panic symptomatology, arguing that the behavioral context as well as the specific behavior be considered. Animal models have emphasized adult psychopathology in the past. However, with increased recognition of psychiatric disorders in children and adolescents, animal modeling of disorders that begin in the development period assumes importance. Studies in the animal modeling of depression and anxiety involving genetic models, psychosocial models, and stress-induction models are the focus of continuing investigations and may be pertinent to child and adolescent psychopathology. They offer hope for learning more about the neurobiologic mechanisms involved in these conditions and for testing new treatment approaches.


Integration of Pharmacy Students Into Family Medicine Residency Clinics.
As interprofessional education opportunities become more prevalent within family medicine residency clinics, the benefit of the integration of pharmacy students is unclear in the current literature. Our study objective was to determine the impact of pharmacy student integration into a family medicine residency clinic on family medicine residents' attitudes toward interprofessional collaboration and satisfaction. Twenty-two pharmacy students on clinical rotation were individually paired with family medicine residents for approximately 4-5 half days per week over a 10-month period. Residents and students were given a pre/post-validated survey on attitudes toward interprofessional collaboration. Satisfaction surveys were also administered to the residents at the end of the study period. Written components of satisfaction surveys were evaluated for commonly occurring themes. Matched survey responses were available for over 80% of the residents. Both pre- and post-survey responses showed positive attitudes toward physician-pharmacist collaboration. A statistically significant positive change was seen for one item in the family medicine resident surveys. Favorable written comments revealed positive themes toward pharmacy students providing mediation reviews, therapeutic recommendations, and patient education. Pharmacy students can be integrated into family medicine residency clinics while maintaining positive levels of interprofessional collaboration and providing a perceived benefit to the family medicine residents.


Surface and bulk modifications to photocrosslinked polyanhydrides to control degradation behavior.
A unique class of surface-eroding polyanhydrides was developed and explored for use in medical applications requiring high-strength biomaterials (e.g., orthopedics). In particular, dimethacrylated anhydride monomers were synthesized that photopolymerize quickly to render densely crosslinked polymer networks that degrade from the surface only by hydrolysis of labile anhydride linkages. Previous research on these materials has shown that the rate of hydrolysis of the degradable linkages is dependent on the hydrophobicity of the network composition. This article demonstrates the versatility in controlling the degradation process and resulting cellular response in these materials through the incorporation of new chemistries and the formation of polymer-polymer composite structures. Specifically, the rate of mass loss was controlled by the addition of hydrophobic linear polymers [e.g., poly(methyl methacrylate)] or monovinyl monomers based on hydrophobic natural components (e.g., cholesterol, steric acid). In addition, a newly established photografting method was used to modify the network surface chemistry with cholesterol- and stearic acid-based polymer grafts to control the degradation front and cellular interactions at the polymer-tissue interface. Finally, a porogen leaching method was used to form porous polyanhydride constructs, which can be subsequently filled with osteoblasts photoencapsulated in a hydrogel, as potential synthetic allograft materials for tissue engineering bone.


Segmentation of mammograms using multiple linked self-organizing neural networks.
A possible first stage in the analysis of the mammographic scene is its segmentation into four major components: background (the nonbreast area), pectoral muscle, fibroglandular region (parenchyma), and adipose region. An algorithm has been developed for this task. It is based on the classification of a feature vector constructed from statistical measures of texture calculated at two window sizes. Separate self-organizing neural networks are trained on sample data taken from each of the four regions. The feature vectors from the entire mammogram are then classified with the trained networks linked via a decision logic. To overcome the variability of texture between mammograms the algorithm uses data from a mammogram to classify itself in a staged approach consisting of several binary decisions. The training regions for each successive stage are determined from geometric information produced by the previous stages. The dataset in the study consisted of thirty (fifteen pairs) digitized normal mammograms of variable radiographic appearance. As a measure of performance, the outlines of the parenchyma were compared to those drawn by a radiologist experienced in reading mammograms. Comparison of the areas and perimeters generated by the human and computer observers gives a relationship with correlation coefficients of 0.74 and 0.59 for each measure, respectively. The overlapping areas of the parenchymas segmented by the observers normalized by the combined area was also calculated for each case. The mean and standard deviation of this measure was 0.69 +/- 0.12.


Ultrasound for diagnosis of infection in revision total hip arthroplasty.
Eighty consecutive patients (85 hips; 43 women; median age, 74 years [range, 33-90 years]) underwent a revision total hip arthroplasty. Preoperatively and guided by ultrasound, biopsy specimens of the joint pseudocapsule were taken, and joint fluid was aspirated for culture. Capsule morphology was investigated with light microscopy. When septic loosening was defined as 2 intraoperative cultures yielding the same microorganism, the prevalence was 12%. Sensitivity of the capsule biopsy cultures was 67%; specificity, 68%; positive predictive value, 22%; and negative predictive value, 94%. Joint fluid was often sparse and always falsely sterile. One specimen from a hip with septic loosening showed histologic changes (> or =3 foci, each with > or =3 plasma cells/high-power field) consistent with chronic infection. The remaining 8 septic loosenings eluded histologic detection, yielding 11% sensitivity. All aseptic loosenings were classified correctly (specificity 100%). Positive and negative predictive values were 100% and 89%. Ultrasound-guided aspiration and capsule biopsy with cultures and histology does not seem to be sufficiently accurate in the preoperative diagnosis of infected total hip arthroplasty.


Properties of free surface of water-methanol mixtures. Analysis of the truly interfacial molecular layer in computer simulation.
Molecular dynamics simulations of the vapor-liquid interface of water-methanol mixtures of five different compositions were performed on the canonical (N,V,T) ensemble at 298 K. In addition, the vapor-liquid interface of the two neat systems was simulated, as well. The obtained configurations were analyzed by means of the novel identification of truly interfacial molecules method, which provides a full list of the molecules that are right at the surface (i.e., at the boundary of the two phases). The molecular level roughness of the surface, the adsorption of the methanol molecules at the surface layer, the orientation of the surface molecules, the residence time of the molecules at the surface layer, as well as the surface aggregation of the molecules were analyzed in detail. Both the frequency and the amplitude of the surface roughness were found to become larger with an increasing methanol content. This effect was found to be stronger for the amplitude, which falls in the range of 2-4 A, depending on the composition of the system. Methanol was found to be adsorbed at the surface layer, being preferentially at the humps of the molecularly rough surface. Surface methanol prefers to orient in such a way that the O-CH(3) bond remains perpendicular to the macroscopic plane of the surface, pointing the methyl group to the vapor phase. The main orientational preference of the water molecules is to lie parallel to the surface. Methanol was found to remain considerably longer at the surface layer of the mixed systems than water. Thus, contrary to the fact that the residence times of the two molecules were found to be rather similar to each other at the surface of their neat liquids, the residence time of the methanol molecules was an order of magnitude larger than that of water molecules at the surface of their mixtures. A strong lateral microscopic segregation of the molecules was observed at the surface layer; the minor component of the system (irrespective of whether it was water or methanol) was found to form two-dimensional aggregates, leaving the rest of the surface empty for the major component. The effect of the vicinity of the vapor phase on the properties of the molecules was found to vanish very quickly: the composition of the second layer as well as the properties of the molecules of this layer (e.g., dynamics and orientation) did not differ considerably from those in the bulk liquid phase.


[Effect of renal polypeptides on lymphocyte activity in experimental nephritis].
A model of experimental nephritis in Wistar rats has been used to show that the pathology mentioned induces sharp morphofunctional changes in the parenchyma of the kidneys. At the same time the state of the T-link (lymphocyte blasttransformation response to phytohemagglutinin) and B-link (a titre of serum antirenal antibodies) of the immunity were studied. It is shown that development of experimental nephritis is accompanied by intensification of the lymphocytic response to phytohemagglutinin and renal tissue antigenes with a simultaneous increase of a titre of antirenal antibodies. To correct these damages a complex of polypeptide substances isolated from the kidney parenchyma was applied. The results obtained demonstrate a normalizing effect of this complex on lymphocyte activity. A conclusion is made on possible tolerogenic action of substances of this complex.


Coexistence of severe parkinsonism and tardive dyskinesia as side effects of neuroleptic therapy.
Neuroleptic-induced parkinsonism and tardive dyskinesia are caused, respectively, by blockade and supersensitivity of dopaminergic receptors in striatum, and represent contrasting syndromes with regard to clinical presentation and management. Two patients are described in whom parkinsonism and tardive dyskinesia developed and coexisted, with marked severity, during chronic neuroleptic administration. Pharmacologic manipulations accelerating nigrostriatal transmission improved akinesia but intensified the dyskinesias, whereas suppression had opposite effects. It is hypothesized that the coexistence of these two opposing side effects is due to simultaneous blockade and supersensitivity of two different subclasses of striatal dopaminergic receptors.


UV-induced bleaching of deep traps in Harshaw TLD LiF:Mg,Cu,P and LiF:Mg,Ti.
The effects of UV-induced bleaching of deep traps on Harshaw thermoluminescent (TL) LiF:Mg,Cu,P and LiF:Mg,Ti materials were investigated. During a normal heating cycle, LiF:Mg,Cu,P is limited to a maximum temperature of 240 °C. LiF:Mg,Ti can be read to higher temperatures; however, encapsulation in polytetrafluoroethylene limits the maximum readout temperature to 300 °C. Generally, for both materials, these respective temperatures are sufficient for emptying traps corresponding to the main dosemetric peaks. However, when the dosemeters are subjected to a high dose level, such as 1 Gy (much higher than individual monitoring dose levels), higher temperature traps are filled that cannot be emptied without exceeding the above-mentioned maximum temperatures. These high temperature traps tend to be unstable during normal readout and can significantly increase the residual TL signal. The purpose of this study was to investigate the applicability of a UV-induced bleaching technique for emptying higher temperature traps following high-dose applications. In addition, in the case of LiF:Mg,Cu,P, where the maximum readout temperature is significantly lower, we investigated the possibility of reducing the residual signal using the application of repeated readout cycles. The optical bleaching approach was found to be effective in the case of LiF:Mg,Ti; however, for LiF:Mg,Cu,P, no reduction in the residual signal was observed. For this latter material, the application of repeatable readout cycles is very effective and residual signals equivalent to dose levels as low as 0.01 mGy were observed following an initial dose of 5 Gy. To the best of our knowledge, this work is the first attempt to apply an 'optical annealing' technique to the Harshaw thermoluminescent dosemeter (TLD) materials.


Keratin and carcinoembryonic antigen in exfoliated mesothelial and malignant cells: an immunoperoxidase study.
Immunoperoxidase technics were used to identify keratin and carcinoembryonic antigen (CEA) in exfoliated cells of fine-needle aspirates and body cavity fluids. Staining was evaluated in cytocentrifuge preparations from 27 malignant and 30 benign cytologic specimens. Most reactive mesothelial cell preparations were strongly positive for keratin and negative or only weakly positive for CEA. Diffuse, peripheral, and perinuclear concentration of staining for keratin was noted in exfoliated reactive mesothelial cells. Positive staining for keratin, predominantly diffuse, was noted in exfoliated cells from 56% of the adenocarcinomas. Sixty-nine per cent of adenocarcinoma preparations were strongly positive for CEA. These findings suggest that keratin proteins are not restricted to squamous cells and that keratin staining does not permit distinction between adenocarcinoma and mesothelial cells in cytologic specimens. Staining for CEA and keratin was compared in cytocentrifuge preparations and histologic sections of 12 adenocarcinomas and 7 lymphomas. In some adenocarcinomas, staining was detected only in cytologic preparations. Possible explanations for these differences are discussed. Variable staining for keratin was observed among exfoliated reactive mesothelial cells, possibly identifying different mesothelial cell populations. All reactive and neoplastic lymphoid cells were negative for keratin and CEA in cytologic and histologic preparations. Immunoperoxidase technics can be applied to rehydrated Papanicolaou-fixed and Papanicolaou-stained cytologic preparations with excellent preservation of cytologic detail.


Macro EMG.
A new EMG recording technique called macro EMG is described. The recording electrode is the cannula of the modified single fiber electromyography (SFEMG) electrode. By means of spike triggered averaging, the contribution from all muscle fibers in a motor unit is extracted. The resulting signal reflects the number and size of muscle fibers in one motor unit. This paper presents the details of the technique, the neurophysiological basis for generation of the macro EMG signal, and the typical findings in normal and diseased muscles. Finally, examples are given of the additional information that can be obtained by combining investigations with SFEMG, conventional EMG, and macro EMG in the same muscles.


Animals living in polluted environments are a potential source of anti-tumor molecule(s).
Despite advances in therapeutic interventions and supportive care, the morbidity and mortality associated with cancer have remained significant. Thus, there is a need for newer and more powerful anti-tumor agents. The search for new anti-tumor compounds originating from natural resources is a promising research area. Animals living in polluted environments are a potent source of anti-tumor agents. Under polluted milieus, species such as crocodiles, feed on rotten meat, are exposed to heavy metals, endure high levels of radiation, and are among the very few species to survive the catastrophic Cretaceous-Tertiary extinction event with a prolonged lifespan. Thus, it is reasonable to speculate that animals such as crocodiles have developed mechanisms to defend themselves against cancer. The discovery of antitumor activity in animals such as crocodiles, whales, sharks, etc. will stimulate research in finding therapeutic molecules from unusual sources, and has potential for the development of novel antitumor compound(s) that may also overcome current drug resistance. Nevertheless, intensive research in the next few years will be required to realize these expectations.


Stilbene-based inhibitors of estrone sulfatase with a dual mode of action in human breast cancer cells.
Estrone sulfate (E1S) is an endogenous prodrug that delivers estrone and, subsequently, estradiol to target cells, after hydrolysis by the enzyme estrone sulfatase, which is active in various tissues including hormone-dependent breast cancer. Blockade of this enzyme should reduce the estrogen level in breast cancer cells and prevent hormonal growth stimulation. In this study, a number of sulfamoyloxy-substituted stilbenes with side chains that guarantee antiestrogenic activity were synthesized and evaluated as inhibitors of estrone sulfatase. They inhibited this enzyme in human MDA-MB 231 breast cancer cells, with IC(50) values in the submicromolar range. The effects of both the free hydroxy derivatives and the sulfamates on gene activation were determined in transfected MCF-7/2a breast cancer cells stimulated either with estradiol or with estrone sulfate. The analysis of data revealed a dual mode of action of the majority of compounds. They blocked gene expression by inhibition of estrone sulfatase and by antiestrogenic action. This pharmacological profile was also observed in assays on antiproliferative activity. The most potent derivative 8 g inhibited the growth of wild-type human MCF-7 cells with an IC(50) value of 13 nM.


Prediction of pain outcomes in Korean older adults: use of a structural equation model.
To construct a structural equation model of pain adjustment outcomes (e.g., depression and fatigue) in Korean older adults based on the cognitive-behavioral model of chronic pain. Nonexperimental research design. Data were collected by questionnaires from 271 Korean older adults. Data analysis was conducted with SPSS 10.1 for descriptive statistics and a PC-LISREL program for covariance structural analysis. In this study, based on the modifications, chi-square statistics were changed, the goodness-of-fit index was 0.97, the adjusted goodness-of-fit index was 0.93, the root mean square residual was 0.04, the normal fit index was 0.98, and the non-normed fit index was 0.98. Path coefficients and their statistical significance for the revised model were as follows: pain adjustment and pain beliefs were found to have a significant direct effect on pain coping. The variable directly related to pain beliefs was pain adjustment, and variables directly influencing fatigue were pain coping and pain beliefs. Lastly, pain adjustment, pain coping, and fatigue were found to have a significant direct effect on depression. Also, pain adjustment, pain coping, and pain beliefs were found to have a significant indirect effect on depression. In conclusion, pain adjustment, pain coping, pain beliefs, and fatigue all contributed to depression. Fifty-four percent of depression could be explained by these variables. This modified model is considered appropriate for explaining and predicting pain adjustment outcomes in Korean older adults. Also, the findings support the development of an intervention strategy to improve pain coping, negative pain beliefs, fatigue, and depression caused by poor pain adjustment.


Minimal benefit of an endorectal balloon for prostate immobilization as verified by daily localization.
We wanted to investigate whether using an endorectal balloon (ERB) in lieu of image guidance is reasonable. We compared daily prostate motion in 2 cohorts of patients with fiducial markers implanted in the prostate, one group with the ERB and the other without. Twenty-nine patients were treated using intensity-modulated radiation therapy: 14 with an ERB, and 15 without. All had fiducial markers placed in the prostate. We reviewed the daily displacements necessary to place the isocenter on the prostate as determined by portal imaging. In addition, we used the data to determine whether there is a change in prostate motion over the treatment course. The average prostate displacement for patients treated without an ERB was slightly greater than the average displacement for patients treated with the ERB. However, the difference observed with the ERB was not statistically significant (p > 0.05). The margins necessary to encompass the prostate 95% of the time for the patients treated without an ERB in the lateral, cranio/caudal, and anterior/posterior dimensions would be 4.8, 12.1, and 15.2 mm, respectively. When using the ERB, the margins necessary would be 4.1, 10.4, and 11 mm, respectively. Prostate motion in the anterior-posterior direction actually increased over the course of treatment in patients without an ERB. This increase was prevented by use of the ERB. Day-to-day variability of the position of the prostate is reduced in all dimensions with the water-filled ERB, but not significantly statistically. Use of the water-filled ERB did not obviate performing some form of image guidance daily.


Silicon nanohybrid-based SERS chips armed with an internal standard for broad-range, sensitive and reproducible simultaneous quantification of lead(ii) and mercury(ii) in real systems.
Lead ions (Pb2+) and mercury ions (Hg2+), the two commonly coexisting heavy metal ions, pose severe risks to environment and human health. To date, no surface-enhanced Raman scattering (SERS) sensor has been reported for the simultaneous quantification of Pb2+ and Hg2+ in real systems. Herein, the first demonstration of SERS chips for simultaneous quantification of Pb2+ and Hg2+ in real systems is presented based on the combination of reproducible silicon nanohybrid substrates and a corrective internal standard (IS) sensing strategy. This chip was made of a silver nanoparticle-decorated silicon wafer via modification of the IS, i.e. 4-aminothiophenol, molecules. The as-prepared chip was further functionalized with Pb2+- and Hg2+- specific DNA strands capable of simultaneously detecting Pb2+ and Hg2+. Quantitatively, upon correction by the IS Raman signals, the broad dynamic ranges from 100 pM to 10 μM for Pb2+ and from 1 nM to 10 μM for Hg2+ were achieved, with the detection limit down to 19.8 ppt for Pb2+ and 168 ppt for Hg2+. For real applications, we further demonstrated that Pb2+ and Hg2+ spiked into industrial wastewater could be readily distinguished via the presented chip, and the relative standard deviation (RSD) value was less than ∼15%. More significantly, the resulting SERS chip can be well coupled with a hand-held Raman instrument and can then be used for the qualitative analysis of both Pb2+ and Hg2+ in real systems in a portable manner. Our results suggest that this high-quality SERS chip is a powerful tool for on-site detection of various heavy metal ions in real samples in the field of food safety and environment protection.


Effects of the new anti-mafia law on the proceeds of crime and on the Italian economy.
In 1982, the Italian authorities enacted a new law against the mafia conspiracy, which provided for the seizure and confiscation of property illegally acquired by criminals and their associates. This law is intended to strike at the accumulation of wealth of the mafiosi, which chiefly motivates their criminal activity. According to the established procedure, the district attorney or the chief of police are authorized to propose the seizure of property suspected of being derived from crimes, and a court of law decides either to accept or reject such a proposal and, where appropriate, orders the confiscation of illegally acquired assets. Two phenomena were identified, particularly in the southern part of Italy, which preceded the adoption of this new law: one was the establishment of an illegal sector of the economy with the development of a vast illicit market of drugs, and the other was an increase in the number of mafia firms and entrepreneurs. In some areas of western Sicily, for example at Palermo and Trapani, the income derived from illegal activities is estimated at approximately 15 to 20 per cent of the total gross income; the illicit sale of drugs nation-wide exceeds 10,000 billion lire, according to estimates. An assessment of the impact of the new law reveals positive results. In four provinces--Calabria, Campania, Lombardy and Sicily--property suspected of being derived from crimes was seized on 352 occasions and illegally acquired property was confiscated on 108 occasions during a period of 21 months following the adoption of the new law; 98 per cent of the seizures and all of the confiscations took place in the above-mentioned four provinces. The effective enforcement of the new law is, in the long run, expected to result in a movement from illegal to legal activity; if the risk involved in persisting in illegal activities becomes high enough, it should trigger a tendency towards avoiding involvement in the illegal activities and converting the assets into property shares protected by legal means. A certain tendency towards such "legalization" and investment in financial affairs rather than in real estate, agriculture and tertiary assets has already been observed. It is, however, unlikely that the mafia will be inclined to give up easily its profits derived from crime and its power of influence in society, and, consequently, it is expected that the confiscation of the illegally acquired properties will for a long time be the cornerstone of every effective struggle against criminal activity on a large scale.


Properties and regulation of chloride channels in cystic fibrosis and normal airway cells.
The present study examines the properties of Cl- channels in cultured respiratory cells of cystic fibrosis (CF) patients and normal (N) individuals. In excised membrane patches the conductances for CF and N Cl- channels were larger at positive as compared to negative clamp voltages (Vc): 74 +/- 2.6 (Vc greater than 0) and 47 +/- 2.0 pS (Vc less than 0) for CF (n = 57) and 69 +/- 3.6 (Vc greater than 0) and 45 +/- 2.3 pS (Vc less than 0) for N (n = 35). The open probability (Po) of the channel increased markedly with depolarization. Both the voltage dependence of the conductance and of Po contribute to the outward rectification of the channel. The time histogram analysis reveals two open and two closed time constants. The selectivity of the channel was Cl- = Br- = I- greater than NO-3 much greater than gluconate. The channel was inhibited reversibly by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) at 10(-7) mol/l to 10(-5) mol/l. While Cl- channels were present in cell attached patches of N cells, they were absent in those of CF cells. The mean conductance for cell attached (N) Cl- channels was 76 +/- 3.2 pS for positive clamp voltages (Vc) and 46 +/- 3.9 pS for negative Vc (n = 8). When the membrane patches were excised from CF cells Cl- currents appeared spontaneously (n = 19). The immediate appearance (within 1 s) of Cl- channels after excision was observed at positive (n = 6) as well as at negative clamp voltage (n = 13). "Excision activation" of CF Cl- channels was observed at low (less than 10(-9) mol/l) or high (10(-3) mol/l) calcium activities on the cytosolic side of the excised patch. Variation of the Ca+ activity (less than 10(-9)-10(-3) mol/l) or pH (6.5-8.5) on the cytosolic side exerted no effects on these Cl- channels. These results suggest that Cl- channels are present in the apical membrane of CF and N respiratory cells but they seem to be inhibited in intact CF cells. Excision of the patch and hence removal of the cytosolic "inhibitor" leads to an activation of Cl- channels. The Cl- channels in excised patches of N and CF cells have identical properties.


c-erbA protooncogenes mediate thyroid hormone-dependent and independent regulation of the rat growth hormone and prolactin genes.
Regulation of gene expression by the thyroid hormones is thought to be mediated by a nuclear-associated receptor found in a wide variety of cells and tissues. Cellular homologues of the avian erythroblastosis virus oncogene, v-erbA, encode proteins which bind thyroid hormone with similar affinities as thyroid hormone receptors. However, it has not been shown that any of the c-erbA proteins can function as receptor and modulate thyroid hormone responsive genes. In this study, using transient expression of chimeric reporter constructs, we document that the chick fibroblast c-erbA-alpha and the human placental c-erbA-beta modulate cis-acting regulatory sequences of two thyroid hormone responsive genes; rat GH and PRL. From these results we conclude: 1) in a receptor deficient cell line (235-1) both c-erbA subtypes act as hormone-dependent modulators of PRL gene expression and hence function as thyroid hormone receptors, 2) in two different receptor containing cell lines (GH4C1 and GH1), both c-erbA proteins act in a hormone-independent fashion to regulate PRL and GH expression. This suggests that events other than ligand binding can result in formation of a c-erbA protein that modulates transcription of thyroid hormone responsive genes, 3) no qualitative functional differences were detected between alpha- and beta-c-erbA subtypes, and 4) depending on the cell-type, L-T3 acts through its endogenous receptor to stimulate (GH4C1) or suppress (GH1) expression of a chimeric PRL construct. In these cells, c-erbA expression results in the same positive or negative response as the endogenous receptor except that the response occurs in the absence of hormone. These results suggest that the endogenous receptor and the c-erbAs act by augmenting the effect of transcription factors which can positively or negatively control gene expression.


Regulation of cation channel voltage and Ca2+ dependence by multiple modulators.
Ion channel regulation is key to controlling neuronal excitability. However, the extent that modulators and gating factors interact to regulate channels is less clear. For Aplysia, a nonselective cation channel plays an essential role in reproduction by driving an afterdischarge in the bag cell neurons to elicit egg-laying hormone secretion. We examined the regulation of cation channel voltage and Ca2+ dependence by protein kinase C (PKC) and inositol trisphosphate (IP3)-two prominent afterdischarge signals. In excised, inside-out patches, the channel remained open longer and reopened more often with depolarization from -90 to +30 mV. As previously reported, PKC could closely associate with the channel and increase activity at -60 mV. We now show that, following the effects of PKC, voltage dependence was shifted to the left (essentially enhanced), particularly at more negative voltages. Conversely, the voltage dependence of channels lacking PKC was shifted to the right (essentially suppressed). Predictably, activity was increased at all Ca2+ concentrations following the effects of PKC; nevertheless, Ca2+ dependence was actually shifted to the right. Moreover, whereas IP3 did not alter activity at -60 mV, it drastically shifted Ca2+ dependence to the right-an outcome largely reversed by PKC. With respect to the afterdischarge, these data suggest PKC initially upregulates the channel by direct gating and shifting voltage dependence to the left. Subsequently, PKC and IP3 attenuate the channel by suppressing Ca2+ dependence. This ensures hormone delivery by allowing afterdischarge initiation and maintenance but also prevents interminable bursting. Similar regulatory interactions may be used by other neurons to achieve diverse outputs.


[The effect of opioid neuropeptides on the cholino- and adrenoreactivity of the sensorimotor cortex cells in rats].
The effect of two neuropeptides, dalargine and betaendorphine, on cholino- and adrenoreactivity of sensorimotor cortex cells has been studied in immobilized rats in acute experiments. Subcutaneous administration of the peptides led to redistribution of cells according to the type of their reaction and to changes in intensity of neuronal reactions to the applied neurotransmitters. The observed changes in chemoreactive properties of cortical neurons under the influence of the neuropeptides may play a certain part in the processes of learning and memory.


Chlamydia pneumoniae genome sequence analysis and identification of HLA-A2-restricted CD8+ T cell epitopes recognized by infection-primed T cells.
In the present study, we performed in silico analysis of Chlamydia pneumoniae genome sequence to identify human HLA-A2-restricted T cell epitopes. Thirty-one Chlamydia-specific protein antigens were selected and peptides were derived thereof using an HLA-A2 epitope predictive algorithm. Firstly, we tested binding of 55 selected 9mer peptides to HLA-A2 in vitro. Next, infection of HLA-A2 transgenic mice with C. pneumoniae elementary bodies and assessment of effector CD8+ T cells allowed us to identify which of the epitopes binding to HLA-A2 in vitro were recognized by C. pneumoniae infection-primed CD8+ T cells. Finally, we could confirm that CD8+ T cells in association with HLA-A2 recognized the most reactive peptides when the corresponding full-length genes were used to DNA-immunize HLA-A2 transgenic mice. By using this approach, a novel HLA-A2-restricted epitope in the outer membrane protein A (OmpA) of C. pneumoniae was identified, which proved to mediate specific lysis of peptide-loaded target cells.


[Evaluation of functional brain condition by EEG biopotential power asymmetry].
The fluctuations of functional brain condition level are evaluated by interhemispheric asymmetry of bioelectric activity power that is a consequence of both hemispheres interplay and involvement of nonspecific brain system in this process. Using neurological examination and electroencephalography, functional CNS condition analysis in patients with chronic brain ischemia and healthy controls was carried out. The results were compared to the indices of interhemispheric asymmetry of biopotential power (IHABP). Different functional CNS condition of both the patients and controls was characterized by different ratio of IHABP for fore- and back brain cortical regions. Controls exhibited a predominance of IHABP for frontal neocortex areas comparing to back ones. In the patients, the identical IHABP indices were detected for both neocortex areas.


Receptor subtypes mediating renal actions of calcitonin gene-related peptide.
We previously reported that the renal arterial infusions of non-hypotensive doses of calcitonin gene-related peptide (CGRP) caused renal vasodilatation and increases in glomerular filtration rate at a low dose, but renal vasoconstriction, natriuresis and kaliuresis at a high dose. In the present study, we examined the effects of the specific CGRP1 receptor antagonist (CGRP-(8-37) (1 and 10 nmol/kg) and the putative CGRP receptor antagonist, [Tyr(0)]CGRP-(28-37)(3 and 30 nmol/kg), on the renal vascular and tubular effects of CGRP in inactin-anaesthetized Sprague-Dawley rats. Renal arterial infusion of single doses of CGRP (0.3-300 pmol/kg per min) did not significantly alter mean arterial pressure or heart rate. However, during the continuous renal arterial infusion of either CGRP-(8-37) or [Tyr(0)CGRP-(28-37) incompletely inhibited the vasoconstriction but did not inhibit diuresis, natriuresis and kaliuresis elicited by a high but non-hypotensive dose of CGRP. On the basis that CGRP-(8-37) is a competitive CGRP1 receptor antagonist, our results suggest: (1) the renal vascular effect of CGRP is completely mediated via the activation of CGRP1 receptors, (2) the renal tubular effects of CGRP are not mediated via CGRP1 receptors, and (3) [Tyr(0)]CGRP-(28-37) is a CGRP1 receptor antagonist with potency and efficacy less than those of CGRP-(8-37).


The imbalance between osteoprotegerin and cathepsin K in the serum of patients with longstanding rheumatoid arthritis.
Osteoprotegerin (OPG) and soluble receptor activator of NF-kappa B ligand (sRANKL) together regulate the bone metabolism among other cytokines, whereby cathepsin K has a potent collagen-degrading activity. An imbalance of this system may be partly responsible for the skeletal complications of RA. Expanding on a previous study, we investigated the relationship between OPG, sRANKL and cathepsin K levels in the serum of patients with longstanding RA. We measured serum levels of OPG, sRANKL and cathepsin K of 100 patients with active, longstanding RA. We detected elevated serum levels of cathepsin K (median 54.8 pmol/l) and OPG (median 4.8 pmol/l), but normal sRANKL levels (median 0.2 pmol/l). Cathepsin K did not show a correlation with the overexpressed OPG (P=0.64) and sRANKL (P=0.81). The radiological destruction correlates significantly with cathepsin K (P=0.004) and OPG (P=0.007). We speculate that the increased levels of OPG are effective in compensating the action of sRANKL, but do not directly prevent bone degradation, as reflected by the elevated serum levels of cathepsin K.


Effect of chewing a single betel-quid on autonomic nervous modulation in healthy young adults.
Betel-quid is widely used around the world as a stimulant for the autonomic nervous system. The aim of this study was to assess the effect of betel-quid chewing on autonomic nervous modulation by using spectral heart rate variability (HRV) analysis. Twenty healthy young adults were included in this study. Each subject chewed a single betel-quid containing one betel nut or a piece of chewing-gum for 60 min on different days in random order. Spectral HRV measures were obtained before, and 5, 30 and 60 min after starting to chew betel-quid or gum. Sequential changes in HRV measures were compared between chewing gum and betel-quid. Heart rate was significantly elevated after 5 min chewing betel-quid, but not after chewing gum. The normalized low-frequency power and low-/high-frequency power ratio were elevated after 5 min chewing gum or betel-quid; however, the normalized high-frequency power was reduced after 5 min chewing gum or betel-quid. The percentage changes in total power after 5, 30 and 60 min chewing betel-quid were significantly lower than those after chewing gum. This study confirms that novice chewing of betel-quid modulates autonomic nervous system activity; transiently enhancing sympathetic activity and gradually suppressing vagal activity in healthy young adults.


Synthesis and antiallergic activity of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]-1,4-dihydro-4-oxopyridine-3 - carboxamides.
A new series of oxopyridinecarboxamide derivatives 3a--g and 5a were synthesized and evaluated for their antiallergic activity. 1,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxamides 3a and 5a exhibited potent antiallergic activity (inhibitory rates of 80.7 and 88.3%, respectively, at 20 mg/kg, p.o.) in the rat passive cutaneous anaphylaxis (PCA) test and also exhibited much more potent in vitro inhibitory activity than caffeic acid against the enzyme 5-lipoxygenase (5-LO). Their in vitro antihistamine activity, however, was weaker than that of ketotifen. Compounds 3a and 5a are viewed as promising candidates for antiallergic agents.


Single-puncture laparoscopic gastrostomy in children.
An original one-puncture technique of performing laparoscopic gastrostomy is described. The implications are analysed. The results of five operations are presented and the advantages and limitations are discussed in the light of current available methods.


The pH of the secretory pathway: measurement, determinants, and regulation.
The luminal pH of the secretory pathway plays a critical role in the posttranslational modification and sorting of proteins and lipids. The pH of each one of the organelles that constitute the pathway is unique, becoming more acidic as the biosynthetic cargo approaches its destination. The methods used for measurement of pH in the secretory pathway, its determinants, and its regulation are the subjects of this review.


Somatic symptoms as a marker for severity in adolescent depression.
This study aims to investigate the prevalence of somatic symptoms in depressed adolescents and in their healthy peers. A second aim is to investigate the correlation, in the depressed adolescents, between the number of somatic symptoms and severe concurrent symptoms, signs and life events. The total population of 16-17 year olds - in the city of Uppsala - was screened for depression and then interviewed using a structured interview questionnaire. Depressed subjects and matched controls were identified. A total of 177 pairs were used for pair-wise analyses of somatic symptoms. Severe symptoms, signs and life events were selected for analysing their relation to depression with somatic symptoms. The adolescents with depressive disorders experienced considerably more somatic symptoms than their healthy controls. The duration and depth of the depression correlated with the number of somatic symptoms. There was a strong correlation between depression with many somatic symptoms and suicidal plans/thoughts, suicidal attempts, disruptive behaviour, as well as multiple stressful relationships. This study demonstrates that somatic symptoms are common in adolescent depression. Multiple somatic symptoms within depression imply a higher severity in terms of duration, depth and psychiatric comorbidity. The strong correlation with suicidal plans, suicidal attempts and disruptive behaviour is concerning.


Protean manifestations of malaria--(multi organ dysfunction syndrome).
Malaria may present with Multi System Organ Failure (MSOF) or Single System Organ Failure (SSOF). Thirteen cases of malaria are presented for their protean manifestations. Five patients presented for chronic urticaria with or without polyarticular arthritis, another mimicking acute rheumatic arthritis. A case of reactivation of pulmonary tuberculosis and the other to with apparent chloroquin resistant malaria who responded to combination of verapamil and chloroquin. A case developing Guillain Barre syndrome and another complicating into dilated cardiomyopathy are the rarities. All the cases are described and the pathogenesis is discussed in detail.


Endothelial and antithrombotic actions of HDL.
It is well recognized that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. However, HDL has multiple additional endothelial and antithrombotic actions that may also afford cardiovascular protection. HDL promotes the production of the atheroprotective signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling. As importantly, there is evidence of a variety of mechanisms by which HDL is antithrombotic and thereby protective against arterial and venous thrombosis, including through the activation of prostacyclin synthesis. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis. With further investigation and resulting greater depth of understanding, these mechanisms may be harnessed to provide new prophylactic and therapeutic strategies to combat atherosclerosis and thrombotic disorders.


[In vitro evaluation of antibacterial substances produced by bacteria isolated from different marine organisms].
Bacteria from several groups of marine organisms were isolated and, using direct antibiograms, identified those that produce antibacterial substances, using a human pathogenic strain of Staphylococcus aureus ATCC6538 as revealing microorganism. Bacteria which produce substances that inhibited S. aureus growth were identified through morphological, physiological and biochemical tests. Out of 290 bacteria, 54 (18.6%) inhibited the growth of S. aureus, but only 27 survived for identification. Bivalves, sponges and corals were the most represented from which 41.2, 33.3 and 29.7%, respectively, produced antibacterial substances of the isolated bacteria in each group. The marine species with highest proportions of these bacteria were the hard coral Madracis decactis (62.5%), the sponges Cliona sp. (57.1%) and the octocoral Plexaura flexuosa (50.0%). Out of the 27 strains that produced antibacterial substances, 51.8% were Aeromonas spp. and 14.8% Vibrio spp. Marine bacteria that produce antibacterial substances are abundant, most belong in the Vibrionacea group and were isolated mainly from corals and bivalve mollusks.


[Evaluation of surgical practice in the treatment of lung cancer in France from the PMSI national database].
In recent years, improving the quality of care has been a concern for health professionals in France, through the certification of institutions, accreditation and continuous professional development. Evaluation of these different measures has rarely been carried out. The objective of the study was to evaluate the quality of surgical management of lung cancer in different regions using hospital mortality as an indicator. From the national database of the Program of Medical Information Systems (PMSI), data on all patients who had undergone surgery for lung cancer were extracted as well as the characteristics of the centers. The main outcome criterion was hospital mortality. Logistic models allowed an estimation of the risk standardized mortality rate for each center. From January 1, 2015 to December 31, 2015, 10,675 patients underwent surgery for lung cancer in 158 French centers. The hospital mortality rate was 3.43% (n=366). Thirty-nine facilities (25%) performed fewer than 15 pulmonary resections. The minimum activity volume was a single pulmonary resection during the year and the maximum was 300 interventions with a coefficient of variation estimated at 147%. Hospital mortality ranged from 0 % to 50% depending on the entries with a coefficient of variation of 112%. For some regions, it is possible to count up to 5 centers per million inhabitants (Languedoc-Roussillon) or 4 centers per million inhabitants (Limousin, Pays-de-Loire). The majority of regions had 3 centers per million inhabitants. Eleven regions have no centers with a standardized mortality rate below 3%. Five regions (Languedoc-Roussillon, Pays-de-Loire, Aquitaine, Brittany and Provence Alpes Côte d'Azur) have at least two centers with a risk standardized rate of mortality above 4%. Among the academic centers, 20% have a risk standardized mortality rate of less than 3%. Among the centers with a risk standardized rate of mortality<3%, 20% performed more than 39 pulmonary resections, 7% between 39 and 15 procedures and 0% for centers with<15 interventions. This work confirms that hospital volume is one of the components of quality of care. The number of centers should be adapted to the actual needs of the population in order to enable patients to access effective services.


Impact of child sexual abuse on mental health: prospective study in males and females.
The lack of prospective studies and data on male victims leaves major questions regarding associations between child sexual abuse and subsequent psychopathology. To examine the association between child sexual abuse in both boys and girls and subsequent treatment for mental disorder using a prospective cohort design. Children (n=1612; 1327 female) ascertained as sexually abused at the time had their histories of mental health treatment established by data linkage and compared with the general population of the same age over a specified period. Both male and female victims of abuse had significantly higher rates of psychiatric treatment during the study period than general population controls (12.4% v. 3.6%). Rates were higher for childhood mental disorders, personality disorders, anxiety disorders and major affective disorders, but not for schizophrenia. Male victims were significantly more likely to have had treatment than females (22.8% v.10.2%). This prospective study demonstrates an association between child sexual abuse validated at the time and a subsequent increase in rates of childhood and adult mental disorders.


Detection of Inositol Phosphates by Split PH Domains.
The pleckstrin homology (PH) domain is a family of structurally conserved proteins which can bind inositol phosphate derivatives. Some proteins involved in cellular signaling and cytoskeletal organization possess split PH domains that assemble into a structure which can bind specific inositol phosphates. Here we describe the design of split PH domain from a structurally well-characterized PH domain of phospholipase C (PLC) δ1 and Bruton's tyrosine kinase (Btk), which selectively bind Ins(1,4,5)P3 and Ins(1,3,4,5)P4, respectively. The PH domains fold into a functional structure when the split halves are brought to close proximity, and can be utilized to detect specific inositol phosphate of interest.


Toxicity of concurrent hyperfractionated radiation therapy and chemotherapy in locally advanced (stage III) non-small cell lung cancer (NSCLC): single institution experience in 600 patients.
to investigate toxicity of hyperfractionated radiation therapy (Hfx RT) with or without concurrent chemotherapy (CHT) in patients with locally advanced non-small cell lung cancer (NSCLC) and factors independently influencing it. Of a total of 600 patients treated during five prospective studies Hfx RT alone was given in 127 and Hfx RT-CHT was given in 473 patients. Hfx RT doses were 64.8 and 69.6 Gy (1.2 Gy bid) and 67.6 Gy (1.3 Gy bid). CHT administration consisted of concurrent carboplatin and etoposide in 409 patients and concurrent carboplatin and paclitaxel in 64 patients. Acute oesophageal toxicity was significantly increased with concurrent CHT (p = 0.034), as well as bronchopulmonary (p = 0.044) and haematological toxicity (p < 0.001). Only late high-grade bronchopulmonary (p = 0.007) toxicity was significantly more frequent in the RT-CHT group. Only acute high-grade haematological toxicity was significantly more frequent in split CHT than in daily CHT and Hfx RT alone (p < 0.001). Only late high-grade bronchopulmonary toxicity remained significantly more frequent in both Hxf RT-CHT groups than in Hfx RT alone. No variable influenced acute high-grade bronchopulmonary, gastric or skin toxicity. Pronounced weight loss influenced increased acute high-grade oesophageal toxicity. Increased weight loss and lower KPS influenced increased haematological toxicity. Pronounced weight loss and concurrent CHT influenced increased late high-grade bronchopulmonary toxicity. This study reconfirmed low acute and late high-grade toxicity in stage III NSCLC treated with concurrent RT-CHT and identified factors influencing it.


Role of peritoneal macrophages and lymphocytes in the development of hypogonadal osteoporosis in an ovariectomized rat model: possible phytoestrogenic efficacy of oil extract of garlic to preserve skeletal health.
This study was to examine whether skeletal health deterioration in the hypogonadal situation is a consequence of an alteration in the functional status of peripheral mononuclear cells and its amelioration, if any, by an oil extract of garlic. The results suggest that hypogonadism-induced oxidative stress of peritoneal macrophages and lymphocytes could be reduced by supplementation with an oil extract of garlic. However, estrogen deficiency did not cause any significant change in DNA fragmentation of peritoneal macrophages. The hypogonadism-induced increase in the serum levels of IL-6 and TNF-alpha were significantly reduced by an oil extract of garlic. Further, such supplementation could revive the hypogonadism-induced decrease in serum estrogen titer and counter-balance the increase in bone turnover as determined by low bone tensile strength and alterations in bone related biochemical variables such as urinary calcium, hydroxyproline, calcium to creatinine ratio and serum tartrate resistant acid phosphatase activity (TRAP). The garlic oil supplemented partial recovery of the serum estrogen titer in hypogonadal rats was found to be persistently associated with reduced oxidative stress of peritoneal macrophages and lymphocytes, reduced serum interleukins and better preservation of bone mass. This study proposes that the hypogonadism-induced bone loss has a direct correlation with the functional status of lymphocytes and peritoneal macrophages, and garlic can prevent this.


Intensive cyclic chemotherapy and transplantation of autologous peripheral blood progenitor cells (PBPC) or whole blood in high-risk breast cancer - follow up at 10 years.
The main aim of our paper is to contribute to objectification of currently widely discussed results of overall survival (OS), disease free survival (DFS) and time from relapse to tumor progression (TTP) in women with breast cancer. Forty consecutive patients fulfilling the eligibility criteria were admitted to the study. Fifty-six women were included in the control group. All patients received 6 cycles of adjuvant intensive cyclic combined chemotherapy with epirubicin 150 mg/m(2) and cyclophosphamide 1250 mg/m(2) (EC) applied each 14 days. To overcome haematological toxicity transplantations of autologous peripheral blood progenitor cells (PBPCs) or whole blood enriched of PBPC were used. We found statistically significant difference in OS regardless of the stage of the disease to the benefit of women treated by intensive cyclic EC chemotherapy when compared with the control group. In evaluation of DFS no statistically significant difference was found in survival between the control group and the group with all stages of the disease. TTP in women without relation to the stage was statistically significantly longer than in the control group. In our study intensive cyclic EC chemotherapy did not show better curative effect when compared with conventional dosage chemotherapy.


Prevention of pressure ulcers in patients undergoing subacute rehabilitation after severe brain injury: An observational study.
To uncover efforts made by healthcare professionals to prevent pressure ulcers in patients with severe brain injury undergoing treatment at a subacute rehabilitation department. Pressure ulcers are a major burden for patients and also generate considerable healthcare costs. Pressure ulcers are, nevertheless, prevalent in both secondary care and primary care. In this qualitative study, we performed 24-hour observation on four patients undergoing rehabilitation for severe brain injury. An observation guide was developed inspired by the Braden Scale and Spradley's theory and methods. Observations were analysed using content analysis. Patricia Benner's aspects of clinical grasp were employed in the interpretation of the observations. One overarching theme was identified: "Professionalism expressed by preventing intervention, involving the patient, employing clinical grasp and professional pride." Seven subcategories were summed up into the following three categories: organisation of clinical practice, professional assessment and interactions with the patient. The healthcare professionals' actions to prevent pressure ulcers consisted of attaining the necessary knowledge about pressure ulcer care and performing the activities. However, our observations revealed one important additional aspect: a very distinct impression that the healthcare professionals were committed to learning about the patients' former life and actively used this knowledge in their planning and provision of daily patient care. We believe this commitment has a very positive effect on prevention of pressure ulcers. Professional knowledge about prevention of pressure ulcer is a necessary requisite, but is not sufficient to ensure effective treatment. To transfer knowledge into practice, we recommend that patients' rehabilitation days be planned in such a manner that activities, mobilisation and training are conducted throughout the day and evening. We also recommend that professional staff are encouraged to seek information about the former life of patients with severe brain injury.


[Blast cell differentiation of a continuous human leukemia line as affected by dimethyl sulfoxide].
The human blast cells line L-101 isolated from blood leukocytes of the patient with the cutaneous erythromyeloleukemia in the media with dimethyl-sulfoxide (DMSO) and maintained by permanent cultivation stimulate myeloid differentiation of this cells. The number of differentiated cells depends on DMSO concentration. Maximum of differentiated cells (up to 75%) have exposed on the 6th day of incubation with 0,75% DMSO. The cell line L-101 is a suitable model for investigation of myeloid differentiation.


Education in primary care psychiatry: research-based audit.
This paper describes some of the difficulties faced by the KCGP Mental Health Education Fellows in designing an educational initiative to enhance the recognition and management of psychiatric illness in general practice. The initiative was evaluated using a consensus technique over six meetings which took place between 1993 and 1995. The results of the exercise illustrated the value of utilizing a validated instrument in identifying mental health problems, but when employed without support created disillusionment and a lack of confidence in the learner. However, when the instrument was applied as a part of a wide educational process examining current practice, learners were stimulated to examine and change their behaviour by synthesizing newly acquired knowledge with their own previous clinical experience.


Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study.
Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant-a neurokinin receptor inhibitor-for management of severe pruritus induced by biological drugs. In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552. Median VAS in the refractory group was 8·00 (95% CI 7·93-8·57) at baseline and 1·00 (0·00-2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43-8·37) at baseline and 0·00 (0·06-1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred. Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials. None.


Building the pipeline: programs to introduce middle school, high school, medical, and veterinary students to careers in epidemiology and public health.
This report describes Centers for Disease Control and Prevention programs that expose students to epidemiology and public health sciences (EPHS). The Science Ambassador workshop targets middle and high school teachers and promotes teaching EPHS in the classroom. The National Science Olympiad Disease Detectives event is an extracurricular science competition for middle and high school students based on investigations of outbreaks and other public health problems. The Epidemiology Elective Program provides experiential learning activities for veterinary and medical students. As of 2016, 234 teachers from 37 states and territories and three other countries participated in SA workshops. Several are teaching units or entire courses in EPHS. The National Science Olympiad Disease Detectives event exposed approximately 15,000 middle and high school students to EPHS during the 2015-2016 school year. The Epidemiology Elective Program has exposed 1,795 veterinary and medical students to EPHS. Students can master fundamental concepts of EPHS as early as middle school and educators are finding ways to introduce this material into their classrooms. Programs to introduce veterinary and medical students to EPHS can help fill the gap in exposing older students to the field. Professional organizations can assist by making their members aware of these programs.