Surgical therapy for drug-refractory ventricular tachycardia: results with mapping-guided subendocardial resection.
Surgical therapy with mapping-guided subendocardial resection was used in 30 patients with drug-refractory ventricular tachycardia. Results of preoperative, intraoperative and postoperative electrophysiologic evaluation and long-term clinical follow-up are reported. Left ventricular aneurysm was located in the inferior wall in 8 patients and in the anterior wall in 22. Left ventricular mapping was performed in 15 patients preoperatively and in all 30 patients intraoperatively. Subendocardial resection was supplemented with cryoablation in 26 patients and with laser photocoagulation in 4. Coronary bypass surgery was performed in 27 patients. The surgical mortality rate was 10%; the three deaths were due to cardiogenic shock, pneumonia and sepsis, respectively. At postoperative electrophysiologic study, ventricular tachycardia was inducible in 8 (30%) of 27 patients. Previously ineffective antiarrhythmic drugs were effective in preventing the induction of ventricular tachycardia in four of these eight patients. Two of the remaining four patients received an automatic implantable cardioverterdefibrillator; the other two were treated with amiodarone. At a mean follow-up period of 18 +/- 17 months (range 1 to 52), there has been one sudden death and one nonfatal recurrence of ventricular tachycardia in the 18 patients without inducible arrhythmias postoperatively. Among the eight patients with inducible ventricular tachycardia after subendocardial resection, there has been one nonfatal ventricular tachycardia recurrence. Thus, among the 27 patients surviving surgery, 17 (63%) were cured with surgery alone, and another 7 (26%) had their ventricular tachycardia controlled with drugs (n = 5) or the defibrillator (n = 2). Inability to completely map the tachycardia, a clinical history of cardiac arrest requiring resuscitation and the presence of myocardial infarction within 2 months predicted postoperative arrhythmia inducibility and recurrence.


On-line sample concentration of organic anions in capillary zone electrophoresis by micelle to solvent stacking.
Micelle to solvent stacking (MSS) is a new on-line sample concentration technique for charged analytes in capillary zone electrophoresis (CZE). Sample concentration in MSS mainly relies on the reversal in the effective electrophoretic mobility of the analyte at the boundary zone between the sample solution (S) and CZE background solution (BGS) inside the capillary. The basic condition for MSS is that the S is prepared in a matrix that contains an additive (i.e., micelles) which interacts with and has an opposite charge compared to the analytes. In addition, the BGS must contain a sufficient percentage of organic solvent. MSS was first reported for organic cations using anionic dodecyl sulfate micelles as additive in the S and methanol or acetonitrile as organic solvent in the BGS. Here, theoretical and experimental studies on MSS are described for organic anions using cationic cetyltrimethyl ammonium micelles as additive in the S and methanol as organic solvent in the BGS. Up to an order of magnitude improvement in concentration sensitivity was obtained for the test hypolipidaemic drugs using MSS in CZE with UV detection. The optimized method was also evaluated to the analysis of a spiked wastewater sample that was subjected to a simple extraction step.


Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes.
To assess the efficacy and safety of a range of doses of a systemic, partial, glucokinase activator, PF-04937319, as add-on therapy to metformin, in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to once-daily PF-04937319 doses of 10, 50, 100 mg, or matching placebo (Study B1621002); or PF-04937319 doses of 3, 20, 50, 100 mg, or matching placebo (Study B1621007). Titrated glimepiride (Study B1621002) or sitagliptin (Study B1621007) were included in a double-dummy manner. The primary measure was change from baseline in glycated haemoglobin (HbA1c) at week 12. Key secondary measures included other glycaemic variables and safety and tolerability. In the 639 patients randomized, the minimally efficacious PF-04937319 dose was identified as 50 mg once daily. At the highest PF-04937319 dose tested (100 mg), on average, a clinically significant reduction in HbA1c [-4.94 or -5.11 mmol/mol (-0.45 or -0.47%), placebo-adjusted], which was similar to that achieved with sitagliptin [-4.69 mmol/mol (-0.43%)] but lower than that achieved with titrated glimepiride [-9.07 mmol/mol (-0.83%)], was observed. At this dose, the effect on fasting plasma glucose was not consistent between the two studies (Study B1621002 vs Study B1621007: placebo-adjusted mean change of -0.83 vs +0.50 mmol/l). PF-04937319 was well tolerated at doses up to 100 mg. Hypoglycaemia was reported in 2.5% of patients (on placebo), 5.1% of patients (on PF-04937319 100 mg), 1.8% of patients (on sitagliptin) and 34.4% of patients (on titrated glimepiride). In patients on metformin monotherapy, the addition of a 100-mg dose of PF-04937319 improved glycaemic control and was well tolerated.


Interferon regulator factor 1/retinoic inducible gene I (IRF1/RIG-I) axis mediates 25-hydroxycholesterol-induced interleukin-8 production in atherosclerosis.
In this study, the role of retinoic inducible gene I (RIG-I)-mediated signalling in the inflammation of atherosclerosis was investigated to explain the pathology of atherosclerosis. Human and mouse primary cells were exposed to 25-hydroxycholesterol followed by examination of gene expression and activation of the signal pathway with biochemical and molecular biological techniques. A mouse atherosclerotic model was also used. We found that RIG-I was induced in macrophages and endothelium by 25-hydroxycholesterol. Interferon regulatory factor 1 is a key transcription factor for the induction of RIG-I by 25-hydroxycholesterol. The induction of interleukin-8 and growth-regulated protein α, the mouse interleukin-8 homologue, by 25-hydroxycholesterol is mediated by RIG-I signalling. RIG-I transduces the signal to downstream molecules, mitochondrial antiviral-signalling protein, transforming growth factor-β-activated kinase 1, and mitogen-activated protein kinase, leading to the activation of nuclear factor κB, activator protein-1, and nuclear factor interleukin-6, all of which are required for the expression of interleukin-8. Finally, we observed that RIG-I is highly expressed in atherosclerotic lesions. Our data demonstrate that RIG-I signalling mediates atherosclerotic inflammation. Targeting RIG-I signalling should provide a way to inhibit atherosclerotic inflammation, which holds potential for the therapy of atherosclerosis.


Protein composition of the phase I Coxiella burnetii soluble antigen prepared by extraction with trichloroacetic acid.
Q fever is a highly infectious, widespread airborne zoonosis caused by Coxiella burnetii bacterium. Humans usually acquire the disease by inhalation of contaminated aerosol produced by infected livestock. Vaccination is the most practical way for prevention and control of the disease in the exposed population. In this work, we reviewed the most important Q-fever outbreaks in Slovakia as well as the progress in vaccine development. One of them represents a soluble antigen complex produced by extraction with trichloroacetic acid from a highly purified C. burnetii phase I strain Nine Mile. It was developed at the Institute of Virology in Bratislava. The protein content of this vaccine was separated by gel electrophoresis and analyzed by mass spectrometry. The study has resulted in the identification of 39 bacterial proteins from which 12 were recognized as immunoreactive. Most of the proteins were involved in bacterium pathogenicity (41.6%) and cell wall maintenance (25%). Four of the immunoreactive proteins may possess the moonlighting activity. Definition of the vaccine components represents a prerequisite for vaccine standardization and approval by governmental authorities.


Photophysics of (1-butyl-4-(1H-inden-1-ylidene)-1,4-dihydropyridine (BIDP): an experimental test for conical intersections.
Fluorescence experiments on (1-butyl-4-(1H-inden-1-ylidene)-1,4-dihydropyridine (BIDP) are reported in liquid and glassy solutions. The data indicate a fast decay in the fluid nonpolar, nonprotic solutions (decay times approximately 10(-12) s) and rapid but considerably slower decay in polar ones. In frozen solutions (polar and nonpolar), the fluorescence quantum yield is much higher (near 0.5 and around 0.1 in polar and nonpolar glasses, respectively). The rapid nonradiative transitions in fluid solutions are assigned to internal conversion in both solvent classes, as intersystem crossing is much slower and no net reaction is observed. These results are in agreement with predictions made for the closely related (in terms of electronic structure) but simpler molecule cyclopentadienyl-1,4-dihydropyridine (CPDHP) for which an S1/S0 conical intersection was recently proposed [Int. J. Quant. Chem. 2005, 102, 961]. The crossing of the two lowest singlet states is calculated to vanish in polar solvents such as methyl cyanide, leading to longer lifetime of S1 of CPDHP. As BIDP has a very similar electronic structure, the model predicts a corresponding change in this larger molecule. The strong fluorescence observed in the glassy environments is rationalized by the hindering of the internal torsion required to reach the geometry of the conical intersection.


Genetic differences in female house mice in aggressive response to sex steroid hormone treatment.
Male mice, genetically selected for aggression, characterized by short attack latency (SAL) or long attack latency (LAL), differ on several testosterone (T)-related parameters during ontogeny and adult age. The variation in aggressive behavior at adult age may be due to differences in degree of androgenization prenatally. When exposed to T at prenatal, neonatal, and/or adult age, nonlactating females also display intraspecific fighting behavior. In the present study, we investigated in females of the SAL and LAL selection lines, whether the differentiation of aggression involves processes similar to ones seen in males. Therefore, we injected females with testosterone propionate (TP) or vehicle on the day of birth, treated them after ovariectomy at adult age with T, estradiol (E), or vehicle, and tested their aggressive response. We found that neonatally vehicle-treated SAL females show a higher aggressive response to chronic T treatment at adult age than LAL females receiving the same treatment. Females of both selection lines treated with vehicle or E as adults were not aggressive. Neonatal TP treatment did not influence the adult T sensitivity and difference between selection lines in response to T at adult age. However, neonatally TP-treated SAL females showed aggressive behavior when treated with E at adult age, whereas LAL females failed to do so. These results suggest a genetic difference in susceptibility to T and E, which plays a major role prenatally, in organizing the development of sex steroid-dependent neural systems.


Avocado (Persea americana) seed as a source of bioactive phytochemicals.
The pulp of avocado (Persea americana, Lauraceae) has been reported to have beneficial cardiovascular health effects. Avocado oil is used for dermatological applications and its unsaponifiable portion is reported to have beneficial effects against osteoarthritis. Although the seed represents a considerable percentage of the total fruit, scientific research on the phytochemistry and biological effects of avocado seeds is in the nascent stages,. Currently, the seed represents an under-utilized resource and a waste issue for avocado processors. There is ethno-pharmacological information on the use of seeds for the treatment of health-related conditions, especially in South American countries where avocados are endemic and currently grown on a large scale. Current research has shown that avocado seeds may improve hypercholesterolemia, and be useful in the treatment of hypertension, inflammatory conditions and diabetes. Seeds have also been found to possess insecticidal, fungicidal, and anti-microbial activities. The avocado seeds and rich in phenolic compounds, and these may play a role in the putative health effects. Historically, extracts of avocado seeds were also used as ink for writing and research in our laboratory has explored the potential colorant properties of a polyphenol oxidase-produced colored avocado seed extract. Here, we review the currently-available data on the bioactivity and other functional properties of avocado seeds. We discuss the strength of the available data, the putative active compounds, and potential directions for future studies.


Bioanalytical considerations in the comparability assessment of biotherapeutics.
Comparison of biotherapeutic products before and after manufacturing changes is required to show that the products are highly similar. Besides in vitro assessment on the critical quality attributes and potency, biocomparability studies are sometimes required to demonstrate similarities in pharmacokinetic and pharmacodynamic characteristics. The complex and diverse nature of biotherapeutics requires multifaceted considerations in the biocomparability study design, bioanalytical measurements of drug concentrations and/or pharmacodynamic responses, immunogenicity analysis, data interpretation and decision making. A major perspective is to understand the structure and biological functions of the biotherapeutics in relation to the indication. Issues of a common standard and the importance of the use of ligand-binding assays that are sensitive to structural changes are discussed. It would not be possible to use the same process and one-size-fit-all criteria for biocomparability studies of all biologics. Previous examples from industry and our experience of the bioanalytical considerations for fit-for-purpose pharmacokinetic support and immunogenicity assessments are presented.


An integrated microfluidic system for rapid detection and multiple subtyping of influenza A viruses by using glycan-coated magnetic beads and RT-PCR.
The influenza A (InfA) virus, which poses a significant global public health threat, is routinely classified into "subtypes" based on viral hemagglutinin (HA) and neuraminidase (NA) antigens. Because there are nearly 200 viral subtypes, current diagnostic approaches require multiplexing or array systems to cover various subtypes of HA and NA. A microfluidic chip featuring a HA × NA array was consequently developed herein for diagnosis and subtyping of InfA viruses via the use of glycan-coated magnetic beads followed by reverse transcription (RT) polymerase chain reaction (PCR). Up to 12 InfA subtypes were simultaneously detected in an automated fashion in less than 100 minutes on this microfluidic platform, representing a significant improvement in analysis speed compared to benchtop RT-PCR and chip-based microarray systems. The limits of detection of the RT-PCR assays ranged from 40 to 3000 copy numbers for the different subtypes of InfA viruses, around two orders of magnitude higher than in previous studies using microfluidic technologies. In summary, the array-type microfluidic chip system provides a rapid, sensitive, and fully automated approach for detection and multiple subtyping of InfA.


Impact of spacing filaments external to hollow fibers on dialysate flow distribution and dialyzer performance.
A new type of dialyzer (PAN 650 SF Asahi) is analyzed in terms of hydraulic properties, solute clearances and dialysate flow distribution. The new type of dialyzer is a polyacrylonitrile hollow fiber filter, equipped with spacing filaments placed externally to the fibers to facilitate dialysate distribution and avoid channeling. The new filter is compared with a similar filter without spacing filaments. For this purpose, blood and dialysate side clearances have been measured in sequential dialysis session carried out randomly in the same patients. Furthermore, a last generation helical scanner (X-Press/HS1, Toshiba) has been utilized to analyze in vitro the flow distribution of dialysate inside the dialyzer. A contrast medium was injected and a sequence of images has been achieved on a longitudinal section of the dialyzer. This new method permits to avoid any bias due to the cylindrical shape of the dialyzer, since a 10 mm thick rectangular section is analyzed and not the entire body of the filter. The dialyzers equipped with spacing filaments displayed a significant improvement of the dialysate distribution as demonstrated by the radiological pattern. In detail, despite a channeling phenomenon in the peripherical region of the bundle is still present, this is remarkably reduced in comparison with the channelling phenomenon observed in the standard dialyzers. This improved distribution is confirmed by a significant improvement of the solute clearances.


The complex structure of calmodulin bound to a calcineurin peptide.
The activity of the protein phosphatase calcineurin (CN) is regulated by an autoinhibition mechanism wherein several domains from its catalytic A subunit, including the calmodulin binding domain (CaMBD), block access to its active site. Upon binding of Ca2+ and calmodulin (Ca2+/CaM) to CaMBD, the autoinhibitory domains dissociate from the catalytic groove, thus activating the enzyme. To date, the structure of the CN/CaM/Ca2+ complex has not been determined in its entirety. Previously, we determined the structure of a fusion protein consisting of CaM and a 25-residue peptide taken from the CaMBD, joined by a 5-glycine linker. This structure revealed a novel CaM binding motif. However, the presence of the extraneous glycine linker cast doubt on the authenticity of this structure as an accurate representation of CN/CaM binding in vivo. Thus, here, we have determined the crystal structure of CaM complexed with the 25-residue CaMBD peptide without the glycine linker at a resolution of 2.1 A. The structure is essentially identical to the fusion construction which displays CaM bound to the CaMBD peptide as a dimer with an open, elongated conformation. The N-lobe from one molecule and C-lobe from another encompass and bind the CaMBD peptide. Thus, it validates the existence of this novel CaM binding motif. Our experiments suggest that the dimeric CaM/CaMBD complex exists in solution, which is unambiguously validated using a carefully-designed CaM-sepharose pull-down experiment. We discuss structural features that produce this novel binding motif, including the role of the CaMBD peptide residues Arg-408, Val-409, and Phe-410, which work to provide rigidity to the otherwise flexible central CaM helix joining the N- and C-lobes, ultimately keeping these lobes apart and forcing "head-to-tail" dimerization to attain the requisite N- and C-lobe pairing for CaMBD binding.


The predictive value of bone loss for fragility fractures in women: a longitudinal study over 15 years.
Fifteen years after their forearm bone mineral content was measured, 366 women were measured again with the same single photon technique. 96 of the women had sustained one or more fragility fractures during that period. The initial bone mineral content was less in those women who were to have fractures. The rate of loss over the years did not differ between fracture and non-fracture women--the initial bone mass was the better predictor. Peak bone mass in the women in this study occurred before the age of 40.


Three-dimensional arrangement of muscle bundles in the outer layers of rodentia vasa deferentia.
Three-dimensional arrangement of the smooth muscle bundles of the outer layer of the vas deferens musculature in mammals (guinea-pigs, rats and mice) was examined under the scanning electron microscope (SEM) after removal of fibrous connective tissue elements. Muscle fibers of all examined animals formed bundles. In the guinea-pig, similar sized bundles extended longitudinally along the tubular vas deferens and branched to anastomose with branches of neighboring bundles to create a net which was regular in form. In the rat, longitudinal muscle bundles constituted an outer layer in the form of a net, which was roughly enmeshed with variously-sized, transverse or oblique bundles in anastomosis with underlying longitudinal bundles. In the mouse, longitudinal bundles of irregular thickness branched into many small bundles and anastomosed not only with neighboring bundles to create an irregular net. In both the rat and the mouse there were bundles extending over many other bundles to anastomose with them at a far point. Junctional structures were well developed between neighboring fibers. Myofibrils were represented as thin streaks on muscle fiber surfaces. Varicosed nerve fibers existed between muscle fibers and in narrow cytoplasmic grooves in all the examined animal species. The findings are discussed in correlation with electrophysiological data.


Self-assembly and induced circular dichroism in dendritic supramolecules with cholesteric pendant groups.
We report on the solid-state structural features of self-assembled chiral supramolecules based on ionic complexation of chiral cholesteric pendant groups with achiral dendritic macromolecules and show that their optical activity exhibits a systematic change in the ultraviolet/visible light (UV-vis) absorption and enhancement in the circular dichroism (CD) signal, indicating the occurrence of supramolecular chirality, also referred to as induced circular dichroism (ICD). We construct a homologous series of complexes by varying systematically from 1 to 3 the generation of dendritic units contained in dendrons, dendrimers, and dendronized polymers. The structural properties of the complexes are investigated by means of small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). Depending on the class of dendritic molecule and the generation, lamellar, columnar hexagonal, oblique columnar, and rectangular columnar phases can be found, with a direct correlation among the degrees of freedom of the dendritic macromolecules used and the level of order achieved in the self-assembled solid-state structures. The enhancement of the optical signals of these mesoscopic structures appears to be correlated with their order in the solid state. Complexes with the longest lattice correlation lengths also show the most enhanced CD signals. These results show the unique versatility of dendritic macromolecules as supramolecular templates capable of organizing low molecular weight chiral pendant units into a variety of solid-state structures with amplified optical properties.


Postural interneurons in the abdominal nervous system of lobster. II. Evidence for neurons having both command and driver roles.
The nature of the synaptic relationship between 7 identified postural interneurons and 5 pairs of superficial motoneurons was examined by obtaining dual intracellular recordings from interneuron-motoneuron pairs in the lobster 2nd abdominal ganglion. For six different interneuron-motoneuron pairs EPSPs recorded from motoneurons occurred with a short (1 to 3 ms) fixed latency following each presynaptic spike recorded from the interneuron. This suggests that there is a monosynaptic relationship between these interneurons and motoneurons. Monosynaptic pathways accounted for 27% of all excitatory connections. Preliminary evidence indicates that the monosynaptic potentials are mediated by an excitatory chemical synapse since: all IPSPs occurred with latencies greater than 5 ms, there was no evidence for electrical coupling, and one of the interneurons produced facilitating PSPs. A majority of all monosynaptic connections were made by two of the flexion producing interneurons (FPIs), 201 and 301. The synaptic outputs of these FPIs were similar in that both made monosynaptic connections with a different bilaterally homologous pair of motoneurons. Both also produced larger EPSPs and more vigorous spiking in contralateral members of the bilateral motoneuron pairs. A previous study demonstrated that interneurons 201 and 301 are the only postural interneurons yet identified that express motor programs indistinguishable from command neurons. Taken together, these results suggest that certain intersegmental interneurons share properties with command neurons and driver neurons, and that there may not be a sharp morphological or functional distinction between these two cell types.


Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial.
Randomized trials of postmenopausal hormone therapy have found differing effects on fasting glucose levels. No trial has evaluated the effect of hormone therapy on diabetes incidence. To evaluate the effect of hormone therapy on fasting glucose level and incident diabetes. Randomized, double-blind, placebo-controlled trial. 20 U.S. clinical centers. 2763 postmenopausal women with coronary heart disease who were followed for 4.1 years. At baseline, 734 women had diabetes, 218 women had impaired fasting glucose, and 1811 women were normoglycemic; the 2029 women without diabetes were followed for incident diabetes. 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily, or placebo. Fasting glucose level was measured at baseline, at year 1, and at the end of the trial. Incident diabetes was defined by self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/L or greater (> or =126 mg/dL), or initiation of therapy with diabetes medication. Fasting glucose levels increased significantly among women assigned to placebo but did not change among women receiving hormone therapy. The incidence of diabetes was 6.2% in the hormone therapy group and 9.5% in the placebo group (relative hazard, 0.65 [95% CI, 0.48 to 0.89]; P = 0.006). The number needed to treat for benefit to prevent one case of diabetes was 30 (CI, 18 to 103). Changes in weight and waist circumference did not mediate this effect. In women with coronary disease, hormone therapy reduced the incidence of diabetes by 35%. This observation provides important insights into the metabolic effects of postmenopausal hormones but is insufficient to recommend the use of hormones for secondary prevention of heart disease.


Variability of filtration and food assimilation rates, respiratory activity and multixenobiotic resistance (MXR) mechanism in the mussel Perna perna under lead influence.
The economic importance that multiculture is conquering in Santa Catarina State (South of Brazil) explains the crescent search for new coastal sites for farming. Physiological and biochemical studies of the mussel Perna perna are important to the establishment of methodologies for program assessment and environmental monitoring, allowing to infer about site quality and possible influences of xenobiotic agents on coastal areas. In order to evaluate effects caused by lead poisoning (1.21 mumol.L-1), the mussels were maintained at constant temperature (25 degrees C) and fed with Chaetoceros gracilis for 15 days. The control group was acclimatized in sea water 30@1000. At the end of this period time, physiological measurements were carried out along with statistic analysis for filtration rates, lead assimilation and overall respiratory activity. The mechanism of multixenobiotic resistance (MXR) was particularly evaluated in standardized gill fragments using rhodamine B accumulation and its quantification under fluorescence optical microscopy. Regarding the control group, results had shown that the mussels maintenance in a lead-poisoned environment caused higher filtration rates (1.04 and 2.3 and L.h-1.g-1; p < 0.05) and lower assimilation rates (71.96% and 54.1%, respectively). Also it was confirmed a lesser rhodamine B accumulation in the assays under influence of lead, suggesting that this metal induces the MXR mechanism expression in mussel P. perna. These results indicate that such physiological and biochemical alterations in the mussels can modify the energy fluxes of its metabolism, resulting in possible problems on the coastal systems used as cultivating sites.


Hemolysis and Kidney Injury in Cardiac Surgery: The Protective Role of Nitric Oxide Therapy.
Acute kidney injury is a common complication after cardiac surgery that is associated with high postoperative morbidity and mortality. Levels of hemolysis are associated closely with the incidence and severity of kidney injury after cardiac surgery. Hemolysis is caused by prolonged surgical procedures and blood transfusions from cell-saver devices and is associated with the use of cardiopulmonary bypass. Plasma oxyhemoglobin is released into the circulation by damaged red blood cells that, via a dioxygenation reaction, depletes vascular nitric oxide (NO), a potent vasodilator molecule responsible for modulating organ perfusion and vascular homeostasis. Depleted plasma NO and increased levels of plasma oxyhemoglobin in the bloodstream lead to impairment of organ perfusion, inflammation, oxidative stress, and direct tubular injury, which, together, contribute to the development of renal injury after cardiac surgery. The administration of NO, a gas originally approved to treat pulmonary hypertension, maintains organ perfusion by preventing vascular NO depletion. In addition, this treatment improves cardiac output by reducing pulmonary vascular resistance and right heart workload. The clinical evidence of renal protection of NO gas therapy is supported by preclinical animal studies exploring the extrapulmonary protective effects of NO. Recent clinical trials showed a significant reduction of postoperative acute kidney injury when NO gas was administered during and after cardiac surgery.


Method for chronic portal vein infusion in unrestrained rats.
Surgical procedures for the chronic cannulation of the portal and the femoral veins in the rat are described. The surgical procedure for portal vein cannulation is delicate and requires practice, but has proven useful for chronic drug administration. Cannulation of the femoral vein was less involved and cannula patency was extended by proper cannula preparation and placement. This dual cannulation of the rat allowed infusion of racemic mephenytoin into the portal vein and blood collection from the femoral vein for characterizing blood concentrations of the individual isomers. Chronic portal vein drug infusions may provide a useful approach to studies of time-dependent change in hepatic metabolism and stereoselective first-pass drug elimination in unrestrained animals.


[Formula-syndrome correlation study of three classical anti-jaundice formulas in inhibition of liver fibrosis induced by dimethylnitrosamine in rats].
To investigate the effects of three classical anti-jaundice formulas Yinchenhao Decoction (YCHD). Yinchen Wuling San (YCWLS) and Zhizi Baipi Decoction (ZZBPD) on liver fibrosis induced by dimethylnitrosamine (DMN) in rats and explore the formula-syndrome relationship. Forty-eight rats were weighted, and divided into five groups: normal control, DMN, YCHD, YCWLS and ZZBPD groups using stratified random method. Liver fibrosis in rats was induced by intraperitoneal injection of DMN for 4 weeks at the dosage 10 mg/kg body weight, once per day for 3 consecutive days in each week. Each groups was gavaged with distilled water (control or model group), YCHD, YCWLS and ZZBPD respectively in the last 2-week modeling period. At the end of the 4th week, rats were sacrificed and their blood sample and liver tissue were taken for detecting pathology and analyzing of hydroxyproline (Hyp) and liver function. Compared with the normal control group, DMN model group showed liver damage and liver fibrosis with remarkably increased Hyp content (P<0.01) and abnormal liver function (P<0.01). Liver fibrosis induced by DMN in rats was improved by administration of YCHD. Compared with DMN model group, content of Hyp was decreased remarkably (P<0.01) and liver function and hepatic histology were improved significantly after 2 weeks of YCHD treatment (P<0.05 or P<0.01)., and content of hepatic Hyp was decreased in the ZZBPD groups. Comparison of various parameters between groups showed that content of serum total bilirubin was decreased significantly in the YCWLS group (P<0.01), and content of hepatic Hyp was decreased in the ZZBPD group. Efficacy of YCHD in inhibition of liver fibrosis induced by DMN in rats is far better than YCWLS and ZZBPD. The pathogenesis of the liver fibrosis induced by DMN is mainly damp-heat. In addition, both damp and heat pathogenic factors play very important role in this model. The syndrome is highly correlated with the prescription YCHD.


Immunosuppression and squamous cell carcinoma: a focus on solid organ transplant recipients.
As transplant medicine advances, new immunosuppressive regimens are increasing the long-term survival of solid organ transplant recipients (SOTRs). This growing population is at significantly increased risk for developing cutaneous malignancies, particularly squamous cell carcinoma (SCC), as a result of chronic immunosuppression. Conventional risk factors for the development of skin cancer, including fair skin type, advanced age, sun exposure, and genetic predisposition, also play a crucial role in the initiation and progression of SCC in SOTRs. Immunosuppressed patients develop more aggressive and more numerous SCCs than immunocompetent individuals, however. It is important to understand the mechanisms underlying immunosuppression-mediated SCC development to identify prognostic markers and to develop effective prevention and treatment strategies. This article addresses the fundamental differences between SCC in SOTRs and those in the general population, focusing on the role that immunosuppression plays in the pathogenesis of this malignancy.


Magnetic resonance imaging reveals distinct bone marrow patterns in indolent and advanced systemic mastocytosis.
Systemic mastocytosis (SM) is broadly subcategorized according to mast cell (MC) burden and organ involvement into indolent (ISM), smoldering (SSM), and advanced SM (AdvSM). However, the pattern and extent of bone involvement remains controversial. In this institutional review board (IRB)-approved study, 115 patients with different forms of SM (ISM (n = 37, 32%), SSM (n = 9, 8%), and AdvSM (n = 69, 60%)) underwent a whole-body magnetic resonance imaging including sagittal and coronal T1 and turbo inversion recovery magnitude (TIRM) sequences of the spine. The evaluation included the pattern and extent of pathologic bone marrow (BM) signals in the spine and extremities, osteolytic lesions, and vertebral fractures. A pathologic BM pattern was observed in 4/37 (11%), 8/9 (89%), and 66/69 (96%); affection of the appendicular skeleton in 3/37 (8%), 8/9 (89%), and 67/69 (97%); and vertebral fractures in 7/37 (19%), 0/9, and 13/69 (19%) patients with ISM, SSM, and AdvSM, respectively. In AdvSM, pathologic BM pattern included activated (62%), diffuse sclerotic (25%), and small-spotted BM (9%), respectively. Only activated/sclerotic BM was associated with significantly higher MC burden, organ damage, and inferior median survival (2.9 years, p = 0.04). Vertebral fractures resembled classical multi-segmental osteoporotic fractures in ISM but not in AdvSM in which they were only found in activated/sclerotic BM. Only one patient with AdvSM had a focal osteolytic lesion in the femur. Activated/sclerotic BM changes of the spine and affection of the appendicular skeleton are indicative for SSM or AdvSM. Osteolytic lesions, which are very rare, and osteoporotic fractures are ineligible for the diagnosis of AdvSM.


Generalized lattice graphs for 2D-visualization of biological information.
Several graph representations have been introduced for different data in theoretical biology. For instance, complex networks based on Graph theory are used to represent the structure and/or dynamics of different large biological systems such as protein-protein interaction networks. In addition, Randic, Liao, Nandy, Basak, and many others developed some special types of graph-based representations. This special type of graph includes geometrical constrains to node positioning in space and adopts final geometrical shapes that resemble lattice-like patterns. Lattice networks have been used to visually depict DNA and protein sequences but they are very flexible. However, despite the proved efficacy of new lattice-like graph/networks to represent diverse systems, most works focus on only one specific type of biological data. This work proposes a generalized type of lattice and illustrates how to use it in order to represent and compare biological data from different sources. We exemplify the following cases: protein sequence; mass spectra (MS) of protein peptide mass fingerprints (PMF); molecular dynamic trajectory (MDTs) from structural studies; mRNA microarray data; single nucleotide polymorphisms (SNPs); 1D or 2D-Electrophoresis study of protein polymorphisms and protein-research patent and/or copyright information. We used data available from public sources for some examples but for other, we used experimental results reported herein for the first time. This work may break new ground for the application of Graph theory in theoretical biology and other areas of biomedical sciences.


Prognostic Factors of Arthroscopic Extensor Carpi Radialis Brevis Release for Lateral Epicondylitis.
The purpose of this study was to analyze factors affecting the treatment outcomes and prognoses of arthroscopic debridement for refractory lateral epicondylitis. We included 45 patients who had undergone arthroscopic extensor carpi radialis brevis release for chronic refractory lateral epicondylitis between October 2008 and December 2012. Demographic data, magnetic resonance imaging studies, and arthroscopic findings were examined and analyzed. The mean age of the enrolled patients (23 men and 22 women) was 45.9 ± 7.8 years, and the mean follow-up duration was 26.9 ± 9.0 months. All the patients showed significant clinical improvement on all parameters assessed using the visual analog scale (6.9 preoperatively to 0.9 postoperatively), the Upper Extremity Functional Scale (34.8 to 66.7), and the Mayo Elbow Score (63.5 to 92.3) (P < .05). There were no reports of serious surgical complications. At final follow-up, 37 patients (82.2%) were satisfied with their outcomes whereas 8 patients (17.8%) were dissatisfied. In terms of demographic factors, female sex was significantly different between the 2 groups. On preoperative magnetic resonance imaging, 7 patients in the satisfied group (18.9%) had a definite tendon lesion (grade III defect, ≥6 mm) whereas 6 patients in the dissatisfied group (75%) had a grade III defect (P = .016). Overall, clinical outcome scores showed improvement after arthroscopic extensor carpi radialis brevis release for refractory lateral epicondylitis. However, preoperative tendon status and sex were associated with dissatisfaction and poor postoperative outcomes after the arthroscopic release procedure. Level IV, therapeutic case series.


Pyrocarbon metacarpophalangeal joint replacement in primary osteoarthritis.
The purpose of this retrospective cohort study was to evaluate the outcomes of 18 primary pyrocarbon metacarpophalangeal joint replacements in 10 patients, performed for primary osteoarthritis. The mean age at operation was 66 years and mean follow-up was 58.6 months. The arc of motion improved from a mean of 30° to 40° and the mean QuickDASH score improved from 35 to 17. All except one patient were satisfied with their outcomes. Radiographically, there has been no evidence of dislocation or overt loosening, although there has been subsidence of some components up to 5 mm. One index finger implant was revised to a silastic implant for perceived alteration of precision pinch. Other complications included one intra-operative fracture that united and an asymptomatic stem fracture of one proximal phalangeal component. We continue to use the implant and aim to review our experience in a further 5 years.


Apparatus for preparing mimics of suspended particles in the troposphere and their controlled deposition onto individual lung cells in culture with measurement of downstream biological response.
Inhalation exposure to particles <10 microm in size that are suspended in the troposphere (PM10) is a factor in respiratory and cardiovascular diseases. The extent of the injury, local to systemic inflammation, is dependent on the number, size, and composition of the particles to which an individual is exposed. The physical properties of and compounds on PM10 that are responsible for these adverse effects on human health are the subject of intense investigation. Here, we report a laboratory method that involved the creation of 1-120 particles per trial that were of known size and composition, followed by deposition of them directly onto individual human lung cells within a cell culture, and after an incubation period, a downstream biological response was measured. To illustrate this methodology, particles that each contained 50 pg of lipopolysaccharide were created and deposited onto individual cells over a region <0.36 mm2 within a genetically modified A549 cell culture. The biological readout was the relative expression of intercellular cell adhesion molecule 1 after 24 h of incubation using an immunocytochemistry assay. The apparatus and methodology introduced here enables studies at the interface between the relevant but diverse areas of atmospheric particle chemistry and lung cell biology to identify the chemical and physical factors of PM10 that cause/exacerbate respiratory and cardiovascular diseases by triggering various biological pathways.


Comparison of a fluoresceinated lectin stain with triple staining for evaluating acrosome reactions of dog sperm.
In this study a technique which utilized a fluoresceinated lectin and a fluorescent supravital stain was compared with the conventional triple stain technique for evaluating the viability and acrosomal status of dog sperm. Ten semen samples obtained from 6 normal beagle dogs were evaluated after incubation in vitro with canine capacitation medium. Sperm viability and acrosomal status were assessed at 0, 4, and 7 hours of incubation. Both staining techniques were capable of detecting the increase in spontaneous acrosome reactions which occurs during in vitro capacitation of dog sperm. High positive correlations were observed between the fluorescent stain and the triple stain in the mean values for the percentage of viable sperm and for the percentage of acrosome-reacted sperm among the viable sperm (r = 0.91, r = 0.97, respectively). However, the fluorescent staining techniques could be carried out much more rapidly than the triple stain technique, and the slides prepared with fluorescent stain were more easily scored because of the higher intensity and greater consistency of staining. These characteristics make the fluoresceinated lectin and the fluorescent supravital stain superior for evaluating acrosome reactions and viability of dog sperm.


Apoptosis, Autophagy, and Pyroptosis: Immune Escape Strategies for Persistent Infection and Pathogenesis of Classical Swine Fever Virus.
Classical swine fever (CSF) is a severe acute infectious disease that results from classical swine fever virus (CSFV) infection, which leads to serious economic losses in the porcine industry worldwide. In recent years, numerous studies related to the immune escape mechanism of the persistent infection and pathogenesis of CSFV have been performed. Remarkably, several independent groups have reported that apoptosis, autophagy, and pyroptosis play a significant role in the occurrence and development of CSF, as well as in the immunological process. Apoptosis, autophagy, and pyroptosis are the fundamental biological processes that maintain normal homeostatic and metabolic function in eukaryotic organisms. In general, these three cellular biological processes are always understood as an immune defense response initiated by the organism after perceiving a pathogen infection. Nevertheless, several viruses, including CSFV and other common pathogens such as hepatitis C and influenza A, have evolved strategies for infection and replication using these three cellular biological process mechanisms. In this review, we summarize the known roles of apoptosis, autophagy, and pyroptosis in CSFV infection and how viruses manipulate these three cellular biological processes to evade the immune response.


Changes in mouse blood pressure, tumor blood flow, and core and tumor temperatures following nembutal or urethane anesthesia.
Female CBA and WHT mice with tumors transplanted into the right leg were immobilized in insulated capsules. Tumor blood flow, blood pressure, and core and tumor temperatures were monitored prior to and during anesthesia with either Nembutal or urethane. Nembutal caused a 5 degree C drop in both core and tumor temperatures in 20 minutes. Urethane induced a small fall in temperatures. Urethane initially caused a small drop in blood pressure followed by recovery; Nembutal caused a steady fall in blood pressure to 50% of resting value.


Oral healthcare experiences of humanitarian migrants in Montreal, Canada.
To understand the oral healthcare experiences of humanitarian migrants in Montreal and their perceptions of ways to improve access to oral healthcare. We used focused ethnography informed by a public health model of the dental care process. The adapted McGill Illness Narrative Interview (MINI) guided interviews of a purposeful sample of humanitarian migrants who received or needed dental care in Montreal. Each interview (50-60 min) was audio-recorded for verbatim transcription. Observation of dental care episodes occurred during mobile dental clinics in underserved communities over the same period (2015-2016). Data analysis combined deductive codes from the theoretical frameworks and inductive codes from interview transcripts and field notes to inform themes. We interviewed 25 participants (13 refugees and 12 asylum seekers) from 10 countries, who had been in Canada for a range of 1 month to 5 years. The dental care experiences of participants included delayed consultation, proximity to dental clinics, quality care, limited treatment choices, high cost, and long waiting times. A more inclusive healthcare policy, lower fees, integration of dental care into public insurance, and creation of community dental clinics were proposed strategies to improve access to dental care. Humanitarian migrants in this study experienced inadequate oral healthcare. Their lived experiences help us to identify gaps in the provision of oral healthcare services, and suggestions of participants have great potential to improve access to oral healthcare.


The influence of the acetabular labrum seal, intact articular superficial zone and synovial fluid thixotropy on squeeze-film lubrication of a spherical synovial joint.
A model of synovial fluid (SF) filtration by articular cartilage (AC) in a step-loaded spherical synovial joint at rest is presented. The effects of joint pathology (such as a depleted acetabular labrum, a depleted cartilage superficial zone consistent with early osteoarthritis and an inflammatory SF) on the squeezed synovial film are also investigated. Biphasic mixture models for AC (ideal fluid and elastic porous transversely isotropic two-layer matrix) and for SF (ideal and thixotropic fluids) are applied and the following results are obtained. If the acetabular labrum is able to seal the pressurised SF between the articular surfaces (as in the normal hip joint), the fluid in the synovial film and in the cartilage within the labral ring is homogeneously pressurised. The articular surfaces remain separated by a fluid film for minutes. If the labrum is destroyed or absent and the SF can escape across the contact edge, the fluid pressure is non-homogeneous and with a small jump at the articular surface at the very moment of load application. The ensuing synovial film filtration by porous cartilage is lower for the normal cartilage (with the intact superficial zone) than if this zone is already depleted or rubbed off as in the early stage of primary osteoarthritis. Compared with the inflammatory (Newtonian) SF, the normal (thixotropic) fluid applies favourably in the squeezed film near the contact centre only, yielding a thicker SF film there, but not affecting the minimum thickness in the fluid film profile at a fixed time. For all that, in the unsealed case for both the normal and pathological joint, the macromolecular concentration of the hyaluronic acid-protein complex in the synovial film quickly increases due to the filtration in the greater part of the contact. A stable synovial gel film, thick on the order of 10(-7)m, protecting the articular surfaces from the intimate contact, is formed within a couple of seconds. Boundary lubrication by the synovial gel is established if sliding motion follows until a fresh SF is entrained into the contact. This theoretical prediction is open for experimental verifications.


[Teaching a teenager approaching the end of life].
When a teenager is diagnosed with a life-threatening condition, priority is given to the provision of care, but the continuation of the adolescent's education is also encouraged, through the hospital school. Thereby, like all children of his age, Issem, suffering from an osteosarcoma, will sit his secondary school exams and will be supported to the end by his teachers. Personal accounts.


Progress in the Rational Design for Polypharmacology Drug.
Polypharmacology plays an important role in drug discovery. Polypharmacology drugs strategy provides a novel way in drug design. However, to develop a polypharmacology drug with desired profile remains a challenge. Owing to the huge progress in computational biology and chemistry, the rational drug design is becoming increasingly important in discovery of polypharmacology drug. Several methodologies on the rational polypharmacology drug design have been developed, which are summarized and classified as ligand based design in polypharmacology, target based design in polypharmacology, and the hybrid of ligand and target based design in polypharmacology. We give an overview of the importance of polypharmacology in drug design and current trends in rational design of polypharmacology, which may be beneficial to the design and development of polypharmacology drugs.


[Effect of Stopangin mouth spray on blood alcohol levels measured by the Alcotest 7410 analyser made by Drager].
During a check-up of a driver by a police patrol in the Czech Republic by means of a breath analyzer of Dräger Co. an alcohol blood level of 0.50 g/kg was assessed. Later the driver reported that before the test he used at 30- and 5-minute intervals the drug Stopangin spray. In the Institute of Forensic Medicine the authors made an experiment which revealed that 22 minutes after administration of the drug the apparatus gave a negative result. Agreement with these conclusions was expressed also by a representative of Dräger Co. and the results were published as an expert opinion with a recommended procedure for the police of the Czech Republic in the South Moravian region.


Do ultra-runners in a 24-h run really dehydrate?
Loss of body mass during a 24-h run was considered to be a result of dehydration. We intended to quantify the decrease in body mass as a loss in fat mass or skeletal muscle mass and to quantify the change in hydration status. Body mass, fat mass, skeletal muscle mass, haematocrit, plasma sodium and urinary specific gravity were measured in 15 ultra-marathoners in a 24-h run. Body mass decreased by 2.2 kg (p = 0.0009) and fat mass decreased by 0.5 kg (p = 0.0084). The decrease in body mass correlated to the decrease in fat mass (r = 0.72, p = 0.0024). Urinary specific gravity increased from 1.012 to 1.022 g/mL (p = 0.0005). The decrease in body mass and the increase in urinary specific gravity indicate dehydration. The decrease in body mass was correlated to the decrease in fat mass and therefore not only due to dehydration.


Shape control of anatase TiO2 nanoparticles by amino acids in a gel-sol system.
Ellipsoidal anatase TiO2 nanoparticles of different aspect ratios were obtained by the gel-sol method in the presence of amino acids in which the resulting particles were basically single crystals, but highly rough surfaces or partly polycrystalline structures were observed with a high concentration of glutamic acid or aspartic acid.


[Assessment of optoelectronic method and molecular test usefulness for cervical intraepithelial neoplasia and cervical cancer detection].
Biophysics and molecular biology are disciplines dynamically entering the area of cervical cancer prevention. The combined test, comprising optoelectronic and molecular diagnostics, may play a significant role in the decrease of cervical cancer incidence and mortality. Assessment of the combined test usefulness--optoelectronic method and HPV test for the presence of oncogenic HPV types, in the detection of cervical intraepithelial neoplasia and cervical cancer. From August 2006 to October 2008 the study included 250 patients from the Laboratory of Pathophysiology of Uterine Cervix in Gynecology and Obstetrics Clinical Hospital of Karol Marcinkowski University of Medical Sciences. The patients underwent the following diagnostic tests: optoelectronic method, PCR test for the presence of DNA HPV HR, colposcopic examination and histopathologic biopsy. Sensitivity of the combined test for low-grade intraepithelial changes in the area of squamous epithelium (CIN 1) was 81%, while for high-grade changes (CIN 2, CIN 3) and carcinoma planoepitheliale together with adenocarcinoma was 100%. Optoelectronic and molecular diagnostics methods are useful in detecting neoplastic cervical changes. Both methods may become a key diagnostic tool of basic and advanced level of cervical screening. The advantage of the combined optoelectronic method and molecular diagnostics method over prevention based on cytodiagnostics and colposcopy has its source in the possibility of test automation and standardization.


The diurnal variability of ventricular premature depolarizations: influence of heart rate, sleep, and wakefulness.
The relationships between ventricular premature depolarizations (VPDs) and heart rate (HR) were determined in 14 patients with ventricular arrhythmias and the influence of these relationships on the diurnal variability of ventricular arrhythmias was evaluated. The influence of sleep state, wakefulness, and level of activity on the frequency of VPDs was also studied. Subjects completed 48-72 h of ambulatory electrocardiographic monitoring and nocturnal sleep recordings. Plots of VPD frequency vs. HR were examined and subjects were categorized as HR-dependent if they manifested log-linear increase in VPDs with increasing HR and as HR-independent if no relation between VPD frequency and HR was detected. Sleep suppression of VPDs was observed in the HR-dependent group (p less than 0.05). The reduction in VPD frequency correlated with the reduction in HR and was independent of sleep state or wakefulness. No change in VPD frequency was observed during wakefulness, rapid eye movement sleep, or non-rapid-eye-movement sleep in the HR-independent group. The influence of level of activity on ventricular arrhythmia frequency was also assessed in seven subjects. Any decreases in VPD frequency observed during inactivity were associated with a decrease in HR. These observations suggest that HR is a major determinant of the diurnal variation of VPD frequency in a subset of patients with frequent VPDs.


Non-high-density lipoprotein cholesterol: an alternate target for lipid-lowering therapy.
Non-high-density lipoprotein (non-HDL) cholesterol level is determined by subtracting the high-density lipoprotein cholesterol level from the total cholesterol level and thus encompasses not only low-density lipoprotein cholesterol, but also the cholesterol contained in atherogenic, triglyceride-rich particles like remnants. This review summarizes data extracted from English-language publications accessible through MEDLINE on the population distribution of non-HDL cholesterol, its relationship to cardiovascular disease, and the potential benefits of treatment. Non-HDL cholesterol levels in the population vary by age, sex, and race and are closely linked to measures of obesity, especially visceral obesity. Several studies in populations with and without cardiovascular disease show that non-HDL cholesterol levels relate to atherosclerosis severity and subsequent cardiovascular morbidity and mortality. Preliminary data also suggest that pharmacologically induced changes in non-HDL cholesterol levels relate to prognosis. In the National Cholesterol Education Program Adult Treatment Panel III report, non-HDL cholesterol has been designated a secondary target of therapy among patients with hypertriglyceridemia.


A placebo-controlled experimental study of steroid inhalation therapy in ammonia-induced lung injury.
The use of corticosteroids in toxic lung injury caused by exposure to an irritating gas such as ammonia has not been adequately studied. To evaluate the effects of budesonide inhalation in a rabbit model of toxic lung injury induced by ammonia. Randomized, blind placebo-controlled laboratory investigation employing 16 New Zealand White rabbits. Lung injury was induced by inhalation of a defined amount of aerosolized ammonia. Thirty minutes later, the rabbits were randomized to receive either inhalation therapy with 0.5 mg budesonide or placebo. After another 2 hours, a second treatment inhalation, identical to the first one, was administered. Airway pressures, hemodynamics, and gas exchange were measured at baseline, 5, and 15 minutes after ammonia administration and every 30 minutes during a 6-hour period after the first blind inhalation of corticosteroids or placebo. The ammonia inhalation resulted in an acute severe lung injury, detected after 15 minutes as a decrease in Pao2 from 23.3 (+/- 3.6) to 11.0 (+/- 3.6) kPa (p < 0.005) and an increase in peak airway pressure from 13 (+/- 2) to 17 (+/- 2) cm H2O (p < 0.005). During the 6-hour observation period, the blood gas parameters improved gradually in all rabbits. In comparison with placebo, budesonide did not result in improved gas exchange or reduced airway pressure levels during the observation period. In this animal model corticosteroid inhalation therapy had no effect on ammonia-induced lung injury.


[A recent trial of chemo-radiation with S-1 against gastric cancer].
A recent development of novel anticancer agents like S-1, CPT-11 or taxanes has improved a therapeutic outcome for advanced gastric cancer, while conventional anticancer agents showed less anticancer effect against gastric cancer. The present main drug in Japan is S-1, which is easily used for outpatient with a high efficacy rate and low toxicity, also shows better effect in combination with other anticancer drugs than S-1 alone. In the present article, we demonstrated significant meaning of additional radiation therapy with anticancer drugs like S-1. With novel anticancer drugs like S-1, we will expose a clinical advantage and appropriateness for chemo-radiation therapy against gastric cancer discussed in the present references according to chemo-radiation therapy. Although chemo-radiation therapy has been recognized as one of the standard therapies for gastric cancer in Western countries, radiation therapy was selected in Japan for palliation therapy of recurrent disease or a terminal cancer to improve patients' QOL. On the other hand, we demonstrated in our trial of chemo-radiation therapy with S-1/low-dose CDDP/radiation (TSLDR), which was applied to initial treatment against highly advanced Stage IV gastric cancer and revealed the usefulness of the regimen in anticancer effect and toxicity. In addition, chemo-radiation therapy including novel anticancer agents like S-1 will be discussed based on various kinds of view points, expecting a better clinical outcome of multimodal therapies against advanced gastric cancer.


Vaginal substitution: attempts to create the ideal replacement.
Vaginal substitution may be necessary for vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), cloacal anomalies and certain intersex disorders or following pelvic exenterative surgery. The ideal method of vaginal replacement should provide a cosmetically acceptable, low maintenance vaginal substitute with minimal morbidity and excellent long-term function. We present the available literature on the various approaches to vaginal substitution, focusing on outcomes, complications and long-term durability in terms of sexual function. We performed an extensive search of the medical literature for nonoperative and operative alternatives for vaginal replacement. We focused on surgical indications, complications, long-term sexual function if available, and inherent advantages and disadvantages of the specified technique. Popular methods of vaginal substitution include passive dilation, inlay skin grafts, rotational myocutaneous flaps and bowel substitute vaginoplasty. These methods have been modified to some extent, and carry inherent advantages and disadvantages. Reports in the literature show the inherent biases of the proponents of different methods. There are many options for vaginoplasty. The ideal method is not currently known and depends on numerous factors including patient preparedness, surgeon experience, and patient and surgeon preference. Despite these issues, patients must be provided with nonoperative and operative options that address individual patient expectations, potential complications, long-term durability and long-term sexual function.


Chaotic mixing induced transitions in reaction-diffusion systems.
We study the evolution of a localized perturbation in a chemical system with multiple homogeneous steady states, in the presence of stirring by a fluid flow. Two distinct regimes are found as the rate of stirring is varied relative to the rate of the chemical reaction. When the stirring is fast localized perturbations decay towards a spatially homogeneous state. When the stirring is slow (or fast reaction) localized perturbations propagate by advection in form of a filament with a roughly constant width and exponentially increasing length. The width of the filament depends on the stirring rate and reaction rate but is independent of the initial perturbation. We investigate this problem numerically in both closed and open flow systems and explain the results using a one-dimensional "mean-strain" model for the transverse profile of the filament that captures the interplay between the propagation of the reaction-diffusion front and the stretching due to chaotic advection. (c) 2002 American Institute of Physics.


The contextual role of alcohol outlet density in college drinking.
The objective of the study is to examine the relationship between the physical availability of off-campus alcohol and drinking outcomes among college students. A multilevel analysis of students (N = 17,051) nested within college campuses (N = 32) was conducted. Four problem-drinking-related outcomes (i.e., average number of drinks when partying, frequency of drunkenness in past 2 weeks, 30-day frequency of drinking, and greatest number of drinks in one sitting) along with individual level covariates of drinking were introduced at the student level. The physical availability of alcohol was assessed as the number of on-premise and off-premise alcohol outlets within 3 miles of campus per 1,000 students enrolled. Higher densities of on-premise alcohol outlets were strongly related to drinking outcomes even after controlling for individual predictors of college drinking. The association indicated that the campus means for the average number of drinks when partying and the number of drinking occasions in the past 30 days were, respectively, 1.13 drinks and 1.32 occasions greater when the outlet density was 2 SDs higher. Off-campus, on-premise outlet density is strongly associated with college-drinking outcomes. Given the limited number of modifiable factors that affect college drinking, on-premise outlet density represents a potential modifiable means of addressing the problem.


Effect of variability in infection period on the persistence and spatial spread of infectious diseases.
The effects of the mean infection (incubation plus infectious) period on the dynamics of infectious diseases are well understood. We examine the dynamics and persistence of epidemics when the distribution of the infection period also is modelled, using the well-documented childhood disease measles as a test case. We pay particular attention to the differences between exponentially distributed and constant periods. The use of constant periods increases the persistence of epidemics by reducing the individual stochasticity. The infection period distribution is also shown to have a significant effect on the spatial spread of disease.


Fijian penis marbles: an example of artificial penile nodules.
Artificial penile nodules are inert objects inserted beneath the skin of the penis to enhance the pleasure of female sexual partners during intercourse. The practice is most common among men from southeast Asia. This report describes a Fijian man who had an artificial penile nodule made from a whittled-down plastic toothbrush handle. Although some authors believe that the use of artificial penile nodules arose after World War II, the practice was discussed in the Kama Sutra, the classic Indian treatise on love.


Walking ability before and after a hip fracture in elderly predict greater long-term survivorship.
The morbidity and mortality after a hip fracture in the elderly population are multifactorial. The aim of this study is to determine the long-term impact of specific factors to mortality rate and mobility after a hip fracture in the elderly. Elderly suffering a hip fracture after a low-energy trauma was included in the study, whereas moribund patients with severe comorbid conditions and high-energy trauma were excluded. All the patients were treated operatively during 2003. Data for survivorship and mobilization was collected six months, one and ten years after the operation. Kaplan-Meier log rang test was used for the survival analysis and cox regression for multivariate analysis of prediction factors such as age, gender, time to surgery after trauma, type of fracture, ambulation status before injury and early walking ability after the surgery. Two hundred and thirty three patients were finally included to the study. Gender (p = 0.64) and type of fracture (p = 0.92) seem to have no statistically significant impact on survivorship. Age (p < 0.001), time of surgery after the trauma (p = 0.001), ambulation status (p < 0.001) and early walking ability after the surgery (p < 0.001) seem to have statistically significant impact on mortality, as independent factors. The significance is present one year and ten years after the surgery. However, according to the multivariate analysis, time to surgery after trauma and age lose significance, while early walking ability remain significant one and ten years after surgery (p < 0.001). Ambulation status seem to lose significance early after surgery, but reach significance ten years postoperatively (p < 0.001). In summary, it could be stated that early walking ability after an operation for a hip fracture in elderly is the most significant prediction factor of survivorship one and ten years postoperatively. Ambulation status before injury is a significant long-term predictor factor for survivorship.


Sp1 and c-Myc regulate transcription of BMI1 in nasopharyngeal carcinoma.
B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1), a member of the polycomb group, has elevated expression and is involved in the pathogenesis of various aggressive cancers, including nasopharyngeal carcinoma (NPC). To date, the mechanisms underlying the high expression of Bmi1 in NPC remain obscure. To gain new insights into the transcriptional regulation of BMI1, we cloned and characterized the promoter region of BMI1. Luciferase reporter assays demonstrated that the region from -783 to +375 showed significant promoter activity. With the use of a series of 5'-deletion and 3'-deletion promoter constructs in luciferase reporter assays, the +167/+232 and -536/-134 regions were found to be sufficient for full promoter activity. Transcriptional activity of the BMI1 promoter was dependent on the Sp1 binding site cluster (+181/+214) as well as the E-box elements (-181), and was abolished after mutation of the two cis-elements. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays demonstrated that Sp1 bound to the region from +181 to +214 within the BMI1 promoter. In addition, gain-of-function and loss-of-function analyses revealed that Sp1 augmented Bmi1 expression. Further investigations using immunohistochemistry and quantitative RT-PCR disclosed a significant positive correlation between the expression of Sp1 and Bmi1 in normal nasopharyngeal epithelial cells, NPC cells, and NPC tissue specimens. In addition, Myc, the known transcription factor for BMI1 in neuroblastomas, also activated the transcription of BMI1 through binding to the E-box element (-181) within its promoter, and showed a positive correlation with the mRNA level of BMI1 in NPC. In conclusion, these findings provide valuable mechanistic insights into the role of Sp1 and c-Myc in BMI1 transcription in NPC, and suggest that targeting of Sp1 or c-Myc may be a potential therapeutic strategy for NPC.


Scanning and transmission electron microscopy of the normal rabbit aortic endothelium after controlled perfusion fixation.
Light microscopy, scanning electron microscopy, and transmission electron microscopy were employed on the anterior wall of the rabbit thoracic aorta with the particular purpose to study endothelial marginal flaps and the structure of stomata under physiological conditions at 100 mm Hg. Intra-aortic pressure monitoring was performed during the whole period of perfusion (2h), restricting pressure variations to a maximum of +/- 5 mm Hg in order to preserve endothelial architecture. We found the endothelial surface uniformly smooth. Marginal flaps of the endothelial cells were mutually overlapping, often forming multiple layers. Underlying flaps might protrude to the lumen between neighbouring flaps as flat mushrooms. Flaps of adjacent cells might diverge for short distances to decover an underlying endothelial cell. Downstream flaps of the cells might be overlapped at their base by flaps of adjacent cells, the extremity of the flap thus appearing as a disc separated from the cell. The small discs and troughs thus formed are considered equivalent to the so-called stomata.


More on recombination and selection in the modifier theory of sex-ratio distortion.
G. Maffi and S.D. Jayakar suggested a model for the two-locus control of sex determination in the mosquito Aedes aegypti (1981, Theor. Pop. Biol. 19, 19-36). This model was extended to multiple alleles and analyzed in mathematical detail by S. Lessard (1987, Theor. Pop. Biol. 31, 339-358). The model supposes that males are "Mm" and females "mm" but the transmission from males is controlled by a second gene with alleles Ai. We show that in addition to the equilibrium in which mAi in females, MAi from males and mAi from males all have the same frequencies, a second class of polymorphic equilibria exists and can be stable. The former class was shown by Lessard to be stable for intermediate and/or loose linkage. The new class of equilibria may be stable for tight linkage under the conditions that preclude stability of the former. We also develop the theory of linkage modification from the neighborhood of the new equilibrium. Successful modifiers of recombination may either reduce or increase the recombination fraction with the outcome depending on the linkage of the modifier to the major genes.


[The most important human aluminoses].
Aluminoses are widespread forms of trace element deficiency of various severity. The organism is protected against a possible pathogenic influence of aluminum by a number of physiological mechanisms the most important among which is a regular urine excretion. A complex of pathological symptoms develops if serious homeostasis disturbances take place e. g. when renal deficiency or direct penetration of the trace element occur. The following forms of aluminosis should be distinguished: 1) simple accumulation in central nervous system which occurs in persons over 65 years; 2) aluminum accumulation in Alzheimer disease, in severe form of presenile and senile dementia; 3) dialysis aluminum encephalopathy; 4) non-dialysis infantile encephalopathy; 5) aluminum encephalopathy in total parenteral nutrition; 6) iatrogenic dialysis aluminum osteodystrophy; 7) jatrogenic peritoneal aluminosis; 8) aluminum pneumoconiosis of an occupational origin; 9) bronchospastic syndrome in aluminum smelter workers.


Patient powered prophylaxis: A 12-month study of individualized prophylaxis in adults with severe haemophilia A.
Adults with severe haemophilia A (SHA) may experience breakthrough bleeds despite standard weight-based FVIII prophylaxis three times weekly. Individualized prophylaxis has evolved to optimize patient outcomes. This study aimed to evaluate the impact of a standardized approach to individualized prophylaxis on annualized bleeding rates (ABR), factor utilization, physical activity and quality of life in adults with SHA. In this prospective cohort study, patients with baseline FVIII:C <2% and ABR >3 on weight-based prophylaxis received a standardized approach to individualized prophylaxis. Changes in ABR, annualized FVIII consumption and adherence from the 12-month prestudy and 12-month intervention period were compared. Changes in Haemo-QoL-A total score, Physical Functioning (PF) subscale and physical activity level measured by accelerometry were also examined. Eighteen patients participated (median age 26 years). Individualized prophylaxis decreased total bleeds in the population by 69% and traumatic bleeds by 73%. The median ABR decreased from 7.5 to 2 (P<.001). Annualized factor consumption increased by 7.3%, as a result of 66% reduction in factor utilization for treatment of bleeds and 25% increase in factor utilization for prophylaxis. Adherence scores for frequency and dosing did not change. There was a significant increase in the Haemo-QoL-A total score (P=.02) and PF score (P=.01) from baseline to 4 months but no change in physical activity. Patients with SHA who switched from standard to individualized prophylaxis show reduced ABR and increased FVIII consumption, and also improved their health-related quality of life. The mechanism is independent of adherence to prescribed prophylactic regimen.


[Acute compression of the optic nerve due to orbital emphysema].
Bony defects of the orbit with connection to the paranasal sinuses can lead to orbital emphysema. A case of compression of the optic nerve due to orbital emphysema in a 39-year-old man is reported. Visual acuity was hand movements only and intraocular pressure was increased to 32 mm Hg with an exophthalmus of 6 mm in comparison to the unaffected side. A sufficient pressure relief could be achieved by canthotomy with cantholysis and radial peritomy.


Cux-2 controls the proliferation of neuronal intermediate precursors of the cortical subventricular zone.
Whereas neurons of the lower layers (VI-V) of the cerebral cortex are first born from dividing precursors at the ventricular zone, upper layer neurons (II-IV) subsequently arise from divisions of intermediate neuronal precursors at the subventricular zone (SVZ). Little is known about mechanisms that control the proliferation of SVZ neuronal precursors. We herein report that the restricted expression of the homeodomain transcription factor Cux-2 in the SVZ regulates the proliferation of intermediate neuronal precursors and the number of upper layer neurons. In Cux-2-deficient mice (Cux-2-/-), there is excessive number of upper layer neurons and selective expansion of SVZ neuronal precursors. Double-labeling experiments demonstrate that Cux-2-/- upper layer precursors reenter the cell cycle in a higher frequency than wild-type precursors. Overexpression studies indicate that Cux-2 controls cell cycle exit in a cell-autonomous manner. Analysis of Cux-1-/-; Cux-2-/- double mutant revealed that Cux-2 controls SVZ proliferation independently of Cux-1, demonstrating that this is a unique function of Cux-2, not redundant with Cux-1 activities. Our results point to Cux-2 as a key element in the control of the proliferation rates of the SVZ precursors and the number of upper cortical neurons, without altering the number of deep cortical layers.


Removal of contrast medium from the coronary sinus during coronary angiography: feasibility of a simple and available technique for the prevention of nephropathy.
Contrast-induced nephropathy (CIN) is a major complication of percutaneous coronary interventions with currently limited preventive measures. To prevent CIN, we assessed the safety and feasibility of contrast removal from the coronary sinus (CS) during coronary angiography. We attempted contrast removal on seven patients undergoing coronary angiography with preexisting renal insufficiency (mean serum creatinine=262+/-56 mg%). In four patients, a balloon catheter could not be successfully deployed in the CS. In three patients, a balloon catheter with distal side holes was positioned in the CS orifice. The balloon was inflated to occlude the CS concurrent with coronary injections, and 12-16 ml of blood was aspirated after each injection. The procedure appeared to be safe, without adverse events and elevations of serum creatinine levels. Contrast media were effectively withdrawn (44%+/-8%) as assessed by fluoroscopy and dilution of blood. The increased venous pressure at the time of injection reduced coronary flow, allowing for small volumes of administered contrast. Occlusion of the CS during coronary angiography with aspiration of contrast media is safe and effective in reducing contrast load during coronary interventions. This procedure may reduce the risk for CIN in prone patients.


Development of a personal dosimetry system based on optically stimulated luminescence of alpha-Al2O3:C for mixed radiation fields.
To develop a personal optically stimulated luminescence (OSL) dosimetry system for mixed radiation fields using alpha-Al2O3:C, a discriminating badge filter system was designed by taking advantage of its optically stimulable properties and energy dependencies. This was done by designing a multi-element badge system for powder layered alpha-Al2O3:C material and an optical reader system based on high-intensity blue light-emitting diode (LED). The design of the multielement OSL dosimeter badge system developed allows the measurement of a personal dose equivalent value Hp(d) in mixed radiation fields of beta and gamma. Dosimetric properties of the personal OSL dosimeter badge system investigated here were the dose response, energy response and multi-readability. Based on the computational simulations and experiments of the proposed dosimeter design, it was demonstrated that a multi-element dosimeter system with an OSL technology based on alpha-Al2O3:C is suitable to obtain personal dose equivalent information in mixed radiation fields.


Soothing pain-elicited distress in Chinese neonates.
To test the effect of nonnutritive sucking (NNS), music therapy (MT), and combined NNS and MT (NNS + MT), versus no intervention, on heart rate, transcutaneous oxygen (TcPaO(2)) levels, and pain behavior of neonates in intensive care units having blood taken by a heel-stick procedure. A within-subjects, counter-balancing, repeated-measures design conducted in a government-funded hospital in Hong Kong, comparing TcPaO(2) levels, heart rate, and pain behavior outcomes in 27 neonates. Repeated-measures multivariate analysis of variance revealed statistically significant differences in outcomes across all interventions (Wilk's lambda =.142; F [3,27] = 31.82; eta2 =.47). One-way analysis of variance revealed that the 3 comfort interventions significantly reduced neonates' heart rate (Wilk's lambda =.647; F [2,27] = 18.93; eta2 =.35), improved their TcPaO(2) levels (Wilk's lambda =.481; F [2,27] = 37.42; eta2 =.51), and reduced their pain behavior (Wilk's lambda =.312; F [2,27] = 76.42; eta2 =.68). Posthoc scheffe tests revealed that NNS + MT had the strongest effect on neonates' TcPaO(2) levels and pain behavior; MT alone had the strongest effect on neonates' heart rate. Health professionals using NNS + MT when doing heel-sticks can improve the TcPaO(2) levels of neonates and reduce their pain. Using MT alone can improve the heart rate of neonates.


Medical reviews before cardiac arrest, medical emergency call or unanticipated intensive care unit admission: their nature and impact on patient outcome.
To measure and describe the extent and consequences of documented medical patient reviews in the 24 hours before a cardiac arrest, medical emergency team (MET) call or an unanticipated intensive care unit admission ("event"), and the use of such reviews as a rapid response system performance measure. Retrospective case-note and database review. Tertiary referral hospital, April-September, 2008. Adult inpatients who had an event and a preceding hospital length of stay > 24 hours. Hospital discharge status, ICU length of stay, not-for-resuscitation order. 443 patients had 575 events (6.1% cardiac arrests, 68.7% MET calls, 25.2% ICU admissions) in the study period. A documented medical review preceded 561 (97.6%) events. Patients whose review was a home team review (HTR; ie, from a general ward) only were older than those with a critical care review (CCR) (70.2 v 63.6 years; P < 0.01). A critical care discharge (CCD) or CCR preceded 39.5% and HTR only, 57.9% of events. A CCD preceded 25.7% of cardiac arrests, 32.4% of MET calls, and 29.0% unanticipated ICU admissions. Patients with a CCR or CCD had lower hospital mortality than those with an HTR only (27.3% v 41.7%; P < 0.01), and shorter median ICU length of stay (2 [interquartile range, 1-3] v 2 [interquartile range, 1-6] days; P = 0.04). Medical reviews in the 24 hours before an adverse event are common. The type of medical review may influence patient outcome and thus may be a useful measure of rapid-response systems and critical care performance.


The human primary somatosensory cortex response contains components related to stimulus frequency and perception in a frequency discrimination task.
Somatosensory stimulation of primary somatosensory cortex (SI) using frequency discrimination offers a direct, well-defined and accessible way of studying cortical decisions at the locus of early input processing. Animal studies have identified and classified the neuronal responses in SI but they have not yet resolved whether during prolonged stimulation the collective SI response just passively reflects the input or actively participates in the comparison and decision processes. This question was investigated using tomographic analysis of single trial magnetoencephalographic data. Four right-handed males participated in a frequency discrimination task to detect changes in the frequency of an electrical stimulus applied to the right-hand digits 2+3+4. The subjects received approximately 600 pairs of stimuli with Stim1 always at 21 Hz, while Stim2 was either 21 Hz (50%) or varied from 22 to 29 Hz in steps of 1 Hz. Both stimuli were 1 s duration, separated by a 1 s interval of no stimulation. The left-SI was the most consistently activated area and showed the first activation peak at 35-48 ms after Stim1 onset and sustained activity during both stimulus periods. During the Stim2 period, we found that the left-SI activation started to differ significantly between two groups of trials (21 versus 26-29 Hz) within the first 100 ms and this difference was sustained and enhanced thereafter (approximately 600 ms). When only correct responses from the above two groups were used, the difference was even higher at later latencies (approximately 650 ms). For one subject who had enough trials of same perception to different input frequencies, e.g. responded 21 Hz to Stim2 at 21 Hz (correct) and 26-29 Hz (error), we found the sustained difference only before 650 ms. Our results suggest that SI is involved with the analysis of an input frequency and related to perception and decision at different latencies.


Timing-Invariant CT Angiography Derived from CT Perfusion Imaging in Acute Stroke: A Diagnostic Performance Study.
Timing-invariant (or delay-insensitive) CT angiography derived from CT perfusion data may obviate a separate cranial CTA in acute stroke, thus enhancing patient safety by reducing total examination time, radiation dose, and volume of contrast material. We assessed the diagnostic accuracy of timing-invariant CTA for detecting intracranial artery occlusion in acute ischemic stroke, to examine whether standard CTA can be omitted. Patients with suspected ischemic stroke were prospectively enrolled and underwent CTA and CTP imaging at admission. Timing-invariant CTA was derived from the CTP data. Five neuroradiologic observers assessed all images for the presence and location of intracranial artery occlusion in a blinded and randomized manner. Sensitivity and specificity of timing-invariant CTA and standard CTA were calculated by using an independent expert panel as the reference standard. Interrater agreement was determined by using κ statistics. We included 108 patients with 47 vessel occlusions. Overall, standard CTA and timing-invariant CTA provided similar high diagnostic accuracy for occlusion detection with a sensitivity of 96% (95% CI, 90%-100%) and a specificity of 100% (99%-100%) for standard CTA and a sensitivity of 98% (95% CI, 94%-100%) and a specificity of 100% (95% CI, 100%-100%) for timing-invariant CTA. For proximal large-vessel occlusions, defined as occlusions of the ICA, basilar artery, and M1, the sensitivity and specificity were 100% (95% CI, 100%-100%) for both techniques. Interrater agreement was good for both techniques (mean κ value, 0.75 and 0.76). Timing-invariant CTA derived from CTP data provides diagnostic accuracy similar to that of standard CTA for the detection of artery occlusions in acute stroke.


[Features associated with retinal thickness extension in diabetic macular oedema].
Clinically significant macular edema has features that are associated with a major risk of visual loss, with thickening that involves the centre of the macula, field 7 or visual deficiency, although it is unknown if these features are related to retinal thickness extension. An observational, analytical, prospective, cross-sectional and open study was conducted. The sample was divided into initial visual acuity ≥0.5, central field thickness, center point thickness, field 7 and macular volume more than the reported 2 standard deviation mean value in eyes without retinopathy. The extension was determined by the number of the central field area equivalent thickening and these features were compared with by Student's t test for independent samples. A total of 199 eyes were included. In eyes with visual acuity of ≥0.5, the mean extension was 2.88±1.68 and 3.2±1.63 in area equivalent in eyes with visual acuity <0.5 (p=0.12). The mean extension in eyes with less than 2 standard deviation of central field thickness, center point thickness, field 7 and macular volume was significantly lower than in eyes with more than 2 standard deviations (1.9±0.93 vs. 4.07±1.49, 2.44±1.47 vs. 3.94±1.52, 1.79±1.07 vs. 3.61±1.57 and 1.6±0.9 vs. 3.9±1.4, respectively, p<0.001). The extension of retinal thickness is related with the anatomical features reported with a greater risk of visual loss, but is not related to initial visual deficiency.


Temporal trend of HIV infection: an update of the HIV surveillance system in Lazio, Italy, 1985-2000.
After the introduction of the highly active antiretroviral therapies, data from AIDS surveillance systems are less useful to describe the HIV epidemic, while HIV surveillance could give more detailed information to provide data for HIV prevention and care programmes. We report the results of the HIV surveillance system update in Lazio, Italy, from 1985 through 2000. New diagnoses of HIV infection were identified through a linkage procedure on the total reports, and underreporting was estimated through a link between the HIV surveillance system and the Hospital Information System of Lazio. As of December 2000, 20,912 new diagnoses of HIV occurred in Lazio. New diagnoses have decreased steadily since 1992. The male/female ratio decreased during the study period, while the number of foreign-born cases increased. Sexual transmission became the main modality of exposure for men in 1996 and for women in 1992. In 2000 the proportion of men infected by sexual transmission reached 54.0% versus 15.2% of those infected by intravenous drug use, whereas the proportion of women was 58.9% and 8.6% respectively. The sensitivity of the system has slightly decreased. HIV infection is increasing in women and immigrants; people are being infected more frequently by sexual transmission than intravenous drug use.


The effect of weaning on blood, hair, fecal and urinary mercury after chronic ingestion of methylmercuric chloride by infant monkeys.
Several studies suggest that infant animals may be more sensitive to toxic insult from methylmercury than adults. In our experiment, newly born infant monkeys were given equivalent daily doses of 50 micrograms Hg/kg body weight orally in the form of methylmercury for more than 60 weeks. Data revealed that after weaning at 200 days, both blood and hair mercury showed a sudden drop which was accompanied by an increase in fecal mercury excretion.


Stories as case knowledge: case knowledge as stories.
Every case contains a human story of illness and a medical story of disease, which together cover person management, case management, health system management and self-management. Much of that management can be learned via a thorough set of stories of typical and atypical core cases compiled by clinical teachers. Stories provide a highly flexible framework for illustrating the lessons of experience, the tips and traps for young players, and the dilemmas requiring careful judgement in the trade-offs between benefits and risks. Listening to real stories unfold is much more fun than being lectured (and better remembered). Stories illustrate 'what can happen' in a case as a guide to 'what to do'. A story begins with a real world situation with some predicament and a (causal) sequence of events or plot in which things are resolved one way or another. Patients tell their illness story; their clinician translates that into a disease story. Stories sort out what is important in such a predicament, consider the strategy and tactics of what to do, and speak about the outcomes. Each local situation provides relevance, context and circumstantial detail. Stories about case management can encapsulate practical knowledge, logical deduction, judgement and decision making, sharing with the student all the ingredients that develop expertise. Sometimes it is the plot that is important, sometimes the detail, sometimes it is the underlying message, the parable that resonates with the listener's experiences and feelings.1 Stories can also accommodate the complexity of multiple variables and the influence of other stakeholders, the uncertainties and dilemmas within the trade-offs, and the niceties of 'informed judgement'. This paper makes four points. First, clinical stories recount pointed examples of 'what happened' that expand our expertise in handling 'a case like that'. Second, cases are the unit of clinical work. Case stories expand the dimensions and details of case knowledge, case-based reasoning and case management. Carefully collated case stories can comprise the 'real life' clinical curriculum. Third, stories provide a framework for 'web' or 'net' thinking that links all the objective and subjective details within the multifaceted complexity of case management. Fourth, personal stories explain how both numerical and non-linear influences determined what decision was actually made in that case.


Intramolecular CH···O hydrogen bonds in the AI and BI DNA-like conformers of canonical nucleosides and their Watson-Crick pairs. Quantum chemical and AIM analysis.
The aim of this work is to cast some light on the H-bonds in double-stranded DNA in its AI and BI forms. For this purpose, we have performed the MP2 and DFT quantum chemical calculations of the canonical nucleoside conformers, relative to the AI and BI DNA forms, and their Watson-Crick pairs, which were regarded as the simplest models of the double-stranded DNA. Based on the atoms-in-molecules analysis (AIM), five types of the CH···O hydrogen bonds, involving bases and sugar, were detected numerically from 1 to 3 per a conformer: C2'H···O5', C1'H···O2, C6H···O5', C8H···O5', and C6H···O4'. The energy values of H-bonds occupy the range of 2.3-5.6 kcal/mol, surely exceeding the kT value (0.62 kcal/mol). The nucleoside CH···O hydrogen bonds appeared to "survive" turns of bases against the sugar, sometimes in rather large ranges of the angle values, pertinent to certain conformations, which points out to the source of the DNA lability, necessary for the conformational adaptation in processes of its functioning. The calculation of the interactions in the dA·T nucleoside pair gives evidence, that additionally to the N6H···O4 and N1···N3H canonical H-bonds, between the bases adenine and thymine the third one (C2H···O2) is formed, which, though being rather weak (about 1 kcal/mol), satisfies the AIM criteria of H-bonding and may be classified as a true H-bond. The total energy of all the CH···O nontraditional intramolecular H-bonds in DNA nucleoside pairs appeared to be commensurable with the energy of H-bonds between the bases in Watson-Crick pairs, which implies their possible important role in the DNA shaping.


Ontogeny and expression of chicken A blood group antigens.
Expression of chicken red blood cell (RBC) surface antigens was studied by using a monoclonal antibody (ISU-cA) specific for chicken A blood group antigens. Erythrocytes were examined from embryos of 3-18 days of incubation and from chicks at hatch up to 21 weeks of age. Specific antigens were detected on embryonic RBC surfaces by immunofluorescence as early as 3 days of incubation. Antigenic expression was examined by both haemagglutination and immunofluorescence and found to increase with age from embryos to mature birds. The antigen concentration on the cell surface was found to be affected by genotype; heterozygotes had an intermediate level of antigen between that of the two parental genotypes. These data confirm the co-dominance that is observed with most blood group antigens. Flow cytometric analysis allowed confirmation that the entire erythrocyte population gradually increased in antigenic expression over time, rather than having an antigen-negative subpopulation being replaced by a positive subpopulation.


Isoniazid-induced neuropathy in a pre-pubertal child.
Isoniazid (INH)-induced peripheral neuritis is not uncommonly reported in adults, especially those with malnutrition and alcoholism, but it is very rare in children. INH leads to peripheral neuritis by causing a deficiency in the serum level of pyridoxine which depends on the dose of INH, duration of treatment and the patient's nutritional and acetylator status. A 12-year-old girl developed tingling and numbness of the lower limbs after commencing anti-tuberculous therapy which included INH 10 mg/kg/day. The symptoms continued despite the dose being reduced to 5 mg/kg/day. Nerve conduction velocity was normal. Her diet was poor: she consumed little or no fruit and vegetables and ate mostly dal and rice. Discontinuation of INH was advised and her therapy was changed to ofloxacin, rifampicin, ethambutol and pyrazinamide along with a high dose of pyridoxine and multi-vitamins. The tingling and numbness subsided within 15 days, after which INH was prescribed at the dose of 10 mg/kg/day. Although INH-induced neuropathy is rare in children, the World Health Organization recommends pyridoxine prophylaxis for children on INH who are malnourished or have HIV infection.


[Magnetic resonance imaging findings on the eyelids of Japanese cadavers for anatomical studies and a comparative examination of their histological pictures].
To clarify ambiguous areas in interpreting MR images of Japanese eyelids, a histological examination was conducted on cadavers after the MRI for a comparative evaluation. Orbital sections including the unilateral upper and lower palpebrae of two Japanese cadavers (an 87-year-old woman and a 49-year-old man) were examined. Following MRI, the specimens of the same cadavers were examined histologically for a comparative evaluation. In both cadavers, a high signal intensity area with a hazy appearance unlike the orbital fat--fibroadipose tissue rich with connective tissue--was recognized between the orbicularis muscle and orbital septum. The same high signal intensity area that appeared to encase the posterior section of the descending orbital fat was also composed of fibroadipose tissue. Because of the presence of this intervening fibroadipose tissue, the posterior surface of the orbicularis muscle and the orbital septum could not come into contact with each other. Although limited to only two subjects, the current observation proved that fibroadipose tissue exists not only in the superficial layer of the orbital fat but that it further descends to surround the lowest portion of the orbital fat. As already reported, it was mainly the fibroadipose tissue, but not the orbital fat, that descends into the palpebral space.