Nanoscale ionic diodes with tunable and switchable rectifying behavior.
Nanoscale ionic diodes have attracted interest as circuit elements for development of nanofluidic devices for a variety of applications, including biosensing, constructing artificial cells, and engineering biological batteries. This paper presents a bottom-up, self-assembly approach for constructing nanopores with rectified conductance behavior in a membrane using semisynthetic derivatives of the ion-channel-forming peptide gramicidin A. The capability to individually access each half of a dimeric gramicidin channel makes it possible to generate asymmetric channels in a membrane that exhibit diodelike conductance properties. The modular nature of these self-assembled channels affords the possibility of tuning their rectifying conductance properties by simple replacement of one peptide derivative with another in the membrane. Additionally, introduction of an external stimulus (here, an enzyme) to change the functional group attached to one side of the gramicidin pore induces diodelike conductance behavior in previously nonrectified channels, demonstrating the possibility of switching the conductance properties of these nanopores in situ in a controlled manner.


[Successful use of mild hypothermia therapy in a patient with severe clinical Reye syndrome].
This report describes a case of two-yr-old female with severe clinical Reye syndrome (Stage III and over), who was treated with not only conventional therapies but also mild hypothermia therapy. She presented acute episodes of tonic convulsion, hepatic dysfunction and intracranial hypertension. The first treatment consisted of the administration of anticonvulsant and mannitol, which were not effective to control intracranial pressure. Therefore, we induced mild hypothermia to rectal temperature of 33-34 degrees C for ten days to control intracranial hypertension as well as barbiturate therapy and hyperventilation under mechanical ventilation. Although she had hypokalemia, atelectasis of the right upper lung lobe and thrombocytopenia as the side effects during this therapy, we effectively controlled ICP. Glucose fluid therapy is recommended for Reye syndrome. We especially should pay attention to hypokalemia because of hyperventilation, absorption of potassium with insulin and transudation of potassium from the intestine. We determined the initiation and weaning of mild hypothermia therapy by findings of MRI as well as intracranial pressure. MRI findings will contribute to the determination of initiation and weaning of mild hypothermia therapy. Mild hypothermia therapy should be considered in patients with severe clinical Reye syndrome if conventional supportive therapies are not effective.


Downstream divergence of the ethylene signaling pathway for harpin-stimulated Arabidopsis growth and insect defense.
Ethylene (ET) signal transduction may regulate plant growth and defense, depending on which components are recruited into the pathway in response to different stimuli. We report here that the ET pathway controls both insect resistance (IR) and plant growth enhancement (PGE) in Arabidopsis (Arabidopsis thaliana) plants responding to harpin, a protein produced by a plant pathogenic bacterium. PGE may result from spraying plant tops with harpin or by soaking seeds in harpin solution; the latter especially enhances root growth. Plants treated similarly develop resistance to the green peach aphid (Myzus persicae). The salicylic acid pathway, although activated by harpin, does not lead to PGE and IR. By contrast, PGE and IR are induced in both wild-type plants and genotypes that have defects in salicylic acid signaling. In response to harpin, levels of jasmonic acid (JA) decrease, and the COI1 gene, which is indispensable for JA signal transduction, is not expressed in wild-type plants. However, PGE and IR are stimulated in the JA-resistant mutant jar1-1. In the wild type, PGE and IR develop coincidently with increases in ET levels and the expression of several genes essential for ET signaling. The ET receptor gene ETR1 is required because both phenotypes are arrested in the etr1-1 mutant. Consistently, inhibition of ET perception nullifies the induction of both PGE and IR. The signal transducer EIN2 is required for IR, and EIN5 is required for PGE because IR and PGE are impaired correspondingly in the ein2-1 and ein5-1 mutants. Therefore, harpin activates ET signaling while conscribing EIN2 and EIN5 to confer IR and PGE, respectively.


Captopril as a replacement therapy in hypertension improving quality of life--a multicentre study.
A multicentre study was undertaken to determine whether side effects induced by hypotensive drugs could be reduced by replacement with low dose captopril. There were 100 patients on combinations of drugs, including diuretics, beta-blocking agents, methyldopa, clonidine and vasodilators. A questionnarie to obtain information on quality of life was completed by the patients. Each patient had major drugs, possibly responsible for side effects, withdrawn. Captopril was added at an initial dose of 12.5 up to 25 mg b.i.d. and titrated to a maximum of 50 mg t.i.d., until the blood pressure was equal to or lower than the level on entry into the study. Blood pressure was measured every two weeks and questionnaries were completed a number of times during the treatment period and scored at random, not in chronological order. A marked drop in blood pressure was obtained: mean systolic blood pressure went down from 173.4 +/- 2 to 154.5 +/- 2 mm Hg and diastolic blood pressure dropped from 104.5 +/- 11 to 9l.5 +/- 12 mm Hg. Neither tachycardia nor orthostasis was observed. Side effects, including inability to concentrate, nightmares, dizziness and sexual dysfunction, were reduced in 36% of the patients. Captopril itself produced no significant additional adverse reactions. It is concluded that captopril is a safe and effective drug, which can replace antihypertensive drugs that have deleterious side effects.


A randomized controlled trial of one bag vs. two bag system of fluid delivery in children with diabetic ketoacidosis: Experience from a developing country.
To compare one vs. two bag system with respect to blood glucose variability (BGV), time for resolution of acidosis and incidence of hypoglycemia, hypokalemia, and cerebral edema in children with diabetic ketoacidosis (DKA). In an open labelled randomized controlled trial, thirty consecutive patients ≤12years with DKA were randomized to either one (n=15) or two bag (n=15) system of intravenous fluid delivery. The two bags had similar electrolyte but differing dextrose concentration (none vs. 12.5%) and changing the rate of fluid, delivered different dextrose concentrations. BGV was primary outcome while hypoglycemia (blood glucose, BG<50mg/dL), hypokalemia (serum potassium<3.5mEq/L), time to resolution of acidosis and cerebral edema were secondary outcomes. The one and two bag systems had similar BGV parameters; median hourly absolute BG change (mg/dL) [44 (30-74.5) vs. 36 (31-49); p=0.54], mean of standard deviation of BG measurements [65.1 (25.1) vs. 65.5 (26.8); p=0.96] and median number of undesirable events (hourly blood sugar change ≥50mg/dL) [4.5 (1.75-6.0) vs. 5.0 (3.0-8.0); p=0.31]. The incidence of hypoglycemia [42.9% (n=6) vs. 26.7% (n=4); p=0.45] and hypokalemia [64% (n=9) vs. 67% (n=10); p=0.23], and mean (SD) time to resolution of acidosis [20.3 (14.8) and 20.3 (7.0); p=0.59] were similar in both the groups. None had cerebral edema. The one and two bag systems were similar to each other with respect to BGV, incidence of complications and time to resolution of acidosis.


Protein secondary structure controlled with light and photoresponsive surfactants.
The interaction of a light-responsive azobenzene surfactant with bovine serum albumin (BSA) has been investigated as a means to examine photoreversible changes in protein secondary structure. The cationic azobenzene surfactant undergoes a reversible photoisomeriztion upon exposure to the appropriate wavelength of light, with the visible-light (trans) form being more hydrophobic and, thus, inducing a greater degree of protein unfolding than the UV-light (cis) form. Fourier transform infrared (FT-IR) spectroscopy is used to provide quantitative information on the secondary structure elements in the protein (alpha-helices, beta-strands, beta-turns, and unordered domains). Comparing the secondary structure changes induced by light illumination in the presence of the photoresponsive surfactant with previous measurements of the tertiary structure of BSA obtained from small-angle neutron scattering (SANS) allows the three discrete conformation changes in BSA to be fully characterized. At low surfactant concentrations, an alpha-helix --> beta-structure rearrangement is observed as the tertiary structure of BSA changes from a heart-shaped to a distorted heart-shaped conformation. Intermediate surfactant concentrations lead to a dramatic decrease in the alpha-helix fraction in favor of unordered structures, which is accompanied by an unfolding of the C-terminal portion of the protein as evidenced from SANS. Further increases in photosurfactant concentration lead to a beta --> unordered transition with the protein adopting a highly elongated conformation in solution. Each of these protein conformational changes can be precisely and reversibly controlled with light illumination, as revealed through FT-IR spectra collected during repeated visible-light <--> UV-light cycles.


Reversible Graphene decoupling by NaCl photo-dissociation.
We describe the reversible intercalation of Na under graphene on Ir(111) by photo-dissociation of a previously adsorbed NaCl overlayer. After room temperature evaporation, NaCl adsorbs on top of graphene forming a bilayer. With a combination of electron diffraction and photoemission techniques we demonstrate that the NaCl overlayer dissociates upon a short exposure to an X-ray beam. As a result, chlorine desorbs while sodium intercalates under the graphene, inducing an electronic decoupling from the underlying metal. Low energy electron diffraction shows the disappearance of the moiré pattern when Na intercalates between graphene and iridium. Analysis of the Na 2p core-level by X-ray photoelectron spectroscopy shows a chemical change from NaCl to metallic buried Na at the graphene/Ir interface. The intercalation-decoupling process leads to a n-doped graphene due to the charge transfer from the Na, as revealed by constant energy angle resolved X-ray photoemission maps. Moreover, the process is reversible by a mild annealing of the samples without damaging the graphene.


Effect of electrode material on the sensitivity of interdigitated electrodes used for Electrical Cell-Substrate Impedance Sensing technology.
This study explores the effect of the electrode material on the sensitivity of interdigitated electrodes (IDEs) used in Electrical Cell-Substrate Impedance Sensing (ECIS) technology. This technique is a label-free method to evaluate cellular activity of adherent cells. IDEs of gold (Au), indium tin oxide (ITO) and ITO functionalized with iridium oxide (IrOx) were characterized with impedance spectroscopy and their interfacial impedances were evaluated in potassium chloride (KCl) solutions. In parallel, ECIS measurements were performed on these three electrode materials during the proliferation of the human breast cancer cell line, MCF-7. The results indicate that the difference in sensitivity to MCF-7 of the three materials might be strongly correlated to their interfacial impedances. We found that ITO electrodes coated with IrOx show slightly higher sensitivity to MCF-7 breast cancer cells while still offering transparency compared to gold, which is considered the conventional material in ECIS devices.


Autologous matrix-induced chondrogenesis for the treatment of osteochondral lesions of the talus: A systematic review.
This study was performed to determine whether Autologous Matrix-Induced Chondrogenesis (AMIC) is an effective and safe treatment option for patients with symptomatic Osteochondral defects of the Talus (OCTs) and to identify factors that influence the clinical outcome. A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Three reviewers independently conducted the literature search using the MEDLINE/PubMed database and the Cochrane Database of Systematic Reviews. The databases were queried using the terms "autologous" AND "matrix" AND "induced" AND "chondrogenesis." Thirteen studies were eligible for review. All studies that compared the preoperative and postoperative mean values of different clinical/functional scores showed significant clinical improvement. The final postoperative mean Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score ranged from 50.9 to 74.5. The included studies indicated that age and body mass index may have a detrimental impact on the postoperative outcome. A higher re-intervention rate is expected with the open technique, mainly because of hardware removal after malleolar osteotomy. This data analysis demonstrated that both arthroscopic and open AMIC procedures are effective and safe for the treatment of OCTs. Level IV, systematic review of therapeutic studies.


Isothermic irrigation during transurethral resection of the prostate: effects on peri-operative hypothermia, blood loss, resection time and patient satisfaction.
To investigate the effect using irrigation fluid at body temperature (isothermic) on patients' (core) temperature during a transurethral resection of the prostate (TURP) and on the amount of peri-operative blood loss, the resection time and the subjective assessment of comfort by the patients. In a randomized study, patients undergoing TURP under spinal anaesthesia were divided into those receiving either isothermic irrigation fluid (Group 1.28 patients) or fluid at room temperature (Group 2.31 patients). In Group 1, a fluid heater maintained the irrigation fluid at body temperature until it reached the bladder. The body temperature of the patients was recorded rectally and orally during and after TURP and the peri-operative blood loss was also measured. The patients were interviewed on the first day after TURP to determine their assessment of comfort during the procedure. The decrease in body temperature was 0.74 degree C in Group 1 and 1.71 degrees C in Group 2, which was significantly different (P < 0.001). There was no significant difference in blood loss or resection-time. In Group 1, only four (14%) of the patients were aware that their body was cooler, compared to 15 (50%) in Group 2 (P = 0.038). Isothermic irrigation during TURP prevents excessive cooling and reduces the level of hypothermia. The reported increased mortality after TURP is probably related to peri-operative cardiac stress, an important factor which could be caused by the rapid decrease in body temperature which accompanies normal irrigation. Because the heating equipment presently available does not interfere with TURP, there are strong arguments for performing every TURP with irrigation fluid at body temperature.


The biological activity of endothelin-1 analogues in three different assay systems.
Endothelin (ET) is a vasoconstrictor peptide with 21-amino acid residues. In this study, we determined the relative potencies of ET-1 analogues to investigate the essential moiety of ET-1 for expression of its biological effect. We synthesized ET-1 analogues with the substitution of one amino acid at positions 2-18 and 21. All ET-1 analogues had the proper intramolecular disulfide bonds. We have conducted a systematic survey to compare the biological activity of ET-1 analogues in three different assay systems: the vasoconstrictor activity in the rat pulmonary artery, the nonvascular smooth muscle contracting activity in the rat trachea, and the pressor activity in the conscious rat. In the pulmonary arterial preparation, the carboxyl groups of Asp8, Glu10, and Asp18, the aromatic groups of Phe14, His16, and Trp21, and the hydrophobic group of Leu17 contributed to the expression of the vasoconstrictor activities. However, the contracting activities in the tracheal preparations were retained even upon replacement of these amino acid residues by alanine or other amino acids. Moreover, substitution of the amino acid residue of ET-1 at positions Ser5, Lys9, and Tyr13 for alanine was found to increase the potency of ET-1 by a factor of about 2. With respect to vasopressor effects, the activities were retained, and all ET-1 analogues showed relative potencies ranging from 5 to 90% of ET-1. These findings suggest that different types of receptors may be present in different organs.


Alterations in biodistribution of cocaine may explain differential toxicity in pregnant and postpartum rats.
Biodistribution of cocaine in female rats before and after delivery of litters was studied in order to provide an explanation for the observed differences in cocaine-induced toxicity in pregnant and postpartum rats. Cocaine (20 mg/kg, ip) given to female rats at 16 days of gestation or 20 days of gestation did not have any apparent neurotoxic effects in the mothers. Similarly, no apparent toxicity was observed in virgin animals injected with the same dosage of cocaine. However, administration of the same dosage of cocaine to rats after delivery caused clonic-tonic convulsions and death within 5 min of injection. In an effort to explain these differences, the biodistribution of cocaine was investigated by injecting levo-[benzoyl-3,4-3H(N)] cocaine (20 mg/20 microCi/kg, ip) to nonpregnant rats and rats at different gestation periods and after delivery. The mean serum/brain ratios (concentration of cocaine in serum divided by cocaine concentration in the brain) of cocaine 5 min after injection in rats at 16 days gestation, 20 days gestation, within a 12-hr period after delivery, and in control virgin animals were 2099, 1132, 427, and 632, respectively. These results indicate that the biodistribution of cocaine is altered at parturition. This may explain the increased central nervous system toxicity in rats treated with cocaine after delivery. Results from this investigation may be useful in evaluating complications during labor and delivery which have been associated with cocaine abuse by pregnant women.


Molecular characterization of a region of DNA associated with mutations at the agouti locus in the mouse.
Molecular characterization of a radiation-induced agouti (a)-locus mutation has resulted in the isolation of a segment of DNA that maps at or near the a locus on chromosome 2 in the mouse. This region of DNA is deleted in several radiation- or chemical-induced homozygous-lethal a-locus mutations and is associated with specific DNA structural alterations in two viable a-locus mutations. We propose that DNA probes from this region of chromosome 2 will be useful for ultimately characterizing the individual gene or genes associated with a-locus function.


The gene Sex-lethal of the Sciaridae family (order Diptera, suborder Nematocera) and its phylogeny in dipteran insects.
This article reports the cloning and characterization of the gene homologous to Sex-lethal (Sxl) of Drosophila melanogaster from Sciara coprophila, Rhynchosciara americana, and Trichosia pubescens. This gene plays the key role in controlling sex determination and dosage compensation in D. melanogaster. The Sxl gene of the three species studied produces a single transcript encoding a single protein in both males and females. Comparison of the Sxl proteins of these Nematocera insects with those of the Brachycera showed their two RNA-binding domains (RBD) to be highly conserved, whereas significant variation was observed in both the N- and C-terminal domains. The great majority of nucleotide changes in the RBDs were synonymous, indicating that purifying selection is acting on them. In both sexes of the three Nematocera insects, the Sxl protein colocalized with transcription-active regions dependent on RNA polymerase II but not on RNA polymerase I. Together, these results indicate that Sxl does not appear to play a discriminatory role in the control of sex determination and dosage compensation in nematocerans. Thus, in the phylogenetic lineage that gave rise to the drosophilids, evolution coopted for the Sxl gene, modified it, and converted it into the key gene controlling sex determination and dosage compensation. At the same time, however, certain properties of the recruited ancestral Sxl gene were beneficial, and these are maintained in the evolved Sxl gene, allowing it to exert its sex-determining and dose compensation functions in Drosophila.


Predictive factors of survival of colorectal cancer patients after para-aortic lymph node metastasis.
Para-aortic lymph node (PALN) metastasis is an ominous manifestation indicating a poor prognosis in colorectal cancer (CRC) patients; however, some treatments prolong survival. In this study, we investigated predictors of prolonged survival in CRC patients after PALN metastasis. We examined 141 patients with CRC that metastasized to the PALNs from CRC with or without extra-PALN metastasis. Among clinicopathological parameters, factors associated with survival after PALN metastasis were identified by multivariate analyses using Cox's proportional hazard models. The mean hemoglobin and albumin values at diagnosis were 12.3 g/dL and 3.7 g/dL, respectively. Rectal cancer was predominant (n = 81). Mutated RAS was detected in 43%. One hundred and four patients had differentiated adenocarcinoma. Patients underwent PALN dissection (n = 11), radiotherapy (n = 6), and systemic therapy (n = 120). Biologics were administered to 95 patients. The median survival time was 29.1 months. On multivariate analysis, independent factors associated with reduced survival after PALN metastasis were low albumin (hazard ratio [HR] 2.33 per -1 g/dL), mutated RAS (HR 2.55), other than differentiated adenocarcinoma (HR 2.75), rectal cancer (HR 3.38 against right-sided colon, and 3.48 against left-sided colon), the presence of extra-PALN metastasis (HR 6.56), and no use of biologics (HR 3.04). This study revealed that hypoalbuminemia as well as RAS mutation, undifferentiated histology, rectal cancer, other site metastasis, and no use of biologics contribute to poor prognosis in CRC patients with PALN metastasis. Nutritional management may be important for improving survival of these patients.


The interplay of sequence and stereochemistry in defining conformation in proteins and polypeptides.
Sequential specification of conformation in proteins and polypeptides is a triangular interplay involving the system of linked peptides, the sequences in side chains, and water as solvent. Stereochemistry in side chain linkages is obviously important in the interaction between all of the players, but no specification of its explicit role, if any, in linking sequence with conformation has been made. Flory and coworkers made a puzzling observation in 1967 that, when mutated from poly-L to alternating-L,D stereochemical structure, polypeptides will suffer a reduction in overall dimension or characteristic ratio by an astonishing factor of 10 and to a value even lower than that predicted for free rotation (Miller, W. G.; Brant, D. A.; Flory, P. J. J Mol Biol 1967, 23, 67-80). Enquiring into this longstanding puzzle, Durani and coworkers found that the stereochemical modification will also abolish conformational sensitivity in polypeptide structure to solvent, because electrostatic interactions in the system of linked peptides are transformed from a condition of mutual conflict to one of harmony (Ramakrishnan, V.; Ranbhor, R.; Kumar, A.; Durani, S. J Phys Chem B 2006, 110, 9314-9323). Thus, poly-L stereochemistry could be the fulcrum linking sequences with phi,psis in protein and polypeptide structures, via dielectric arbitrations in a conflicting type of interpeptide electrostatics, in agreement with the electrostatic screening model of Avbelj and Moult (Avbelj, F.; Moult, J. Biochemistry 1995, 34, 755-764).


Ultrastructural, immunocytochemical and flow cytometry study of mouse peritoneal cells stimulated with carrageenan.
In the present paper we performed a morphological characterization of mouse peritoneal cells stimulated in vivo for 24 h with carrageenan (CAR) and lipopolysaccharide (LPS) by ultrastructural and flow cytometry analysis. In all samples, the flow cytometry studies showed the presence of three major populations consisting of monocytes, macrophages and lymphocytes. A special recruitment of monocytes was detected in CAR-injected mice. Macrophages and monocytes from CAR-treated mice displayed a characteristic phenotype, with a larger number of cytoplasmic vacuoles and numerous membrane projections, as compared to the cells collected from LPS- and PBS-injected mice. The induction of vacuolization was also confirmed upon in vitro treatment with CAR for 15 min to 24 h. The in vivo CAR-induced vacuoles were not related to lipid storage as judged by the lack of lipidic labeling after imidazole treatment at the ultrastructural level. In order to investigate the acidic nature of the vacuoles we used acidothropic probes, Lysotracker Yellow (LY) and Acridine Orange (AO). CAR injection activated the ability of peritoneal cells to incorporate LY around 2-5 times higher than control cells. However, the AO incorporation was 10-fold lower in CAR-stimulated cells than in LPS-stimulated ones. It is possible that the increase in intracellular vacuolization observed in CAR-stimulated cells could be related to exocytosis, since in most vacuoles the inflammatory protein MRP-14 was immunolocalized. The presence of MRP-14 in the culture supernatant of adherent peritoneal cells from CAR-injected mice was further comfirmed by ELISA, suggesting the discharge of MRP-14 enriched vacuole contents in the extracellular medium. We concluded that the morphological characteristics of activated monocytes and macrophages may depend on the nature of the triggering stimuli. Our observations reflect different functional phenotypes of monocytes/macrophages after in vivo stimulation with inflammatory agents such as CAR and LPS.


Dynamic consequences of differences in male and female vocal tract dimensions.
Phonetic differences between male and female speakers are generally considered in terms of the static acoustic and perceptual consequences of different articulatory dimensions. This article investigates the dynamic acoustic and articulatory implications of differences in mean male and female vocal tract dimensions. The temporal acoustic consequences of time-varying twin-tube resonators of different dimensions are explored, and the possible implications for human speech production are considered. Empirical support for the theoretical predictions is sought by investigating the kinematic and acoustic patterns in diphthong productions from 26 female and 22 male speakers in the University of Wisconsin X-ray Microbeam Speech Production Database. Aside from expected acoustic differences, the shape of male and female formant tracks plotted in Bark space is found to be very similar. Male and female patterns of tongue movement, however, are found to be very dissimilar. The mean male diphthong, defined by the tracks of four midsagittal pellets, is characterized by greater pellet excursions, higher pellet speed, and consistently larger dorso-palatal strictures than its female counterpart. The empirical findings suggest that gender-specific dynamic behavior could be an important factor in accounting for nonuniform vowel system differences, but at the same time having more wide-ranging implications for transitional phenomena and undershoot.


Oral and oropharyngeal cancer surgery with free-flap reconstruction in the elderly: Factors associated with long-term quality of life, patient needs and concerns. A GETTEC cross-sectional study.
To assess the factors associated with long-term quality of life (QoL) and patient concerns in elderly oral or oropharyngeal cancer (OOPC) patients after oncologic surgery and free-flap reconstruction. Patients aged over 70 years who were still alive and disease-free at least 1 year after surgery were enrolled in this cross-sectional multicentric study. Patients completed the EORTC QLQ-C30, -H&N35 and -ELD14 QoL questionnaires, and the Hospital Anxiety and Depression Scale (HADS). Patient needs were evaluated using the Patient Concerns Inventory (PCI). Factors associated with these clinical outcomes were determined in univariate and multivariate analysis. Sixty-four patients were included in this study. Long-term QoL, functioning scales and patient autonomy were well-preserved. Main persistent symptoms were fatigue, constipation and oral function-related disorders. Salivary and mastication/swallowing problems were the main patient concerns. The mean number of patient concerns increased with the deterioration of their QoL. Psychological distress (HADS score ≥ 15) and patient frailty (G8 score < 15) were significantly associated with poor QoL outcomes. We found a negative correlation between the number of patient concerns and QoL. Dental rehabilitation and psychological and nutritional supportive measures are of critical importance in the multidisciplinary management of elderly OOPC patients.


Intramedullary cavernoma: A surgical resection technique.
Intramedullary spinal cavernoma is a rare vascular disease constituting 5-12% of all spinal vascular tumors. The clinical course is usually characterized either by an acute neurological deterioration, recurrent episodes of neurological deficits or by a slowly progressive neurological decline. Microsurgical removal is recommended when the symptoms become clinically relevant and the lesion appears accessible. In this article, we present a surgical technique to completely resect an intramedullary cavernoma with the aid of intraoperative electrophysiological monitoring and intraoperative real-time ultrasound guidance. A brief description of current management of this pathology is also presented.


Dissipative particle dynamics for systems with high density of charges: Implementation of electrostatic interactions.
In this work, we study the question of how to introduce electrostatic interactions in dissipative particle dynamics (DPD) method in order to correctly reproduce the properties of systems with high density of charges, including those with inhomogeneous charge distribution. To this end, we formulate general requirements for the electrostatic force in DPD and propose a new functional form of the force which suits better for satisfying these requirements than the previously used ones. In order to verify the proposed model, we study the problem of a single polyelectrolyte chain collapse and compare the results with molecular dynamics (MD) simulations in which the exact Coulomb force is used. We show that an excellent quantitative agreement between MD and DPD models is observed if the length parameter D of the proposed electrostatic force is chosen properly; the recommendations concerning the choice of this parameter value are given based on the analysis of a polyelectrolyte chain collapse behavior. Finally, we demonstrate the applicability of DPD with the proposed electrostatic force to studying microphase separation phenomenon in polyelectrolyte melts and show that the same values of D as in the case of single chain collapse should be used, thus indicating universality of the model. Due to the charge correlation attraction, a long-range order in such melts can be observed even at zero Flory-Huggins parameter.


Fecal microbiome in dogs with inflammatory bowel disease and intestinal lymphoma.
Although alteration of commensal microbiota is associated with chronic gastrointestinal (GI) diseases such as inflammatory bowel disease (IBD) in dogs, the microbiota composition in intestinal lymphoma, an important differential diagnosis of canine IBD, has not been investigated. The objective of this study was to compare the fecal microbiota in dogs with IBD, dogs with intestinal lymphoma, and healthy dogs. Eight dogs with IBD, eight dogs with intestinal lymphoma, and fifteen healthy dogs were included in the study. Fecal samples were analyzed by 16S rRNA gene next-generation sequencing. Rarefaction analysis failed to reveal any difference in bacterial diversity among healthy dogs and diseased dogs. Based on PCoA plots of unweighted UniFrac distances, the bacterial composition in dogs with intestinal lymphoma was different from those observed in dogs with IBD and healthy dogs. When compared with healthy dogs, intestinal lymphoma subjects showed significant increases in organisms belonging to the Eubacteriaceae family. The proportion of the family Paraprevotellaceae and the genus Porphyromonas was significantly higher in dogs with IBD compared to healthy dogs. These observations suggest that dysbiosis is associated with intestinal lymphoma as well as IBD in dogs.


[Amoebic liver abscess: echographic aspects].
Amoebic liver abscess is the most frequent location of the extra-intestine amibiasis with an epidemio-endemic repartition in our areas. We are reporting in this study the main echographic patterns that can be found. 117 documents were collected and studied between 1982 and 1988 in the main hospitals of Dakar (SENEGAL). Most of the patients were young, the range of age being between 25 and 55 years old and 83% of them, were male. The diagnosis of the amoebic liver abscess was evocated on the basis of the following clinical and biological symptoms: 54.38% of painful haetomegaly, 42.10% of pleuro-pulmonary and digestive signs, 3.50% of long lasting isolated fever, non specific biological sign of inflammation, 74.57% of positive hemaglutination test. An echographic test was performed before the anti-parasitic treatment with an echotomograph PHILIPS SDR 1500 in real time using a probe of 3 MHZ. The amoebic abscess of liver was detected by the echography in all cases. The unique abscess (83.10%) was the most frequent form. It was localized in the right liver (64%) and had an heterogeneous echostructure (55.70%). The hypo-echogeneous form (36.50%) was the earlier stage of the collecting abscess. The liquid form (07.80%) was observed in the latter stages of the disease. Some difficulties to determine the amoebic abscess may appear when primitive liver cancer or pyogensus abscess are present. In these cases it is necessary to analyse the liquid of ponction to be affirmative.


Anticardiolipin antibodies (ACA) are most often not associated with lupus-like anticoagulant (LLAC) in human immunodeficiency virus (HIV) infection.
Anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LLAC) have been studied in a group of 142 non-hospitalized and a group of 72 hospitalized HIV infected patients. We observed a variable frequency of ACA positivity ranging from 7.7% to 30.3% according to the groups of patients and the isotype of immunoglobulin fraction containing ACA activity. None of the patients investigated presented a prolongation of the activated partial thromboplastin time (APTT) compatible with the presence of a LLAC. Some patients presented a weak anticoagulant activity only detected by the tissue thromboplastin inhibition (TTI) test. No positive correlation was found between this latter test and ACA. We conclude that, like in syphilitic patients, ACA present in HIV infected patients are most often not associated with LLAC.


The use of in vivo confocal microscopy in fungal keratitis - Progress and challenges.
Fungal keratitis (FK) is a serious and sight-threatening corneal infection with global reach. The need for prompt diagnosis is paramount, as a delay in initiation of treatment could lead to irreversible vision loss. Current "gold standard" diagnostic methods, namely corneal smear and culture, have limitations due to diagnostic insensitivity and their time-consuming nature. PCR is a newer, complementary method used in the diagnosis of fungal keratitis, whose results are also sample-dependent. In vivo confocal microscopy (IVCM) is a promising complementary diagnostic method of increasing importance as it allows non-invasive real-time direct visualization of potential fungal pathogens and manifesting infection directly in the patient's cornea. In numerous articles and case reports, FK diagnosis by IVCM has been evaluated, and different features, approaches, sensitivity/specificity, and limitations have been noted. Here, we provide an up-to-date, comprehensive review of the current literature and present the authors' combined recommendations for fungal identification in IVCM images, while also looking to the future of FK assessment by IVCM using artificial intelligence methods.


Biphasic developmental expression of adrenocorticotropin receptor messenger ribonucleic acid levels in the baboon fetal adrenal gland.
We have previously shown an estrogen-dependent developmental regulation of placental oxidation of cortisol to cortisone that results in enhanced fetal pituitary ACTH production and the induction of steroidogenic enzymes in and de novo cortisol production by the fetal adrenal in the second half of baboon pregnancy. However, it is not known whether the receptor for ACTH is simultaneously generated at this time in development to provide a mechanism for mediating the tropic action of ACTH on steroidogenesis in the primate fetal adrenal gland. Therefore, in the present study we determined the levels of ACTH receptor messenger RNA (mRNA) and correlated ACTH receptor expression with appearance of the mRNA for delta5-3beta-hydroxysteroid dehydrogenase/isomerase (3betaHSD), the enzyme protein that signals functional maturation of the definitive cortical zone in the baboon fetal adrenal. A baboon ACTH receptor complementary DNA was cloned and hybridized with polyadenylated RNA isolated from baboon (Papio anubis) fetal adrenals obtained in early (days 58-64; RNA from seven baboon fetuses pooled to yield three samples), mid-(days 99-103; RNA from five baboons pooled to yield four samples), and late (days 165-168; RNA of four individual baboon fetuses) gestation (term = 184 days). Expression of the primary 3.4-kilobase ACTH receptor mRNA transcript, determined by Northern blot and expressed as a ratio of beta-actin mRNA, was minimal early in gestation (mean +/- SE, 0.11 +/- 0.05 arbitrary densitometric units). However, fetal adrenal ACTH receptor mRNA levels increased (P < 0.001, by ANOVA) approximately 13-fold to 1.41 +/- 0.16 at midgestation, then declined by 70% (P < 0.001) to 0.41 +/- 0.10 in late gestation. To determine whether the decrease in ACTH receptor expression by the fetal adrenal in the second half of pregnancy reflected programmed cell death, the integrity of genomic DNA was assessed by 32P-labeled DNA gel electrophoresis and in situ DNA end labeling. Because DNA oligonucleosomes and apoptotic DNA strand breaks characteristic of apoptosis were absent in the adrenal glands of fetal baboons, the decline in ACTH receptor mRNA levels in the fetal adrenal did not seem to reflect programmed cell death. Expression of the single 2.0-kilobase mRNA transcript for 3betaHSD, an enzyme localized specifically in the definitive zone of the fetal adrenal, was minimal in early (0.01 +/- 0.00 arbitrary units) and mid- (0.10 +/- 0.01) gestation. However, 3betaHSD mRNA levels were markedly increased late in gestation to a value (1.38 =/- 0.34) approximately 13-fold greater (P < 0.001) than that in midgestation. These findings indicate that there was a biphasic monomodal developmental expression of the ACTH receptor in the baboon fetal adrenal, which contrasted with the progressive increase in adrenal weight, 3betaHSD expression, and de novo cortisol production previously determined. Because the fetal adrenal is comprised mainly of the fetal cortical zone throughout gestation, the decrease in ACTH receptor expression between mid- and late gestation seems to occur primarily in the latter zone and may signal a selective decline in tropic responsivity of and delta5-C19-steroid, e.g. dehydroepiandrosterone, biosynthesis within the baboon fetal adrenal gland.


Immunohistochemical characterization of "hyperplasia-adenoma sequence" in the pituitaries of transgenic mice expressing a human growth hormone-releasing factor gene.
The morphology of hyperplastic pituitaries in seven human growth hormone-releasing factor (hGRF) transgenic mice were compared to those of two normal control mice. Under continuous stimulation by hGRF, both the total volume of the pituitary and the size of individual cells increased, and a nodular lesion, designated a "hypertrophic nodule", was identified. Immunohistochemically, the hyperplastic pituitaries consisted of various numbers of cells immunoreactive for rGH, rPRL, hACTH, rLH beta, hFSH beta, and r alpha SU, whereas the "hypertrophic nodule" was composed of rGH, rPRL, and rTSH beta positive cells, similar to the adenoma. The presence of the "hypertrophic nodule", which was intermediate in appearance between the controls and the adenomas, suggests a close relation between continuous hGRF stimulation and the development of a hyperplasia-adenoma sequence in the pituitary.


The psychopathology of Gilles de la Tourette's syndrome. A controlled study.
The present study compares adults with Gilles de la Tourette's syndrome (GTS) with depressed adults and normal controls on questionnaires measuring obsessionality, depression, and anxiety. The GTS and depressed groups scored significantly higher than the normal controls on all measures. The GTS subjects had similar scores on measures of obsessionality to those of the depressed subjects, but significantly lower scores on measures of depression and anxiety. This suggests that obsessionality is a prominent feature of GTS, and that the psychopathological profile is different to that of patients with major depressive disorder.


Thyrotropin releasing hormone (TRH): its changes in discrete hypothalamic areas after treatment with triiodothyronine, thyroidectomy and acute cold exposure.
In order to elucidate the specific thyrotropic area in the hypothalamus, thyrotropin releasing hormone (TRH) content and concentration were measured in discrete hypothalamic nuclei and areas after triiodothyronine (T3) administration (T3 10 micrograms/rat/day for 6 days), thyroidectomy (TX) and acute cold exposure in male rats. In th TX and T3 groups, serum TSH levels were significantly increased in TX group and markedly decreased in T3 and TX with T3 groups as compared to the sham operated control group (Sham). TX produced a slight but nonsignificant decrease in TRH content in most of the hypothalamic nuclei examined as compared with the Sham group. However, a significant increase in TRH contents was seen in the anterior hypothalamic nucleus (AHN), median eminence (ME) and posterior pituitary (PP) in TX with T3 group as compared to the rats with only TX. In the acute cold stress experiments, serum TSH levels were elevated from 15 to 30 min of 4 degrees C exposure. Together with these peripheral changes, TRH content and concentration in the suprachiasmatic nucleus (SC) were increased significantly at 15 min and had returned to the normal level by 30 min after 4 degrees C cold exposure. However, in the paraventricular nucleus (PV) and dorsal premammillary nucleus (PMD), marked decrease in TRH concentrations were observed with this stress. Therefore, 1) decreased TSH release in TX rats treated with T3 was induced by the block of TRH release from the AHN and ME as compared with the TX group, and 2) elevated serum TSH levels in 4 degrees C cold stress might be induced by the release of TRH from the PMD and PV. These experiments demonstrate that the specific hypothalamic area for TSH release was located in some of the anterior and posterior hypothalamic nuclei and in the ME.


[Changing trends in illegitimate live births in the Czech Republic].
The authors analyze changes in the rate of illegitimate births in the Czech Republic. They find that "the slowly but fluently increasing percentage of illegitimate live births...is accompanied by a faster decline of infant mortality of these children compared to legitimate ones and by the same decline of the percentage of births having a low natality weight in both groups.... The differences of the percentage of illegitimate children born to mothers of various age groups were almost constant in the years 1974-1988, i.e. the number of illegitimate children delivered by mothers of different age, had grown approximately equally." (SUMMARY IN ENG AND RUS)


Cornell Thomson scattering system.
A Thomson scattering system has been designed and constructed for probing a relativistic electron beam heated plasma. Ruby laser light scattered through 90 degrees is resolved by a polychromator and detected by one of six photomultipliers. The system is capable of resolving electron temperatures of 150 eV at densities of n(e)<10(13) cm(-3) with a 4-J ruby laser and an f/9 throughput collection system. Scaling to a 10-J, f/5 system would allow resolving densities of approximately 10(12) cm(-3). System design, calibration, alignment, and data reduction are discussed. At elevated temperatures (T(e) approximately 600 eV) evidence of the relativistic blue shift was observed.


Masked Hypertension: Lessons for the Future.
Masked hypertension (MH) is a commonly overlooked phenotype of hypertension in practice. Lifestyle factors and conditioned stress response specific to out of clinic blood pressure readings may be the mechanisms leading to this phenomenon. 24-hour ambulatory blood pressure monitoring or home blood pressure monitoring in an out of office setting are required for its reliable diagnosis. MH has a high risk of progressing to sustained hypertension with comparable cardiovascular and mortality risk. In this review, we discuss current evidence-based perspectives on definition, pathological mechanisms, risk factors, screening, clinical implications, and treatment of MH.


Microfluidic assembly of lipid nanoparticles for delivery of antisense oligonucleotides.
Microfluidically (MF) synthesized lipid nanoparticles (LNPs) for antisense oligonucleotides (ODN) delivery have been shown to be superior to those prepared by bulk mixing (BM). In this study, a 5-inlet MF chip was used to synthesize LNPs loaded with LOR-2501, an antisense ODN targeting the ribonucleotide reductase R1 subunit. The size distribution of ODN- LNPs was measured by dynamic light scattering. The cytotoxicity of ODN- LNPs was determined by MTS assay. Gene silencing activity of ODN- LNPs was investigated by qRT-PCR and by Western blot. Results showed that MF synthesis produced ODN-LNPs that have lower average size and polydispersity values. The highest antisense activity was shown by LNs synthesized by the MF T2 chip, with downregulation of R1 mRNA by 32.5%. In conclusion, given their simplicity, affordability and reproducibility, MF is an attractive method for synthesis of LNs for ODN delivery.


Long-range surface plasmon resonance and surface-enhanced Raman scattering on X-shaped gold plasmonic nanohole arrays.
A multilayered architecture including a thin Au film supporting an X-shaped nanohole array and a thick continuous Au film separated by a Cytop dielectric layer is reported in this work. Long-range surface plasmon resonance (LR-SPR) was generated at the top Au/water interface, which also resulted in a long-range surface-enhanced Raman scattering (LR-SERS) effect. LR-SPR originates from the coupling of surface plasmons (SPs) propagating along the opposite sides of the thin Au film embedded in a symmetric refractive index environment with Cytop (n = 1.34) and water (n = 1.33). The finite-difference time-domain (FDTD) simulation method was used to investigate the optimal dimensions of the substrate by studying the reflectance spectra and electric field profiles. The calculated optimal structure was then fabricated via electron beam lithography, and its LR-SERS performance was demonstrated by detecting rhodamine 6G and 4-mercaptobenzoic acid in the refractive index-matched environment. We believe that this structure as a LR-SPR or LR-SERS substrate can have broad applications in biosensing.


Short- and long-latency contributions to reciprocal inhibition during various levels of muscle contraction of individuals with cerebral palsy.
Deficits in reciprocal inhibition likely contribute to excessive antagonist muscle cocontraction during voluntary movements of individuals with cerebral palsy. This study examined neural contributions to reciprocal inhibition of the soleus motoneurons of individuals with spastic, diplegic cerebral palsy and nondisabled individuals during various levels of voluntary tibialis anterior contraction. A condition-test H-reflex paradigm examined short- and long-latency contributions to reciprocal inhibition of soleus neural pools during changing levels of voluntary tibialis anterior contraction. Electrically induced short- and long-latency inhibition was similar between healthy, neurologically intact control subjects and subjects with cerebral palsy during rest. With increasing levels of tibialis anterior contraction, control subjects experienced increasing levels of soleus motoneuron inhibition, especially of long-latency inhibitory responses. In contrast, there was no evidence of modulation of short- or long-latency inhibition with increasing levels of tibialis anterior contraction among subjects with cerebral palsy. Deficits in long-latency (presynaptic) inhibition appear to contribute prominently to voluntary movement impairment of individuals with cerebral palsy.


Training Medical Students to Create and Collaboratively Review Multiple-Choice Questions: A Comprehensive Workshop.
Multiple-choice question (MCQ) creation is an infrequently used active-learning strategy. Previous studies demonstrated that medical students find value in the process, but have minimal training, which may limit potential learning benefits. We therefore developed a process for question-creation that required students to complete in-depth training, in addition to collaborative question-writing and editing. We created a question-writing workshop consisting of three components: (1) training in MCQ writing utilizing NBME online modules, a practice MCQ-writing session, and a training session, (2) writing MCQs independently after choosing topics from an institutionally generated blueprint, and (3) reviewing and editing MCQs via an in-person session. To understand students' perceptions, we held two four-student focus groups and recorded/transcribed the data. We iteratively reviewed the transcripts to generate a codebook and corresponding themes. We used the focus group data to generate a survey with Likert-scale questions, which we sent to the remaining 10 students and analyzed using Microsoft Excel. Eighteen second-year medical students participated in this workshop. Students perceived that question-writing training (3.7/5.0±0.5) and question writing (3.9/5.0±0.3) benefitted their learning. Students perceived that MCQ writing required concept integration (4.1/5.0±0.6). Students described how question writing allowed them to recognize subtle distinctions between therapies and diagnoses. Each MCQ required about 1.5 hours to write and collaboratively edit. Our results demonstrated that students perceived question writing to benefit their learning. More importantly, students felt that question writing actively engaged them to integrate content and compare concepts; students' engagement suggests that they learned from this question-writing activity.


Prediction of extra virgin olive oil varieties through their phenolic profile. Potential cytotoxic activity against human breast cancer cells.
The aim of this work was to develop a rapid resolution liquid chromatography coupled to electrospray ionization time-of-flight mass spectrometry (RRLC-ESI-TOF-MS) method followed by tetrazolium salt (MTT)-based cell viability assays for qualitative and quantitative classification of extra virgin olive oil (EVOO) varieties by phenolic and other polar compound contents as well as for rapid characterization of putative cytotoxic activities against human cancer cells. Five different Spanish EVOO varieties were analyzed, and RRLC-ESI-TOF-MS method was applied for qualitative and quantitative identification of most important phenolic compounds. We finally employed MTT-based cell viability protocol to assess the effects of crude EVOO phenolic extracts (PEs) on the metabolic status of cultured SKBR3 human breast cancer cells. MTT-based cell viability assays revealed a wide range of breast cancer cytotoxic potencies among individual crude PE obtained from EVOO monovarietals. Remarkably, breast cancer cell sensitivity to crude EVOO-PEs was up to 12 times higher in secoiridoids enriched-PE than in secoiridoids-low/null EVOO-PE.


A dual protease approach for expression and affinity purification of recombinant proteins.
We describe a new method for affinity purification of recombinant proteins using a dual protease protocol. Escherichia coli maltose binding protein (MBP) is employed as an N-terminal tag to increase the yield and solubility of its fusion partners. The MBP moiety is then removed by rhinovirus 3C protease, prior to purification, to yield an N-terminally His6-tagged protein. Proteins that are only temporarily rendered soluble by fusing them to MBP are readily identified at this stage because they will precipitate after the MBP tag is removed by 3C protease. The remaining soluble His6-tagged protein, if any, is subsequently purified by immobilized metal affinity chromatography (IMAC). Finally, the N-terminal His6 tag is removed by His6-tagged tobacco etch virus (TEV) protease to yield the native recombinant protein, and the His6-tagged contaminants are removed by adsorption during a second round of IMAC, leaving only the untagged recombinant protein in the column effluent. The generic strategy described here saves time and effort by removing insoluble aggregates at an early stage in the process while also reducing the tendency of MBP to "stick" to its fusion partners during affinity purification.


[External trabecular excision--alternative to filtering glaucoma operation in patients with open angle glaucoma].
Postoperative complications concerning glaucoma filtering surgery (trabeculectomy, goniotrepanation) often include hypotonia that may lead to athalamia or choroidal detachment, which are difficult to handle. Cystic non filtering blebs are due to postinflammatory reactions, and may limit the success of filtering surgery. Aim of the study was to compare the success and the complications of a new operating technique, which will be described, with those of usual glaucoma filtering surgery. In 24 open angle glaucoma patients with mean intraocular pressure of 28.12 mm Hg (+/- 8.6) we performed external trabecular excision in 25 eyes since June 1997. Preoperative visual acuity and peak intraocular pressure were compared retrospectively in all eyes with the values of the first postoperative day, in 22 eyes after one month and in 17 eyes after 3 months. Intraocular pressure measured between 0 mm Hg and 16 mm Hg on the first postoperative day (7.64 mm Hg +/- 4.3), after one month between 10 mm Hg and 30 mm Hg (17.81 mm Hg +/- 5.5) and after 3 months between 9 mm Hg and 26 mm Hg (15.29 mm Hg +/- 4.2). After 1 month 10 of 22 (45%) and after 3 months 7 of 17 eyes (42%) required antiglaucomatous drugs; 3 eyes needed gonitrepanation (2 weeks, 1 month, 3 months after ETE). Concerning postoperative complications, we observed 6 choroidal detachments, once erythrocoytes in the anterior chamber, twice hyphemata, twice inflammatory reaction in the anterior chamber, two flat anterior chambers and twice a positive seidel test. Complications after ETE are similar to those after filtering surgery. Postoperative intraocular pressure dip after ETE in most eyes was not as pronounced as after goniotrepanation or trabeculectomy, and postoperative complications were all reversible. 45% of the eyes again needed antiglaucomatous drugs after one month and 42% after 3 months. A prospective long-term study has to verify the success respectively the complications of ETE.


Robustness portraits of diverse biological networks conserved despite order-of-magnitude parameter uncertainty.
Biological networks are robust to a wide variety of internal and external perturbations, yet fragile or sensitive to a small minority of perturbations. Due to this rare sensitivity of networks to certain perturbations, it is unclear how precisely biochemical parameters must be experimentally measured in order to accurately predict network function. Here, we examined a model of cardiac β-adrenergic signaling and found that its robustness portrait, a global measure of steady-state network function, was well conserved even when all parameters were rounded to their nearest 1-2 orders of magnitude. In contrast, β-adrenergic network kinetics were more sensitive to parameter precision. This analysis was then extended to 10 additional networks, including Escherichia coli chemotaxis, stem cell differentiation and cytokine signaling, of which nine exhibited conserved robustness portraits despite the order-of-magnitude approximation of their biochemical parameters. Thus, both fragile and robust aspects of diverse biological networks are largely shaped by network topology and can be predicted despite order-of-magnitude uncertainty in biochemical parameters. These findings suggest an iterative strategy where order-of-magnitude models are used to prioritize experiments toward the fragile network elements that require precise measurements, efficiently driving model revision. email@example.com Supplementary data are available at Bioinformatics online.


[Effect of indomethacin and ibuprofen on blood pressure of patients treated with nifedipine or captopril].
Non-steroidal anti-inflammatory agents may moderately increase blood pressure thus affecting hypotensive agents effectiveness. This study aimed at evaluating arterial blood pressure, serum 6-keto-PGF1 and aldosterone as well as plasma renin activity in hypertensive patients treated with indomethacin or ibuprofen with captopril or indomethacin or ibuprofen with nifedipine. Captopril given at the same time as indomethacin or ibuprofen did not decrease both systolic and diastolic blood pressures. However, no interaction between nifedipine administered simultaneously with indomethacin or ibuprofen was noted. Serum 6-keto-PGF1 and aldosterone as well as plasma renin activity were decreased in both groups of treated patients. Mechanism of indomethacin and ibuprofen hypertensive action seems to se related with their ability to inhibit prostacyclin biosynthesis.


Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases.
Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here.


[Diverticular disease of colon].
Diverticular disease of the colon is one from the most common diseases, especially in the Western world. This disease is symptomatic in only 20-30% patients, but it could be the cause of considerable morbidity and mortality. Pathogenesis is not entirely known. Presumably there are more causing factors - intestinal dysmotility, that is induced by abnormal regulation, structural changes of the colonic wall, genetic factors, diet. The aim of this article is to review the state of our nowadays knowledge in pathogenesis, symptomatology, diagnostic methods and treatment.


Isolation and Partial Purification of Prophenoloxidase from Daucus carota L. Cell Cultures.
The enzyme, phenoloxidase, was isolated and partially purified as an inactive enzyme, a proenzyme, from plant cell cultures of Daucus carota, Nicotiana tabacum, and Haplopappus gracilis. The prophenoloxidase was found to be specifically activated by Ca(2+) or Mn(2+) ions in concentrations above 1 millimolar. Calmodulin was not involved in this activation. Concentrations of Ca(2+) or Mn(2+) below 1 millimolar could not induce activation of the prophenoloxidase, but if trypsin was added simultaneously with Ca(2+) or Mn(2+) at a concentration of 1 millimolar or below, the proenzyme was converted to its active form. The inactive form of phenoloxidase was found to be a soluble enzyme, whereas after activation the enzyme aggregated, and a significant amount of the enzyme activity could become pelleted.


Evaluation of a U.S. National Cohort to Determine Utilization in Colectomy Rates for Ulcerative Colitis Among Ethnicities.
Colectomy is the curative management for ulcerative colitis (UC). Multiple studies have reported racial disparities for colectomy before the advent of anti-TNF alpha agents. The aim of this study was to describe racial and geographic differences in colectomy rates among hospitalized patients with UC after anti-TNF therapy was introduced. We examined all patients discharged from the hospital between 2010 and 2014 with a primary diagnosis of UC or of complications of UC. The data were evaluated for race and colectomy rates among the hospitalized patients with UC. The unadjusted national colectomy rate among hospitalized patients with UC between 2010 and 2014 was 3.90 per 1000 hospitalization days (95% confidence interval, 3.72-4.08). The undajusted colectomy rates in African American (2.33 vs 4.35; P < 0.001) and Hispanic patients (3.99 vs 4.35; P ≤ 0.009) were considerably lower than those for White patients. After adjustment for confounders, the incidence rate ratio for African American as compared to White patients was 0.43 (95% confidence interval, 0.32-0.58; P < 0.001). Geographic region of the United States also showed significant variation in colectomy rates, with western regions having the highest rate (4.76 vs 3.20; P < 0.001). Racial and geographical disparities persist for the rate of colectomy among hospitalized patients with UC. The national database analysis reveals that colectomy rates for hospitalized African American and Hispanic patients were lower than those for White patients. Further studies are important to determine the social and biologic foundations of these disparities.


Procedural Pain Assessment in Infants Without Analgosedation: Comparison of Newborn Infant Parasympathetic Evaluation and Skin Conductance Activity - A Pilot Study.
Objective: New technologies to measure pain responses, such as heart rate variability and skin conductance hold promise in the development of tools that can be reliable and quantifiable of detecting pain. The main objective of this study was to assess the capability of two monitors i.e., Newborn Infant Parasympathetic Evaluation (NIPE) and Skin Conductance Algesimeter for detecting procedural pain in non-anesthetized infants. Materials and Methods: Thirty-three non-anesthetized infants were enrolled to the study. To detect pain caused by heel stick, NIPE, and Skin Conductance monitors and behavioral pain scales were used. Three minutes before and just after heel stick, pain was evaluated by behavioral scales, and simultaneously over the whole period by NIPE and SCA. Results: A statistically significant decrease of NIPE Index and an increase of SCA values were found after the HS procedure. There were no statistically significant differences between the decrease in NIPEi values and the increase in PPS values between subgroups based on pain assessment by behavioral-scale scores. Conclusion: Both NIPE and SCA can be useful for detection of procedural pain and may constitue an additional valuable tool for better handling of pain among patients treated in NICUs. More studies on larger groups of patients are needed.


Rebuilt 3D structure of the chloroplast f1 ATPase-tentoxin complex.
The F1 part of the chloroplast H+ adenosine triphosphate (ATP)-synthase (CF1) strongly interacts with tentoxin, a natural fungous cyclic tetrapeptide known to inhibit the chloroplast enzyme and not the mammalian mitochondrial enzyme. Whereas the synthesis or the hydrolysis of ATP requires the stepwise rotation of the protein rotor gamma within the (alphabeta)3 crown, only one molecule of tentoxin is needed to fully inhibit the complex. With the help of an original homology modeling technique, based on robust distance geometry protocols, we built a tridimensional model of the alpha3beta3gamma CF1) subcomplex (3200 esidues), in which we introduced three different nucleotide occupancies to check their possible influence on the tentoxin binding site. Simultaneous comparison of three available high-resolution X-ray structures of F1, performed with a local structural alignment search tool, led to characterizing common structural blocks and the distorsions experienced by the complex during the catalytic turnover. The common structural blocks were used as a starting point of the spinach CF1 structure rebuilding. Finally, tentoxin was docked into its putative binding site of the reconstructed structure. The docking method was initially validated in the mitochondrial enzyme by its ability to relocate nucleotides into their original position in the crystal. Tentoxin binding was found possible to the two alpha/beta interfaces associated with the empty and adenosine diphosphate (ADP)-loaded catalytic sites, but not to the one associated with the ATP-loaded site. These results suggest a mechanism of CF1 inhibition by one molecule of tentoxin, by the impossibility of the alpha/beta interface bearing tentoxin to pass through the ATP-loaded state.


Variation in Amygdalin Content in Kernels of Six Almond Species (Prunus spp. L.) Distributed in China.
Amygdalin, a naturally occurring compound, is one of the main active ingredients of the Chinese raw bitter almond. The variation in amygdalin composition of seed kernels among the six almond species was determined, and relationships with geoenvironmental factors were analyzed. The amygdalin content exhibited great diversity, ranging from 0.0004 to 9.73 g/100 g. The highest level of amygdalin was detected in Tangut almond, with 5.45-9.73 g/100 g. The other kernels showed a range from 3.14 to 6.80 g/100 g in wild almond and from 3.00 to 4.22 g/100 g in longstalk almond. Amygdalin in common almond was almost undetectable. Factor analysis showed that amygdalin content in Prunus spp. kernels increased with altitude and decreased with the degree of aspect. Many environmental factors were closely related to amygdalin content, including annual precipitation (Bio12), UV intensity, and topsoil base saturation (T_BS), which all had a significant effect on amygdalin content. The amygdalin content is closely related to rainfall indicators, especially annual precipitation (Bio12), with the highest factor analysis value (3.63). Water regulates amygdalin in diverse ways. Since amygdalin is water-soluble, water can reduce the inhibitory effect of amygdalin on germination and regulate the synthesis of amygdalin at the late stage of germination by activating the amygdalin synthesis genes CYP79D16 and CYP71AN24. This study expands the understanding of amygdalin in almond resources and provides the direction for the regulation of amygdalin.


Effect of betel quid on catecholamine secretion from adrenal chromaffin cells.
Health damage and environmental pollution are serious problems caused by betel quid chewing in Taiwan. Many people acquire the habit of chewing betel quid due to its physiological effects, including increased stamina and a general feeling of well-being. In this study, a sympathetic model system of adrenal chromaffin cells and sensory evaluation were used to examine the physiological effects of betel quid and the interaction of all the ingredients (areca fruit, Piper betle inflorescence and red time paste) in betel quid. Physiological effects of cardioacceleration, a slightly drunk feeling, sweating and salivation occurred during the chewing of betel quid (a mixture of areca fruit, Piper betle inflorescence and red lime paste) and a mixture of areca fruit and red lime paste. Both induced much more basal catecholamine secretion from adrenal chromaffin cells than did other ingredients and combinations of ingredients. It was evident that the responses in the sympathetic model system were closely correlated with the physiological feeling of well-being. The inhibitory effects of all the chewing juices on catecholamine secretion evoked by carbachol and a high concentration of potassium (high K+) showed that they perhaps affected the calcium influx through voltage-sensitive channels or the steps involved in secretion after calcium entry to stimulate basal catecholamine secretion from chromaffin cells.


[The role of small bowel microflora in the development of secondary lactase deficiency and the possibilities of its treatment with probiotics].
To estimate the incidence of secondary lactase deficiency (SLD) in patients with postinfectious irritable bowel syndrome (PIBS) and the value of the small bowel microflora in its development and to elaborate treatment options for SLD. One hundred and thirty-eight patients with PIBS, including 112 (81.2%) women and 26 (18.8%) men, were examined. The patients' mean age was 33.9 +/- 9.1 years. The duration of the disease was 2.6 +/- 1.4 years. Lactase deficiency (LD) was diagnosed using the color scale to test biopsy specimens from the duodenal retrobulbar region. The bacterial overgrowth syndrome (BOS) was identified by a 2-hour lactulose (20 ml) hydrogen breath test. Sixty patients with moderate SLD were randomized to 2 groups: 1) 41 patients received basic therapy (mesim forte as one tablet t.i.d., no-spa, 40 mg, t.i.d.) and combined probiotic bifiform (Ferrosan) containing Bifidobacterium longum 107, Enterococcus faecium 107 as one capsule t.i.d. for 14 days. Group 2 patients (n = 19) had basic therapy in combination with placebo. SLD was detected in 59.4% of the patients with PIBS, including 43.5 and 15.9% with moderate and severe forms, respectively. In all cases, SLD was accompanied by BOS in the small bowel lumen, as confirmed by the results of a hydrogen breath test [101 +/- 37 ppm (a normal value of < 20 ppm)]. After a 14-day course of therapy with the combined probiotic bifiform, restoration of eubiosis in the small bowel lumen was achieved in 70.8% of the patients, as shown by the lesser degree of BOS (86.9 +/- 40.9 and 17.4 +/- 6.6 ppm before and after treatment, respectively; p < 0.01) and by normalization of the lactase test (p < 0.01). In the comparative placebo group, 68.4% showed no clear positive changes, SLD and BOS remained. The changes in the small bowel intraluminal microflora, which developed after prior intestinal infection, played a great role in the development of SLD. Bifiform belongs to the currently available probiotics and may be recommended to correct SLD in patients with PIBS resulting from the impaired microbiota of the small bowel and to prevent BOS.


Genetic diversity and structure of Sinopodophyllum hexandrum (Royle) Ying in the Qinling Mountains, China.
Sinopodophyllum hexandrum is an important medicinal plant whose genetic diversity must be conserved because it is endangered. The Qinling Mts. are a S. hexandrum distribution area that has unique environmental features that highly affect the evolution of the species. To provide the reference data for evolutionary and conservation studies, the genetic diversity and population structure of S. hexandrum in its overall natural distribution areas in the Qinling Mts. were investigated through inter-simple sequence repeats analysis of 32 natural populations. The 11 selected primers generated a total of 135 polymorphic bands. S. hexandrum genetic diversity was low within populations (average He = 0.0621), but higher at the species level (He = 0.1434). Clear structure and high genetic differentiation among populations were detected by using the unweighted pair group method for arithmetic averages, principle coordinate analysis and Bayesian clustering. The clustering approaches supported a division of the 32 populations into three major groups, for which analysis of molecular variance confirmed significant variation (63.27%) among populations. The genetic differentiation may have been attributed to the limited gene flow (Nm = 0.3587) in the species. Isolation by distance among populations was determined by comparing genetic distance versus geographic distance by using the Mantel test. Result was insignificant (r = 0.212, P = 0.287) at 0.05, showing that their spatial pattern and geographic locations are not correlated. Given the low within-population genetic diversity, high differentiation among populations and the increasing anthropogenic pressure on the species, in situ conservation measures were recommended to preserve S. hexandrum in Qinling Mts., and other populations must be sampled to retain as much genetic diversity of the species to achieve ex situ preservation as a supplement to in situ conservation.


Suicidal behaviour among adults in Cabo Verde in 2020.
The aim of the investigation was to evaluate past 12-month suicidal behaviour (PSB) among adults in Cabo Verde. Data from 4,563 adults (mean age 41.4 years) that participated in the 2020 Cabo Verde STEPS survey were analysed. Results indicate that the proportion of PSB (attempt 0.6%, plan 1.5% and ideation 3.3%) was 3.7% (2.4% men/5.0% women). In adjusted logistic regression analysis, younger age, female sex, unemployed, widowed or divorced, alcohol family problem, heart attack, angina or stroke, current smokeless tobacco use and low fruit/vegetable intake were associated with PSB. Almost 4% of participants had PSB and several associated factors were identified that can guide public health interventions.


Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations.
Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.


Chronic Inflammation-Related HPV: A Driving Force Speeds Oropharyngeal Carcinogenesis.
Oropharyngeal squamous cell carcinoma (OPSCC) has been known to be a highly aggressive disease associated with human papilloma virus (HPV) infection. To investigate the relationship between HPV and chronic inflammation in oropharyngeal carcinogenesis, we collected 140 oral mucous fresh specimens including 50 OPSCC patients, 50 cancer in situ, 30 precancerous lesions, and 10 normal oral mucous. Our data demonstrated that there was a significantly higher proportion of severe chronic inflammation in dysplastic epithelia in comparison with that in normal tissues (P<0.001). The positive rate of HPV 16 was parallel with the chronic inflammation degrees from mild to severe inflammation (P<0.05). The positive rate of HPV 16 was progressively improved with the malignant progression of oral mucous (P<0.05). In addition, CD11b+ LIN- HLA-DR-CD33+ MDSCs were a critical cell population that mediates inflammation response and immune suppression in HPV-positive OPSCC. These indicated that persistent chronic inflammation-related HPV infection might drive oropharyngeal carcinogenesis and MDSCs might pay an important role during this process. Thus, a combination of HPV infection and inflammation expression might become a helpful biomedical marker to predict oropharyngeal carcinogenesis.


Statins for the prevention of perioperative cardiovascular complications in vascular surgery.
Perioperative cardiovascular complications in vascular surgery remain a significant problem despite recent advancements in perioperative care. This clinical update summarizes the results of recent studies on the effectiveness and safety of perioperative statin use for the prevention of these perioperative cardiovascular complications. Five studies in patients undergoing major noncardiac vascular surgery and two studies in patients undergoing carotid endarterectomy are described. All studies reported a significant reduction in perioperative cardiovascular events in statin users compared with nonusers. The safety of perioperative statin use has not yet been fully elaborated, although current evidence suggests there is no extra risk from statin-induced side effects in the perioperative period.


The role of p38 mitogen-activated protein kinase in IL-6 and IL-8 production from the TNF-alpha- or IL-1beta-stimulated rheumatoid synovial fibroblasts.
We examined the role of p38 mitogen-activated protein (MAP) kinase in the tumor necrosis factor alpha (TNF-alpha)- or interleukin-1beta (IL-1beta)-induced production of interleukin-6 (IL-6) and interleukin-8 (IL-8) in fresh rheumatoid synovial fibroblast (RSF) cultures concomitantly with the induction of p38 MAP kinase activity. Pretreatment of RSF with a specific p38 MAP kinase inhibitor, SB203580, blocked the induction of IL-6 and IL-8 without affecting nuclear translocation of nuclear factor kappaB (NF-kappaB) or IL-6 and IL-8 mRNA levels. These findings suggest that p38 MAP kinase inhibitor may have synergistic, rather than additive, effect for the treatment of rheumatoid arthritis.


The effects of nebulized ketamine and intravenous magnesium sulfate on corticosteroid resistant asthma exacerbation; a randomized clinical trial.
Asthma exacerbation is defined as an acute attack of shortness of breath with more than 25% decrease in morning peak flow compared to the baseline on 2 consecutive days, which requires immediate standard therapy. The majority of asthmatic patients are considered to be steroid-sensitive; however, corticosteroid-resistant asthma is a subset of asthma with poor response to corticosteroids and is responsible for frequent hospital admissions. In this study we aimed to compare the effects of two enhancing strategies, the nebulized ketamine and IV magnesium sulfate, in treatment of severe steroid resistant asthma. This double-blind randomized clinical trial was conducted on patients who presented to a referral clinic in Alborz, Iran. Using random allocation, patients were divided into two groups. The first group was treated with nebulized ketamine and the second group was treated with intravenous magnesium sulfate. Peak expiratory flow rates were assessed before the intervention, 30 and 60 min after the intervention and compared with the aid of SPSS software. The Peak expiratory flow rates before the intervention, 30 min and 60 min after the intervention was statistically significantly different in both ketamine and magnesium sulfate groups. Peak expiratory flow rates change between 0 and 60 min were 29.4 and 15.2% in the ketamine and magnesium sulfate group respectively. Although the ketamine group showed much higher increase in mean PEFR compared to the MgSO4 groups, there was no statistically significant difference across both groups. Our study concluded that combined with standard therapy, both ketamine and IV magnesium sulfate are effective agents in the improvement of PEFR in patients with acute severe asthma that failed to respond to traditional therapies. However, there were no statistically significant difference between the two groups.


Nuclear chromatin variations in human spermatozoa undergoing swim-up and cryopreservation evaluated by the flow cytometric sperm chromatin structure assay.
The sperm chromatin structure assay (SCSA) is a flow cytometric (FCM) technique which exploits the metachromatic properties of Acridine Orange to monitor the susceptibility of sperm chromatin DNA to in-situ acid denaturation. SCSA was used to study the chromatin structure variations of human spermatozoa in semen, both before and after swim-up and after cryopreservation. Semen samples were provided by 19 healthy normozoospermic subjects attending pre-marriage checks. Each sample was divided into three aliquots: the first aliquot was evaluated without further treatment, the second underwent swim-up, and the third was stored according to standard cryopreservation techniques in liquid nitrogen at -196 degrees C. Samples were also analysed by light and fluorescence microscopy (after Acridine Orange staining to evaluate the number of green fluorescent sperm heads), and by computer-assisted semen analysis. The results showed that post-rise spermatozoa represent a subpopulation characterized by a general improvement of the morphological (reduction of the percentage of abnormal forms and heads, increase of the green head sperm percentage) and kinetic parameters. This subpopulation also exhibited improved chromatin structure properties, confirming that these cells have the best structural and functional characteristics, indicative of optimal fertilizing ability. On the other hand, overall sperm quality deteriorates after cryopreservation. When thawed spermatozoa underwent an additional swim-up round, a general improvement of nuclear maturity was seen in the post-rise spermatozoa.


Manipulating the genetic identity and biochemical surface properties of individual cells with electric-field-induced fusion.
A method for cell-cell and cell-liposome fusion at the single-cell level is described. Individual cells or liposomes were first selected and manipulated either by optical trapping or by adhesion to a micromanipulator-controlled ultramicroelectrode. Spatially selective fusion of the cell-cell or cell-liposome pair was achieved by the application of a highly focused electric field through a pair of 5-micrometer o.d. carbon-fiber ultramicroelectrodes. The ability to fuse together single cells opens new possibilities in the manipulation of the genetic and cellular makeup of individual cells in a controlled manner. In the study of cellular networks, for example, the alteration of the biochemical identity of a selected cell can have a profound effect on the behavior of the entire network. Fusion of a single liposome with a target cell allows the introduction of the liposomal content into the cell interior as well as the addition of lipids and membrane proteins onto the cell surface. This cell-liposome fusion represents an approach to the manipulation of the cytoplasmic contents and surface properties of single cells. As an example, we have introduced a membrane protein (gamma-glutamyltransferase) reconstituted in liposomes into the cell plasma membrane.


Efficacy and safety of dihydroartemisinin-piperaquine (Artekin) in Cambodian children and adults with uncomplicated falciparum malaria.
The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children.


Organ Culture System for Assessing the Toxicity of Intraocular Treatment Excipients and Pharmaceuticals.
As the leading cause of blindness, cataracts are a significant burden for the tens of millions of people affected globally by this condition. Chemical exposures, among other environmental factors, are an established cause of cataracts. Ocular toxicity testing can assess whether pharmaceuticals and their components may contribute to lens damage that may lead to cataracts or aid the treatment of cataracts. In vitro studies and in vivo animal testing can be used for assessing the safety of chemicals prior to clinical studies. The Draize test-the current in vivo standard for ocular toxicity and irritancy testing-has been criticized for lack of sensitivity and objective measurements of determining ocular toxicity. In vitro cell-based assays are limited as cell cultures cannot appropriately model an intact functional lens. The method described here is a sensitive in vitro alternative to animal testing, designed to evaluate the response of the intact bovine lens to treatment at both the cellular activity level and for overall refractive performance. The non-toxic reagent resazurin is metabolized in proportion to the level of cell activity. The lens laser-scanner assay measures the ability of the lens to refract incident beams of light to a single point with minimal error, directly relevant to its natural function. The method may be used to determine both acute and delayed changes in the lens, as well as the recovery of the lens from chemical or environmental exposures.


[Differentiated thyroid cancers. 20 years' results of a protocol based on simple prognostic criteria].
To study the long-term results of an aggressive management protocol based on a new-simple classification and to determine the duration for patient follow-up according to this classification. For the 509 patients with differentiated thyroid carcinoma, the classification was: group 1: cancer < 1 cm (n = 117), group 2A: cancer without extension in patients of age less than 45 years (n = 100), group 2B: cancer without extension in patients aged more than 45 (n = 94), group 3: cancer with nodal extension alone (n = 102), group 4: high risk cancer in patients having either distant metastases or local tissular extension or in whom after iodine-131 ablation, Tg level was > 3 micrograms/l off hormone therapy (n = 96). Total thyroidectomy was the rule except for group 1 and some patients of group 2A in whom the tumor was solitary, relatively small, well-differentiated, with no capsular or capillary invasion. Iodine 131 ablation was carried out after a total thyroidectomy and repeat treatments with iodine 131 were given whenever necessary. In group 1, 2A and 3, the 20 years death rate of cancer was 0 p. 100. For group 2B, patients cancer death rate was 8 p. 100 and for group 4 it was 32 p. 100. Distant metastases were the cause of death except for one patient who died from local recurrence. Clinical inspection, Tg measurement, iodine 131 whole-body scan and chest X-ray were all useful in discovering local or distant recurrences. Our results justify the use of an aggressive initial management for differentiated thyroid carcinoma and an appropriate scoring system. When this protocol is applied, patients of group 1, 2 and 3 should have an excellent prognosis. However patients follow-up should not be shorter than 15 years for patients of group 1 and 2A and than 20 years for all other groups.


Changes and challenges.
Although I have discussed the challenges associated with establishing this role, on reflection I think this is possibly one of the best jobs in midwifery today. The diversity experienced through the post is amazing and the ability to work clinically, while having a leadership role that impacts on the service, research and education agendas, is both powerful and unique. I hope this has given you some insight into my post and demonstrated how innovative and exciting the consultant role actually is. I believe these posts have real potential to influence our profession and the service we provide for women and families and hope this is evident. However, none of this can be achieved without networking and having the support of a range of people across a variety of organisations.


Arachidonate initiated protein kinase C activation regulates HeLa cell spreading on a gelatin substrate by inducing F-actin formation and exocytotic upregulation of beta 1 integrin.
HeLa cell spreading on a gelatin substrate requires the activation of protein kinase C (PKC), which occurs as a result of cell-attachment-induced activation of phospholipase A2 (PLA2) to produce arachidonic acid (AA) and metabolism of AA by lipoxyginase (LOX). The present study examines how PKC activation affects the actin- and microtubule-based cytoskeletal machinery to facilitate HeLa cell spreading on gelatin. Cell spreading on gelatin is contingent on PKC induction of both actin polymerization and microtubule-facilitated exocytosis, which is based on the following observations. There is an increase in the relative content of filamentous (F)-actin during HeLa cell spreading, and treating HeLa cells with PKC-activating phorbol esters such as 12-O-tetradecanoyl phorbol 13-acetate (TPA) further increases the relative content of F-actin and the rate and extent to which the cells spread. Conversely, inhibition of PKC by calphostin C blocked both cell spreading and the increase of F-actin content. The increased F-actin content induced by PKC activators also was observed in suspension cells treated with TPA, and the kinetics of F-actin were similar to that for PKC activation. In addition, PKC epsilon, which is the PKC isoform most involved in regulating HeLa cell spreading in response to AA production, is more rapidly translocated to the membrane in response to TPA treatment than is the increase in F-actin. Blocking the activities of either PLA2 or LOX inhibited F-actin formation and cell spreading, both of which were reversed by TPA treatment. This result is consistent with AA and a LOX metabolite of AA as being upstream second messengers of activation of PKC and its regulation of F-actin formation and cell spreading. PKC appears to activate actin polymerization in the entire body of the cell and not just in the region of cell-substrate adhesion because activated PKC was associated not only with the basolateral plasma membrane domain contacting the culture dish but also with the apical plasma membrane domain exposed to the culture medium and with an intracellular membrane fraction. In addition to the facilitation of F-actin formation, activation of PKC induces the exocytotic upregulation of beta 1 integrins from an intracellular domain to the cell surface, possibly in a microtubule-dependent manner because the upregulation is inhibited by Nocodazole. The results support the concept that cell-attachment-induced AA production and its metabolism by LOX results in the activation of PKC, which has a dual role in regulating the cytoskeletal machinery during HeLa cell spreading. One is through the formation of F-actin that induces the structural reorganization of the cells from round to spread, and the other is the exocytotic upregulation of collagen receptors to the cell surface to enhance cell spreading.


Grasping psychoanalysts' practice in its own merits.
The central objective of this presentation is to reflect on the obstacles involved in the task proposed by the Chicago Congress, which is to explore convergences and divergences in psychoanalytic practice. The author discusses two major obstacles. First, the epistemological and methodological problems in relation to the construction of theory in psychoanalysis and especially the inaccessibility, in any reliable way, of what psychoanalysts really do in the intimacy of their practice. He proposes to separate, at least in part, theory from practice in psychoanalysis, in an attempt to grasp psychoanalysts' practice in its own merits. He then outlines a phenomenology of the practice of psychoanalysis, which reveals that, in their work with patients, analysts are guided more by practical reasons than theoretical reasons; that is, their interventions are predictions rather than explanations. Since these practical reasons need to be validated constantly in the analytic relationship based on their effects, he discusses the subject of validation in the clinical context of the core theory of therapeutic change in psychoanalysis, that is, the conditions required for clinical practice to satisfy the thesis of an inseparable union between gaining knowledge and cure. He ends by challenging the core of the psychoanalytic theory of change, arguing that it neither does justice to the practice of psychoanalysts nor to contemporary knowledge of processes and mechanisms of therapeutic change. Finally, he proposes that we detach practice from theory, in order to study the former in its own merits, utilising a plurality of methods ranging from systematic investigation to the recent methodology of the Working Party.


Local norms of maternal serum alpha-fetoprotein values in early second trimester: a prelude to a Down's syndrome screening programme incorporating maternal serum alpha-fetoprotein values.
Maternal alpha-fetoprotein in (MSAFP) has recently been proposed for screening of Down's syndrome. This is based on the association of a lowered MSAFP level at a given gestational age in Down's syndrome (DS) pregnancies. Most conventional 'screening' programmes in DS are based on the maternal age alone, selecting older mothers, who are at greater risk of having a DS infant born, for antenatal karyotyping. However, as 75% of DS infants are born to mothers less than 35 years old, a combination of blood tests including MSAFP and maternal age as independent risk factors would screen the younger mothers as a good cost-benefit ratio in selecting the 'at-risk' mothers for karyotyping. In this study, the gestational age was calculated from the first day of the last menstrual period (LMP) as well as from ultrasound cephalometry. The local MSAFP levels follow the same trend at a slightly higher level as those based on clinical evaluation of the Abbot AFP-EIA Monoclonal kits.


TDRG1 regulates chemosensitivity of seminoma TCam-2 cells to cisplatin via PI3K/Akt/mTOR signaling pathway and mitochondria-mediated apoptotic pathway.
We previously identified TDRG1 (testis developmental related gene 1), a novel gene with exclusive expression in testis, promoted the proliferation and progression of cultured human seminoma cells through PI3K/Akt/mTOR signaling. As increasing evidence reveal that aberrant activation of this signaling is involved in cisplatin resistance. Then, in this study, we further explored whether TDRG1 regulated the chemosensitivity of seminoma TCam-2 cells to cisplatin. Our researches showed TDRG1 could regulate the viability of TCam-2 cells following cisplatin treatment in vitro through control of both cell apoptosis and cell cycle. Mechanistically, we observed TDRG1 positively regulated the expression levels of the key elements in PI3K/Akt/mTOR pathway including p-PI3K, p-Akt and p-mTOR and also affected the translocation of nuclear p-Akt in TCam-2 cells during cisplatin treatment. Meanwhile, the levels of Bad, cytochrome c, caspase-9 ratio (activated/total), caspase-3 ratio (activated/total) and cleaved-PARP were negatively modulated by TDRG1, which meant the involvement of mitochondria-mediated apoptotic pathway. Furthermore, we found the effect of TDRG1 knockdown or TDRG1 overexpression could be reversed by IGF-1, a PI3K signaling activator, or LY294002, a inhibitor of this pathway, respectively. Similar effects of TDRG1 on cisplatin chemosensitivity and associated molecular mechanism were also confirmed in vivo by employing xenograft assays. In addition, the positive correlation between TDRG1 and p-PI3K, or p-Akt, was found in tumor tissues from seminoma patients. In conclusion, we uncover that TDRG1 regulates chemosensitivity of TCam-2 cells to cisplatin through PI3K/Akt/mTOR signaling and mitochondria-mediated apoptotic pathway both in vitro and in vivo.


Determination of rimantadine in human urine by HPLC using a monolithic stationary phase and on-line post-column derivatization.
In the present study, we propose the first HPLC method coupled to postcolumn derivatization for the determination of rimantadine in human urine samples. The analyte and amantadine (internal standard) were isocratically separated using an RP monolithic stationary phase (100 × 4.6 mm id) with a mobile phase consisting of CH3OH/phosphate buffer (25 mmol/L, pH 3.0) at a volume ratio of 50:50. Postcolumn derivatization involved on-line reaction with o-phthalaldehyde (20 mmol/L) and N-acetyl-cysteine (5 mmol/L) at alkaline medium (100 mmol/L borate pH 11.0). Spectrofluorimetric detection at λ(ex)/λ(em) = 340/455 nm enabled the selective and sensitive determination of rimantadine in urine samples at a range of 50-500 ng/mL with an LOD of 5 ng/mL. Human urine samples were analyzed successfully after SPE using hydrophilic-lipophilic balanced RP cartridges (30 mg/mL, Oasis HLB). Recoveries ranged between 89.7 and 102.7%.


Early diagnosis and prevention of impaction of the maxillary canine.
If there is no evidence of a canine bulge, and the tooth appears to be tipped medially in the frontal radiograph, with the crown medial to the lateral border of the nasal cavity, a future impaction of the maxillary canine is a significant possibility.