Biotechnology of the medicinal plant Rhazya stricta: a little investigated member of the Apocynaceae family.
Rhazya stricta Decne. (Apocynaceae) is an important medicinal plant that is widely distributed in the Middle East and Indian sub-continent. It produces a large number of terpenoid indole alkaloids (TIAs) some of which possess important pharmacological properties. However, the yields of these compounds are very low. Establishment of a reliable, reproducible and efficient transformation method and induction of hairy roots system is a vital prerequisite for application of biotechnology in order to improve secondary metabolite yields. In the present review, recent biotechnological attempts and advances in TIAs production through transformed hairy root cultures in R. stricta are reviewed to draw the attention to its metabolic engineering potential.


Long-term litter manipulation alters soil organic matter turnover in a temperate deciduous forest.
Understanding soil organic matter (OM) biogeochemistry at the molecular-level is essential for assessing potential impacts from management practices and climate change on shifts in soil carbon storage. Biomarker analyses and nuclear magnetic resonance (NMR) spectroscopy were used in an ongoing detrital input and removal treatment experiment in a temperate deciduous forest in Pennsylvania, USA, to examine how above- and below-ground plant inputs control soil OM quantity and quality at the molecular-level. From plant material to surface soils, the free acyclic lipids and cutin, suberin, and lignin biomarkers were preferentially retained over free sugars and free cyclic lipids. After 20years of above-ground litter addition (Double Litter) or exclusion (No Litter) treatments, soil OM composition was relatively more degraded, as revealed by solid-state 13C NMR spectroscopy. Under Doubled Litter inputs, soil carbon and phospholipid fatty acid (PLFA) concentrations were unchanged, suggesting that the current OM degradation status is a reflection of microbial-mediated degradation that occurred prior to the 20-year sampling campaign. Soil OM degradation was higher in the No Litter treatments, likely due to the decline in fresh, above-ground litter inputs over time. Furthermore, root and root and litter exclusion treatments (No Roots and No Inputs, respectively) both significantly reduced free sugars and PLFAs and increased preservation of suberin-derived compounds. PLFA stress ratios and the low N-acetyl resonances from diffusion edited 1H NMR also indicate substrate limitations and reduced microbial biomass with these treatments. Overall, we highlight that storage of soil carbon and its biochemical composition do not linearly increase with plant inputs because the microbial processing of soil OM is also likely altered in the studied forest.


Characteristics of long-term survivors following sorafenib treatment for advanced hepatocellular carcinoma: report of a workshop at the 50th Annual Meeting of the Liver Cancer Study Group of Japan.
Little data are available on the long-term survival of patients treated with sorafenib for advanced hepatocellular carcinoma (HCC). During a consensus workshop at the 50th annual meeting of the Liver Cancer Study Group of Japan held in Kyoto (June 5-6, 2014), experts met to discuss the characteristics of long-term (>3 years) survivors of advanced HCC following sorafenib treatment. A total of 70 long-term survivors following sorafenib treatment at eight institutions were included, and the long-term survival rate (>3 years) at each institution ranged from 2.6 to 6.9% (mean, 4.5). The long-term survival-related factors presented can be categorized as follows: (1) conversion options, including hepatic resection following successful sorafenib treatment, (2) additional salvage options when progressive disease is confirmed, (3) long-term sorafenib treatment, (4) effective post-sorafenib options to prolong postprogression survival, and (5) good pretreatment liver function. Sorafenib monotherapy exceeding 3 years is rare, and most of the patients receiving sorafenib required other treatment modalities in the form of multidisciplinary therapy. The overview obtained from the workshop reflects the pattern of management in practice for long-term survivors following sorafenib treatment for HCC in Japan and may also provide valuable information for other countries.


Extraction of Time-Varying Spatiotemporal Networks Using Parameter-Tuned Constrained IVA.
Dynamic functional connectivity analysis is an effective way to capture the networks that are functionally associated and continuously changing over the scanning period. However, these methods mostly analyze the dynamic associations across the activation patterns of the spatial networks while assuming that the spatial networks are stationary. Hence, a model that allows for the variability in both domains and reduces the assumptions imposed on the data provides an effective way for extracting spatiotemporal networks. Independent vector analysis (IVA) is a joint blind source separation technique that allows for estimation of spatial and temporal features while successfully preserving variability. However, its performance is affected for higher number of datasets. Hence, we develop an effective two-stage method to extract time-varying spatial and temporal features using IVA, mitigating the problems with higher number of datasets while preserving the variability across subjects and time. The first stage is used to extract reference signals using group-independent component analysis (GICA) that are used in a parameter-tuned constrained IVA framework to estimate time-varying representations of these signals by preserving the variability through tuning the constraint parameter. This approach effectively captures variability across time from a large-scale resting-state fMRI data acquired from healthy controls and patients with schizophrenia and identifies more functionally relevant connections that are significantly different among healthy controls and patients with schizophrenia, compared with the widely used GICA method alone.


Heat shock RNA levels in brain and other tissues after hyperthermia and transient ischemia.
A number of studies have demonstrated increased synthesis of heat shock proteins in brain following hyperthermia or transient ischemia. In the present experiments we have characterized the time course of heat shock RNA induction in gerbil brain after ischemia, and in several mouse tissues after hyperthermia, using probes for RNAs of the 70-kilodalton heat shock protein (hsp70) family, as well as ubiquitin. A synthetic oligonucleotide selective for inducible hsp70 sequences proved to be the most sensitive indicator of the stress response whereas a related rat cDNA detected both induced RNAs and constitutively expressed sequences that were not strongly inducible in brain. Considerable polymorphism of ubiquitin sequences was evident in the outbred mouse and gerbil strains used in these studies when probed with a chicken ubiquitin cDNA. Brief hyperthermic exposure resulted in striking induction of hsp70 and several-fold increases in ubiquitin RNAs in mouse liver and kidney peaking 3 h after return to room temperature. The oligonucleotide selective for hsp70 showed equivalent induction in brain that was more rapid and transient than observed in liver, whereas minimal induction was seen with the ubiquitin and hsp70-related cDNA probes. Transient ischemia resulted in 5- to 10-fold increases in hsp70 sequences in gerbil brain which peaked at 6 h recirculation and remained above control levels at 24 h, whereas a modest 70% increase in ubiquitin sequences was noted at 6 h. These results demonstrate significant temporal and quantitative differences in heat shock RNA expression between brain and other tissues following hyperthermia in vivo, and indicate that hsp70 provides a more sensitive index of the stress response in brain than does ubiquitin after both hyperthermia and ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Arterial blood pressure and hyperviscosity in sickle cell disease.
Abnormal rheologic behavior of sickle cells is the result of increased viscosity of the blood caused by the polymerization of hemoglobin S and the resultant production of dense, dehydrated sickle erythrocytes. As the viscosity of sickle cells increases, there is a negative impact on blood flow, which contributes to the vascular occlusion process, the hallmark of the sickling disorders. Blood flow is directly proportional to the blood pressure and inversely proportional to the blood viscosity. Blood flow has important implications for the diagnosis and management of hypertension in sickle cell patients and for transfusion therapy for the acute and chronic complications of this disease.


Hyperthermic radiosensitization of cells from a human melanoma xenograft.
Cells derived directly from a human melanoma xenograft were exposed to radiation and/or hyperthermia under aerobic conditions in vitro. Single cell survival was assayed in soft agar. The activation energies for heat treatment alone were 420 +/- 40 kcal/mole (41.5-42.5 degrees C) and 170 +/- 10 kcal/mole (43.0-45.5 degrees C). Heat doses of 41.5 degrees C (30 min) or 43.5 degrees C (30 min) did not cause a reduction in the shoulder of the X-ray survival curve of the cells, but the D0 value was reduced. The thermal enhancement ratios (the ratio of the D0 values) were in the ranges 1.0-1.3 (41.5 degrees C, 30 min) and 1.1-1.7 (43.5 degrees C, 30 min), depending on the sequence and the time between the treatments. Repair of sublethal radiation damage was not significantly inhibited when treatments with 41.5 degrees C (30 min) or 43.5 degrees C (30 min) preceded irradiation, but was inhibited when 44.5 degrees C (30 min) was given immediately before radiation and when 41.5 degrees C (120 min) was given immediately after radiation. Implications of the results for clinical treatment of malignant melanomas are discussed.


Genetic control of wiring specificity in the fly olfactory system.
Precise connections established between pre- and postsynaptic partners during development are essential for the proper function of the nervous system. The olfactory system detects a wide variety of odorants and processes the information in a precisely connected neural circuit. A common feature of the olfactory systems from insects to mammals is that the olfactory receptor neurons (ORNs) expressing the same odorant receptor make one-to-one connections with a single class of second-order olfactory projection neurons (PNs). This represents one of the most striking examples of targeting specificity in developmental neurobiology. Recent studies have uncovered central roles of transmembrane and secreted proteins in organizing this one-to-one connection specificity in the olfactory system. Here, we review recent advances in the understanding of how this wiring specificity is genetically controlled and focus on the mechanisms by which transmembrane and secreted proteins regulate different stages of the Drosophila olfactory circuit assembly in a coordinated manner. We also discuss how combinatorial coding, redundancy, and error-correcting ability could contribute to constructing a complex neural circuit in general.


Exploring the beneficial role of telmisartan in sepsis-induced myocardial injury through inhibition of high-mobility group box 1 and glycogen synthase kinase-3β/nuclear factor-κB pathway.
In the present experimental study, cecal ligation and puncture significantly increased the myocardial injury assessed in terms of excess release of creative kinase-MB (CK-MB), cardiac troponin I (cTnI), interleukin (IL)-6 and decrease of IL-10 in the blood following 12 h of laparotomy procedure as compared to normal control. Also, a significant increase in protein expression levels of high-mobility group box 1 (HMGB1) and decreased phosphorylation of glycogen synthase kinase-3β (GSK-3β) was observed in the myocardial tissue as compared to normal control. A single independent administration of telmisartan (2 and 4 mg/kg) and AR-A014418 (1 and 2 mg/kg) substantially reduced sepsis-induced myocardial injury in terms of decrease levels of CK-MB, cTnI and IL-6, HMGB1, GSK-3β and increase in IL-10 and p-GSK-3β in the blood in sepsis- subjected rats. The effects of telmisartan at dose 4 mg/kg and AR-A014418 at a dose of 2 mg/kg were significantly higher than the telmisartan at a dose of 2 mg/kg and AR-A014418 1 mg/kg respectively. Further, no significant effects on different parameters were observed in the sham control group in comparison to normal. Therefore it is plausible to suggest that sepsis may increase the levels of angiotensin II to trigger GSK-3β-dependent signaling to activate the HMGB1/receptors for advanced glycation end products, which may promote inflammation and myocardial injury in sepsis-subjected rats.


Treatment of benign prostatic hyperplasia with phytosterols.
In a randomised, double-blind study, the preparation Curbicin, obtained from pumpkin seeds and dwarf palm plants (Cucurbita pepo L. and Sabal serrulata), was compared with a placebo in the treatment of symptoms caused by prostatic hyperplasia; 53 patients took part in the study, which was carried out over a 3-month period. Urinary flow, micturition time, residual urine, frequency of micturition and a subjective assessment of the effect of treatment were all significantly improved in the treatment group. No untoward side effects were noted.


Structure, function and dynamics in adenovirus maturation.
Here we review the current knowledge on maturation of adenovirus, a non-enveloped icosahedral eukaryotic virus. The adenovirus dsDNA genome fills the capsid in complex with a large amount of histone-like viral proteins, forming the core. Maturation involves proteolytic cleavage of several capsid and core precursor proteins by the viral protease (AVP). AVP uses a peptide cleaved from one of its targets as a "molecular sled" to slide on the viral genome and reach its substrates, in a remarkable example of one-dimensional chemistry. Immature adenovirus containing the precursor proteins lacks infectivity because of its inability to uncoat. The immature core is more compact and stable than the mature one, due to the condensing action of unprocessed core polypeptides; shell precursors underpin the vertex region and the connections between capsid and core. Maturation makes the virion metastable, priming it for stepwise uncoating by facilitating vertex release and loosening the condensed genome and its attachment to the icosahedral shell. The packaging scaffold protein L1 52/55k is also a substrate for AVP. Proteolytic processing of L1 52/55k disrupts its interactions with other virion components, providing a mechanism for its removal during maturation. Finally, possible roles for maturation of the terminal protein are discussed.


The Effect of Reiki and Aromatherapy on Vital Signs, Oxygen Saturation, and Anxiety Level in Patients Undergoing Upper Gastrointestinal Endoscopy: A Randomized Controlled Study.
This randomized controlled study aimed to determine the effect of Reiki and aromatherapy on vital signs, oxygen saturation, and anxiety level in patients undergoing upper gastrointestinal endoscopy. The sample consisted of 100 patients divided into Reiki (n = 34), aromatherapy (n = 33), and control (n = 33) groups. Data were collected 3 times (before, during, and after the procedure) using a descriptive characteristics questionnaire, a follow-up form, and the State Anxiety Subscale. The Reiki group had a mean State Anxiety Subscale score of 53.59 ± 2.98 and 43.94 ± 4.31 before and after the procedure, respectively. The aromatherapy group had a mean State Anxiety Subscale score of 54.03 ± 4.03 and 43.85 ± 3.91 before and after the procedure, respectively. The control group had a mean State Anxiety Subscale score of 38.79 ± 4.68 and 53.30 ± 7.26 before and after the procedure, respectively (P < .05). The results showed that the Reiki and aromatherapy groups had significantly lower State Anxiety Subscale scores than the control group after the procedure, indicating that Reiki and aromatherapy help reduce anxiety levels. There was a significant difference in the mean respiratory rates and oxygen saturation levels between the groups (P < .05). In conclusion, patients who do Reiki or undergo aromatherapy are less likely to experience anxiety before upper gastrointestinal endoscopy.


[Palliative treatment of esophageal cancer].
The AA. describe the indications, the technique and the complications of application of oesophageal endoprosthesis (Celestin or Haring) for palliative treatment of oesophageal cancer and they value the results of 34 applications of these prosthesis that were executed about Surgical Clinic in Verona with satisfactory results during the period 1974-77. They show the improvement of survival conditions in these patients, the rareness of complications, the absence of absolute contra-indications.


Comparison of anticancer activity of biocompatible ZnO nanoparticles prepared by solution combustion synthesis using aqueous leaf extracts of Abutilon indicum, Melia azedarach and Indigofera tinctoria as biofuels.
Recently, there has been an upsurge in the use of naturally available fuels for solution combustion synthesis (SCS) of nanoparticles. Although many reports suggest that these biofuels pose less harm to the environment, their strategic advantages and reliability for making NPs has not been discussed. In the present work, we try to address this issue using plant extracts as biofuels for the SCS of zinc oxide nanoparticles as a model system. In the present work, combustion synthesis of ZnO NPs using lactose and aqueous leaf extracts of Abutilon indicum, Melia azedarach, Indigofera tinctoria as biofuels has been carried out. A comparative analysis of the obtained powders has been conducted to understand the strategic advantages of using plant extracts over a chemical as combustion fuel for the synthesis of zinc oxide nanoparticles. The X-ray diffractograms of the samples revealed the presence of Wurtzite hexagonal structure with varying crystallite sizes. Morphological studies indicated that samples prepared using biofuels had smaller diameter than those prepared using lactose as fuel. Surface characteristics of the samples were measured by X-ray photoelectron spectroscopy. Qualitative phytochemical screening of aqueous leaf extracts revealed the presence of many phytochemicals in them, which might be responsible for combustion. Gas chromatography mass spectrum was carried out to detect the phytochemicals present in the aqueous extracts of the leaves. Further, anticancer evaluation carried out against DU-145 and Calu-6 cancer cells indicated higher anticancer activity of zinc oxide nanoparticles prepared using biofuels. The results of blood haemolysis revealed the biocompatibility of zinc oxide nanoparticles at lower concentrations. In conclusion, we propose that multiple other studies would be required in order to vindicate the potential advantages of using naturally available fuels in SCS.


Understanding catalyst behavior during in situ heating through simultaneous secondary and transmitted electron imaging.
By coupling techniques of simultaneous secondary (SE) and transmitted electron (TE) imaging at high resolution in a modern scanning transmission electron microscope (STEM), with the ability to heat specimens using a highly stable MEMS-based heating platform, we obtained synergistic information to clarify the behavior of catalysts during in situ thermal treatments. Au/iron oxide catalyst 'leached' to remove surface Au was heated to temperatures as high as 700°C. The Fe2O3 support particle structure tended to reduce to Fe3O4 and formed surface terraces; the formation, coalescence, and mobility of 1- to 2-nm particles on the terraces were characterized in SE, STEM-ADF, and TEM-BF modes. If combined with simultaneous nanoprobe spectroscopy, this approach will open the door to a new way of studying the kinetics of nano-scaled phenomena.


Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.
It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies. For example, both metabotropic glutamate receptor (mGluR) and muscarinic Ach receptor (mAchR) activation can cause rhythmic bursting at alpha/theta frequencies. Interestingly, key differences exist between mGluR- and mAchR-induced bursting, with the former involving extensive dendritic Ca2+ electrogenesis and being mimicked by a non-specific block of K+ channels with Ba2+, whereas the latter appears to be more reliant on proximal Na+ channels and a prominent spike afterdepolarization (ADP). This likely relates to the differential somatodendritic distribution of mGluRs and mAChRs and may have important functional consequences. We also show here that in similarity to some neocortical neurons, inhibiting large-conductance Ca2+-activated K+ channels in TC neurons can lead to fast rhythmic bursting (FRB) at approximately 40 Hz. This activity also appears to rely on a Na+ channel-dependent spike ADP and may occur in vivo during natural wakefulness. Taken together, these results show that TC neurons are considerably more flexible than generally thought and strongly endorse a role for the thalamus in promoting a range of cognitively-relevant brain rhythms.


Capillary zone electrophoresis of DNA fragments in a novel polymer network: poly(N-acryloylaminoethoxyethanol).
Migration of DNA fragments in the 51 to 21226 bp size range has been investigated by capillary zone electrophoresis in entangled solutions of linear poly(N-acryloylaminoethoxyethanol) from 8 to 16%. Plots of log mobility vs. log size (in base pairs, bp) clearly evidence three different migration regimes: according to Ogston (i.e. as spherical globules) up to 200 bp, reptation without stretching up to 3-4000 bp and reptation with partial stretching for larger fragments. Guidelines on the % polymer to be used for optimum resolution can be obtained from plots of peak spacing (in seconds per base pair) vs. % of polymer in solution and from standard plots of peak resolution vs. % polymer. An optimum linear poly(N-acryloylaminoethoxyethanol) concentration, allowing for good resolution of most fragments, from small to large, is found in the range 10% to 12% polymer (as opposed to conventional polyacrylamide, where a sharp maximum is obtained at 6% polymer). It is hypothesized that in situ polymerization allows for formation of a large distribution of polymer sizes, thus facilitating simultaneous separation of short and long DNA fragments based on the principle that shorter polyacrylamide chains will sieve shorter DNA fragments and vice versa. Due to the fact that the novel monomer is 500 times more resistant to hydrolysis and more hydrophilic than acrylamide, its polymeric solutions allow repeated sample injections (> 35) with minimal absolute standard deviations (of the order of +/- 3%). No carry-over nor sample precipitation at the injection port is experienced with the new matrix composed of poly(N-acryloylaminoethoxyethanol).


Impact of foetal-onset hypothyroidism on the epididymis of mature rats.
It is well established that congenital hypothyroidism leads to male infertility. However, there is a dearth of information on foetal-onset hypothyroidism-induced changes in the epididymis. With regard to transient hypothyroidism, the existing literature deals mainly with the testis. However, it is not known whether there is any corresponding alteration in epididymal morphology and physiology under such a condition. The present study is therefore aimed at understanding the impact of persistent and transient hypothyroidism on the concentration of epididymal sex steroids, as they play a vital role in maintaining the normal structure and function of the epididymis. Normal rats of 90 days of age served as controls (Group I). Hypothyroidism was induced by using pregnant/lactating mothers and post-weaning rats to 0.05% (w/v) methimazole (MMI) in the drinking water. Group II were subjected to persistent hypothyroidism from day 9 of post-coitum (pc) to 90 days. Group III rats were subjected to transient hypothyroidism from day 9 day pc to day 1 post-partum (pp), 21 pp or 35 pp (IIIa, b and c, respectively) and group IV rats were given simultaneous T3 supplementation (3 microg/100 g body wt./day i.m.) with MMI from day 9 pc to day 1 pp; 21 pp and 35 pp (Group IVa, b and c). Animals from all groups were killed on day 90 pp. Serum thyroid stimulating hormone (TSH) and thyroid hormones confirmed euthyroidism in group I, IIIa, b and c and IVa, b and c rats and hypothyroidism in group II rats. Caput and cauda epididymal concentration of testosterone, dihydrotestosterone (DHT), estradiol (E2) and androgen binding protein (ABP) markedly decreased in group II rats. While the concentration of testosterone, E2 and ABP increased in group III rats, that of DHT remained unaltered. However, group IV rats maintained normal concentration of the sex steroid and ABP. The activity of 5-alpha-reductase in the epididymis of all the groups followed the same trend as that of the concentration of epididymal DHT. From the present data it is evident that persistent hypothyroidism diminishes the bioavailability of androgens and oestrogens, while transient hypothyroidism enhances the same, indicating the importance of euthyroidism during foetal and neonatal period towards the maintenance of optimal hormonal status in the epididymis required for its maturation.


[Factors affecting clinical application of sex therapy for erectile dysfunction].
To discuss the factors that affect the clinical application of sex therapy for erectile dysfunction (ED). Urological researchers recommended free sex therapy to ED patients and their partners in the outpatient department and studied the factors affecting the patients of Medicaid their partnersology, acceptance of sex therapy by interview and observation. Many patients refused sex therapy. Only 11 pairs of volunteers underwent it, of whom 5 pairs gave up halfway, 1 pair were stopped by the therapist due to the breakup of their marriage, and merely 5 pairs accomplished the whole course. Among the 5 pairs of quitters, 2 pairs thought of their problem as organic and turned to drug therapy, 1 pair withdrew because the patient's girlfriend broke up with him, 1 pair gave up because they lived in another city too far away from the clinic, and the other pair discontinued because they could not spare the time from their work. Many factors affect the clinical application of sex therapy for ED in China. Apart from the shortage of qualified professional sex therapists, some factors from the patients and their partners are at work, such as stress of work, lack of time, home location, education background, relationship between the patient and his partner, attitude to sex therapy, and so on.


Allogeneic hematopoietic stem cell transplant for high-risk adult patients with chronic granulomatous disease: first case report from Iran.
We describe the successful hematopoietic stem cell transplant of a 22-year-old patient with chronic granulomatous disease at our center. Our case was a relatively old male patient compared with other patients having the diagnosis of chronic granulomatous disease who underwent hematopoietic stem cell transplant. The patient was diagnosed as chronic granulomatous disease at the age of 1 year when he developed repeated bacterial infections since 2 months of age and laboratory test revealed 0% of normal control value on nitroblue tetrazolium test. In December 2011, at 22 years of age, he underwent an allogeneic hematopoietic stem cell transplant from human leukocyte antigen fully matched sibling. Conditioning regimen was busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. He received methotrexate and cyclosporine as prophylaxis for graft-versus-host disease. Engraftment was achieved at day 13. At the time of this writing, the patient is alive and well with no serious complication and without any evidence of graft-versus-host disease or rejection 12 months after stem cell transplant.


Comparison of remimazolam-remifentanil and propofol-remifentanil during laparoscopic cholecystectomy.
Remimazolam is a novel benzodiazepine with fast onset and short half-life. We compared the effects of remimazolam and propofol on recovery profiles for general anesthesia in patients undergoing laparoscopic cholecystectomy. We randomly assigned 108 patients to either a remimazolam (n=54) or propofol (n=54) group. Remimazolam and propofol were used for induction and maintanance of anesthesia. Following anesthesia, we recorded the time until an Aldrete score of 9 was achieved as the primary surrogate marker of complete recovery. The time to reach a Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score of 2 and the time from the end of anesthesia to eye opening time, recovery time of orientation, time to spontaneous breathing, extubation time, and the time required for analgesics were measured. Heart rate, blood pressure, and bispectral index were assessed before, during, and after pneumoperitoneum. We included 101 patients in the analysis. In the remimazolam group, it took longer to reach an Aldrete score of 9 after the drug infusion ended (P = 0.031). There was no difference in the time to reach MOAA/S 2 between the two groups. The time to eye opening, recovery time of orientation, and time required for analgesics were longer and heart rate was higher in the remimazolam group. Neither blood pressure, nor extubation time differed between groups. Remimazolam and propofol provided safe induction and maintenance of anesthesia in patients undergoing laparoscopic cholecystectomy. The recovery time from anesthesia was longer than that with propofol. Fewer hemodynamic changes were observed with remimazolam, but further studies are needed.


ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth.
Tumor cell adaptation to hypoxic stress is an important determinant of malignant progression. While much emphasis has been placed on the role of HIF-1 in this context, the role of additional mechanisms has not been adequately explored. Here we demonstrate that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR), which adapts cells to endoplasmic reticulum (ER) stress. Inactivation of ISR signaling by mutations in the ER kinase PERK and the translation initiation factor eIF2alpha or by a dominant-negative PERK impairs cell survival under extreme hypoxia. Tumors derived from these mutant cell lines are smaller and exhibit higher levels of apoptosis in hypoxic areas compared to tumors with an intact ISR. Moreover, expression of the ISR targets ATF4 and CHOP was noted in hypoxic areas of human tumor biopsy samples. Collectively, these findings demonstrate that activation of the ISR is required for tumor cell adaptation to hypoxia, and suggest that this pathway is an attractive target for antitumor modalities.


Tinnitus in an active duty navy diver: A review of inner ear barotrauma, tinnitus, and its treatment.
This case elucidates subtle cues that must be appreciated by the examiner in diving related injuries, who may not have experience with barotrauma-mediated pathology. Inner-ear barotrauma (IEBT) does not mandate ostensible hearing loss or vertigo; tinnitus may be the sole manifestation. Symptoms may present hours or even days post-dive. A common misconception exists that there are no efficacious treatment options for IEBT short of surgery for an overt perilymphatic fistula. Treatment options are available including acute high dose steroid administration, as prescribed for acute noise-induced or idiopathic hearing loss, optimally administered within three weeks of the acute insult. Tinnitus does not necessarily constitute a chronic untreatable symptom, which the patient must learn "to live with".


Inactivation of the ampD gene causes semiconstitutive overproduction of the inducible Citrobacter freundii beta-lactamase.
In Citrobacter freundii and Enterobacter cloacae, synthesis of AmpC beta-lactamase is inducible by the addition of beta-lactams to the growth medium. Spontaneous mutants that constitutively overproduce the enzyme occur at a high frequency. When the C. freundii ampC beta-lactamase gene is cloned into Escherichia coli together with the regulatory gene ampR, beta-lactamase expression from the clone is inducible. Spontaneous cefotaxime-resistant mutants were selected from an E. coli strain carrying the cloned C. freundii ampC and ampR genes on a plasmid. Virtually all isolates had chromosomal mutations leading to semiconstitutive overproduction of beta-lactamase. The mutation ampD2 in one such mutant was caused by an IS1 insertion into the hitherto unknown ampD gene, located between nadC and aroP at minute 2.4 on the E. coli chromosome. The wild-type ampD allele cloned on a plasmid could fully trans-complement beta-lactamase-overproducing mutants of both E. coli and C. freundii, restoring the wild-type phenotype of highly inducible enzyme synthesis. This indicates that these E. coli and C. freundii mutants have their lesions in ampD. We hypothesize that induction of beta-lactamase synthesis is caused by blocking of the AmpD function by the beta-lactam inducer and that this leads directly or indirectly to an AmpR-mediated stimulation of ampC expression.


Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration.
After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired-a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.


Cytopathologic diagnosis of oncocytic type intraductal papillary mucinous neoplasm: Criteria and clinical implications of accurate diagnosis.
Cytologic findings of pancreatic oncocytic-type intraductal papillary mucinous neoplasms (IPMNs)/intraductal oncocytic papillary neoplasms (IOPNs) are largely unknown. Five IOPNs encountered by the authors were analyzed. Four IOPNs were located in the pancreatic head, and 1 was located in the pancreatic body/tail in 2 men and 3 women ages 56 to 84 years (mean age, 66 years). Radiologic diagnoses included pancreatic ductal adenocarcinoma (PDAC) in 2 patients, invasive cancer associated with IPMN in 1 patient, IPMN versus mucinous cystic neoplasm in 1 patient, and cystic mass in 1 patient. Cytologic findings included: hypercellular smears (4 of 5 cases) containing well formed clusters of oncocytic cells (5 of 5 cases) with prominent, slightly eccentric nucleoli (4 of 5 cases), predominantly arranged in sheets/papillary units (5 of 5 cases), with punched-out intercytoplasmic spaces (4 of 5 cases), and with occasional 3-dimensional groups and focal necrosis (3 of 5 cases). The intracytoplasmic mucin and thick extracellular mucin typical of other IPMNs were observed only in 2 cases and were very limited. The mean size on resection was 4.5 cm. Invasion was observed in 3 cases (0.1, 0.3, and 2.0 cm) of tubular-type IPMN. Initial cytologic evaluation was performed by the authors in 4 of 5 cases, which were diagnosed as IOPN (n = 3) and IPMN versus cystic PDAC (n = 1). One case was initially misdiagnosed as PDAC and, on resection, proved to be noninvasive IOPN. Cytologic features of IOPNs are classical, similar to their histologic counterparts, and differ significantly from other IPMN subtypes. Because of their highly complex appearance, they are often radiologically misdiagnosed as PDAC; thus, failure to recognize their characteristic features on fine-needle aspiration may lead to inappropriate treatment. Patients with IOPN have an incomparably better prognosis than patients with ordinary PDAC, even when their neoplasms are invasive.


How do messenger RNA splicing alterations drive myelodysplasia?
Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS.


Assessment of arteriovenous malformations with 3-Tesla time-resolved, contrast-enhanced, three-dimensional magnetic resonance angiography.
Although conventional catheter angiography is commonly used in the evaluation of intracranial arteriovenous malformations (AVMs), less invasive tools are more suitable for screening or follow-up. Older MR angiography techniques cannot provide high enough temporal and spatial resolution for assessing AVMs. Threetesla time-resolved imaging of contrast kinetics (TRICKS)-a time-resolved, contrast-enhanced 3D MR angiography technique-achieves subsecond time resolution without sacrificing spatial resolution. The purpose of this study was to assess the accuracy of TRICKS at 3 T in the evaluation of AVMs. Between November 2006 and November 2007, 31 patients who were known to have AVMs underwent evaluation in a 3-T unit with the TRICKS technique. The TRICKS images were then evaluated independently by 2 radiologists for nidus detection, early venous filling detection, and Spetzler-Martin classification, and these results were compared with the results of catheter angiography. Time-resolved imaging of contrast kinetics achieved 96% sensitivity and 100% specificity both in nidus detection and early venous filling detection. The Spetzler-Martin grades also showed excellent correlation with catheter angiography findings (kappa= 0.89). Although this is a preliminary study, the authors' results indicate that time-resolved contrast-enhanced 3D MR angiography at 3 T is a good tool to assess AVMs, and has the potential to replace catheter angiography in screening or follow-up examinations of patients with AVMs.


[Professor V.A. Dunaevsky (on the occasion of the 100th anniversary)].
The purpose of the work is to highlight the scientific, clinical, pedagogical and social activities of the famous dentist, participant of the Great Patriotic War, Doctor of Medical Sciences, Professor Vladimir Arsenievich Dunaevsky in connection with the 100th anniversary of his birth, and also to note the peculiarities of his personality, character and merits in the organization dental care to the population.


[Effect of astragaloside on myocardial fibrosis in chronic myocarditis].
To investigate the effect of astragaloside (Astr), one of the active components of the Chinese medical herb Astragulus membranaceus, on cardiac fibrosis in chronic myocarditis and its relevant mechanisms. Eighty mice were randomized into 3 groups, the control group (n=20), the model group (n=30) and the Astr group (n=30). Mice in the model group and the Astr group were monthly intraperitoneally inoculated with CVB3, but to the control group equal amount of culture fluid was given instead. Mice in the control and the model group were fed with drinking water while those in the Astr group with drinking water containing Astr-sodium carboxymethycellulose at a concentration of 300 mg/L. All the survived mice were sacrificed 3 months later. Heart tissue of mice was stained by picrosirius red for calculating collagen volume fraction (CVF) with an automatic image analysis system. Expressions of transforming growth factor beta1 (TGF-beta1), platelet derived growth factor (PDGF), matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1), MMP-13 and MMP-14 in heart tissue were detected by Western blot analysis. As compared with the model group, in the Astr group, the mortality and CVF were significantly lower (53.3% vs. 23.3%, chi2 = 4.23, P < 0.05), and (17.4 +/- 1.2% vs. 8.6 +/- 0.9%, chi2 = 5.38, P < 0.05), respectively. As compared with the control group, Western blot analysis showed that expression of TGF-beta1 was decreased, MMP-1 and TIMP-1 were down-regulated, while expressions of MMP-13 and MMP-14 were up-regulated after Astr treatment. Astr could lower the mortality and alleviate the myocardial fibrosis of mice with chronic myocarditis. Its antifibrotic effect might be realized by way of inhibiting TGF-beta1 expression and up-regulating the expressions of MMP-13 and MMP-14 in the heart tissues.


Novel gold-capped nanopillars imprinted on a polymer film for highly sensitive plasmonic biosensing.
Herein, a nanoporous alumina was fabricated to use as a mold in transforming nanopillar structures onto a thin film polymer by thermal nanoimprint lithography (NIL). The size of the pores was successfully controlled by varying the applied voltages and etching time. These nanoporous structures were transferred to the Cyclo-olefin polymer (COP) film surface from the porous mold by a thermal nanoimprinting process. A plasmonic substrate was fabricated by sputtering a thin layer of gold onto this nanopillar polymer structure, and the refractive index response in a variety of media was evaluated. Finally, the biosensing capacity of this novel plasmonic substrate was verified by analysis of Human immunoglobulin and achieved a minimum detection limit of 1.0 ng/mL. With the advantages of mass production with consistent reproducibility stemming from the nanoimprint fabrication process, our gold-capped polymeric pillars are ready for the transition from academic interest into commercialization systems for practical use in diagnostic applications.


An Interplay between Senescence, Apoptosis and Autophagy in Glioblastoma Multiforme-Role in Pathogenesis and Therapeutic Perspective.
Autophagy, cellular senescence, programmed cell death and necrosis are key responses of a cell facing a stress. These effects are partly interconnected, but regulation of their mutual interactions is not completely clear. That regulation seems to be especially important in cancer cells, which have their own program of development and demand more nutrition and energy than normal cells. Glioblastoma multiforme (GBM) belongs to the most aggressive and most difficult to cure cancers, so studies on its pathogenesis and new therapeutic strategies are justified. Using an animal model, it was shown that autophagy is required for GBM development. Temozolomide (TMZ) is the key drug in GBM chemotherapy and it was reported to induce senescence, autophagy and apoptosis in GBM. In some GBM cells, TMZ induces small toxicity despite its significant concentration and GBM cells can be intrinsically resistant to apoptosis. Resveratrol, a natural compound, was shown to potentiate anticancer effect of TMZ in GBM cells through the abrogation G2-arrest and mitotic catastrophe resulting in senescence of GBM cells. Autophagy is the key player in TMZ resistance in GBM. TMZ can induce apoptosis due to selective inhibition of autophagy, in which autophagic vehicles accumulate as their fusion with lysosomes is blocked. Modulation of autophagic action of TMZ with autophagy inhibitors can result in opposite outcomes, depending on the step targeted in autophagic flux. Studies on relationships between senescence, autophagy and apoptosis can open new therapeutic perspectives in GBM.


Tissue and cellular biomechanics during corneal wound injury and repair.
Corneal wound healing is an enormously complex process that requires the simultaneous cellular integration of multiple soluble biochemical cues, as well as cellular responses to the intrinsic chemistry and biophysical attributes associated with the matrix of the wound space. Here, we document how the biomechanics of the corneal stroma are altered through the course of wound repair following keratoablative procedures in rabbits. Further we documented the influence that substrate stiffness has on stromal cell mechanics. Following corneal epithelial debridement, New Zealand white rabbits underwent phototherapeutic keratectomy (PTK) on the right eye (OD). Wound healing was monitored using advanced imaging modalities. Rabbits were euthanized and corneas were harvested at various time points following PTK. Tissues were characterized for biomechanics with atomic force microscopy and with histology to assess inflammation and fibrosis. Factor analysis was performed to determine any discernable patterns in wound healing parameters. The matrix associated with the wound space was stiffest at 7days post PTK. The greatest number of inflammatory cells were observed 3days after wounding. The highest number of myofibroblasts and the greatest degree of fibrosis occurred 21days after wounding. While all clinical parameters returned to normal values 400days after wounding, the elastic modulus remained greater than pre-surgical values. Factor analysis demonstrated dynamic remodeling of stroma occurs between days 10 and 42 during corneal stromal wound repair. Elastic modulus of the anterior corneal stroma is dramatically altered following PTK and its changes coincide initially with the development of edema and inflammation, and later with formation of stromal haze and population of the wound space with myofibroblasts. Factor analysis demonstrates strongest correlation between elastic modulus, myofibroblasts, fibrosis and stromal haze thickness, and between edema and central corneal thickness. Tissue biomechanics during the course of corneal wound healing is documented for the first time through atomic force microscopy, and is correlated with advanced clinical imaging and immunohistochemistry. Parameters obtained from the study are applied in a multivariate statistical model to cluster the data for better classification and monitor the wound repair process. Elastic modulus of the anterior corneal stroma is dramatically altered following wounding and correlates initially with the development of edema and inflammation, and later with formation of stromal haze and population of the wound space with myofibroblasts. Importantly, the occurrence of myofibroblasts is preceded by changes in tissue mechanics, which is important to consider in light of crosslinking procedures applied to treat corneal diseases.


Rapid spontaneous Raman light sheet microscopy using cw-lasers and tunable filters.
We perform rapid spontaneous Raman 2D imaging in light-sheet microscopy using continuous wave lasers and interferometric tunable filters. By angularly tuning the filter, the cut-on/off edge transitions are scanned along the excited Stokes wavelengths. This allows obtaining cumulative intensity profiles of the scanned vibrational bands, which are recorded on image stacks; resembling a spectral version of the knife-edge technique to measure intensity profiles. A further differentiation of the stack retrieves the Raman spectra at each pixel of the image which inherits the 3D resolution of the host light sheet system. We demonstrate this technique using solvent solutions and composites of polystyrene beads and lipid droplets immersed in agar and by imaging the C-H (2800-3100cm(-1)) region in a C. elegans worm. The image acquisition time results in 4 orders of magnitude faster than confocal point scanning Raman systems, allowing the possibility of performing fast spontaneous Raman·3D-imaging on biological samples.


Absorption kinetics of low-dose chewable aspirin--implications for acute coronary syndromes.
This study describes the implications of the pharmacokinetics of low-dose chewable aspirin for acute coronary syndromes. Current guidelines recommend the administration of 162-325 mg aspirin chewing tablets for the treatment of acute myocardial infarction. Although aspirin is widely used and a cornerstone in myocardial infarction, there is no information available on the pharmacokinetics of low doses of chewable aspirin. This prospective trial assessed the pharmacokinetics of acetylsalicylic acid and its metabolite salicylic acid after intake of 162 mg chewable low-dose aspirin in 35 healthy volunteers. Plasma drug and metabolite levels were analysed using high-performance liquid chromatography, and corresponding pharmacodynamics were determined by impedance aggregometry. Acetylsalicylic acid was rapidly absorbed with a mean Tmax of 27 ± 8 min. Tmax of salicylic acid was 69 ± 21 min. Mean Cmax was 1·8 ± 0·6 mg/L and 7·6 ± 1·4 for acetylsalicylic acid and salicylic acid, respectively. Arachidonic acid-induced aggregation showed maximum platelet inhibition 30 min after drug ingestion. The characterization of the plasma-time profile fills the gap between the lack of data on pharmacokinetics and the pharmacodynamics and the recommendation for using low-dose chewable aspirin for acute coronary syndromes. We describe for the first time that a 162-mg dose of chewable aspirin is rapidly absorbed and achieves plasma concentrations of the active metabolite salicylic acid required to maximally inhibit platelet aggregation. However, a 162-mg dose is truly a minimum, and doubling this dose might be better for patients with myocardial infarction.


The multidrug transporter ABCG2: still more questions than answers.
ABCG2 is one of at least three human ATP binding cassette (ABC) transporters which can facilitate the export from cells of a wide range of chemically unrelated drug molecules. This capacity for multidrug transport is not only a confounding factor in chemotherapy, but is also one of the more perplexing phenomena in transporter biochemistry. Since its discovery in the last decade of the 20th century much has been revealed about ABCG2's localization, physiological function and its broad substrate range. There have also been many investigations of its structure and molecular mechanism. In this mini review article we take a Rumsfeldian approach to ABCG2 and essentially ask what we do know about this transporter, and what we will need to know about this transporter if we wish to use modulation of ABCG2 activity as a therapeutic approach.


Malaria Vectors Insecticides Resistance in Different Agroecosystems in Western Kenya.
Malaria vector control efforts have taken malaria related cases down to appreciable number per annum after large scale of intervention tools. Insecticides-based tools remain the major control option for malaria vectors in Kenya and, therefore, the potential of such programs to be compromised by the reported insecticide resistance is of major concern. The objective of this study was to evaluate the status of insecticide resistance in malaria vectors in different agro ecosystems from western Kenya. The study was carried out in the lowlands and highlands of western Kenya namely; Ahero, Kisian, Chulaimbo, Emutete, Emakakha, Iguhu, and Kabula. World Health Organization tube bioassays was conducted using standard diagnostic dosages of Lambdacyhalothrin, Deltamethrin, Permethrin, DDT, Bendiocarb, and Malathion tested on Anopheles mosquitoes collected from seven sites; Ahero, Kisian, Chulaimbo, Emutete, Emakakha, Iguhu, and Kabula. Biochemical assays, where the enzymatic activity of three enzymes (monooxygenases, esterases, and glutathione S-transferases) were performed on susceptible and resistant mosquito populations. Wild mosquito populations were identified to species level using polymerase chain reaction (PCR). The species of the wild mosquito populations were identified to species level using PCR. Real-time PCR was performed on the susceptible and resistant mosquitoes after the WHO tube bioassays to determine the presence of knockdown resistance (kdr) allele. WHO susceptibility tests indicated that Anopheles gambiae showed resistance to Pyrethroids and DDT in all the study sites, to Bendiocarb in Iguhu and Kabula and susceptible to Malathion (100% mortality) in all the study sites. There was an elevation of monooxygenases and esterases enzymatic activities in resistant An. gambiae mosquito populations exposed to Lambdacyhalothrin, Permethrin, Deltamethrin and DDT but no elevation in glutathione S-transferases. A high frequency of L1014S allele was detected in An. gambiae s.s. population, but there was no kdr allele found in Anopheles arabiensis mosquitoes. An. gambiae mosquitoes from western Kenya have developed phenotypic resistance to pyrethroids and DDT. Therefore, there is a need for further research covering different climatic zones with different agroeconomic activities for detailed report on current status of insecticide resistance in malaria vectors.


Lead concentrations of enamel and dentine of deciduous teeth of children from two Finnish towns.
The proton-induced x-ray emission method was used to analyze lead concentrations in enamel and dentine of deciduous teeth of 105 6- and 9-yr-old children living in two Finnish towns. Helsinki, the capital city, was assumed to represent high lead exposure and Kuopio, a country town in the middle of Finland, low or moderate lead exposure. In all but two teeth the enamel contained higher lead concentrations than dentine. The individual enamel-dentine lead concentration ratio was not stable but varied greatly. The median dentine lead concentration for 9-yr-old children in Helsinki and Kuopio was 2.0 ppm and 2.9 ppm, respectively, and for 6-yr-old children was 2.5 ppm and 2.7 ppm, respectively. The enamel lead concentrations found in 9-yr-olds in Helsinki and Kuopio were 4.2 and 4.5 ppm, and in 6-yr-olds were 9.1 and 4.4 ppm, respectively. The results reveal low or moderate lead concentrations. Nevertheless, a twofold and statistically significant (P less than .01) increase was found in the enamel of Helsinki children born in 1974 compared with those born in 1971.


Expression and localization of angiogenin in placenta: enhanced levels at term over first trimester villi.
Human angiogenin, a 14-kDa non-glycosylated polypeptide with both angiogenic and ribonucleolytic activities, is implicated in angiogenesis, a complex process of proliferation and formation of new capillary blood vessels from existing blood vessels. Placental growth requires extensive angiogenesis, which develops its vascular structure in both fetal chorionic villi and maternal deciduas. In this study, we investigated the expression profiles of angiogenin in placental villi from early and late gestation at both mRNA and protein levels using explant cultures in vitro followed by RT-PCR, immunoblot, and immunohistochemical analyses. From functionally active placental explants, angiogenin was detected in conditioned media of all the samples from first trimester and term group. The mean levels of angiogenin produced by term villi were found to be 2.6-, 2.1-, and 2.2-fold higher (P < 0.01) than first trimester villi at 24, 48, and 72 hr of culture, respectively. Expression profiles of angiogenin from term and first trimester villi seem to agree with its mRNA levels and immunoblot analysis; the expression in term villi was twice that in first trimester villi. The presence of angiogenin in placental villi and upregulation of its production towards term indicate that angiogenin production by the placenta is specific to the developmental stage. In conclusion, the observed changes in the localization and mRNA expression of angiogenin during placental development raise the possibility that it is involved in morphological and angiogenic changes in this endocrine organ vital to the successful fetal outcome during pregnancy.


Nonadiabatic effects in electronic and nuclear dynamics.
Due to their very nature, ultrafast phenomena are often accompanied by the occurrence of nonadiabatic effects. From a theoretical perspective, the treatment of nonadiabatic processes makes it necessary to go beyond the (quasi) static picture provided by the time-independent Schrödinger equation within the Born-Oppenheimer approximation and to find ways to tackle instead the full time-dependent electronic and nuclear quantum problem. In this review, we give an overview of different nonadiabatic processes that manifest themselves in electronic and nuclear dynamics ranging from the nonadiabatic phenomena taking place during tunnel ionization of atoms in strong laser fields to the radiationless relaxation through conical intersections and the nonadiabatic coupling of vibrational modes and discuss the computational approaches that have been developed to describe such phenomena. These methods range from the full solution of the combined nuclear-electronic quantum problem to a hierarchy of semiclassical approaches and even purely classical frameworks. The power of these simulation tools is illustrated by representative applications and the direct confrontation with experimental measurements performed in the National Centre of Competence for Molecular Ultrafast Science and Technology.


Gastric lesser curve superficial seromyotomy: an experimental study in dogs.
Lesser curve superficial myotomy has been investigated in the dog. The anatomical basis for the operation is discussed. The operation has the advantage of being easily performed and the risk of damage to the nerve of Latarjet or ischemic necrosis of the lesser curvature is obviated. Acid studies in the dogs confirmed that the operation was capable of producing secretory inhibition in keeping with vagotomy of the parietal cell area. The experiment needs further investigation in animals and in man, for assessment of the potential of the operation to replace other forms of vagotomy in patients with duodenal ulcer.


Economic inequality increases the number of hours worked and decreases work-life balance perceptions: longitudinal and experimental evidence.
International institutions' attention to work-life balance (WLB) demonstrates the global breadth of this issue. Yet the scientific community has thus far paid little attention to its structural underpinnings and to the interplay between these macro-level underpinnings and individual psychological factors. We examine the contextual role of economic inequality at the national level as a significant factor influencing working time and WLB perceptions using multiple empirical strategies. In the first set of studies (1a and 1b), we compared countries with different levels of inequality (Study 1a with 37 countries, Study 1b with longitudinal data from 34 countries, N = 254) and found increased working time and reduced WLB in highly unequal countries. In a pilot study (N = 81) and in the pre-registered Studies 2 (N = 338) and 3 (N = 499) we corroborated this evidence with an experimentally induced inequality perception, reporting an indirect effect of inequality on WLB (Studies 2 and 3) and working time (Study 3) through status anxiety and competitiveness. In Study 2, we manipulated socio-economic class in addition to economic inequality, showing that the detrimental effect of inequality on WLB is especially marked for participants assigned to a low-class condition. This research contributes to an integrated understanding of the impact of economic inequality and socio-economic class in shaping WLB and provides useful insights for organizations to develop context-specific policies to improve employees' WLB that take both individual and structural factors into account.


Left ventricular endocardial calcification in a patient with myeloproliferative disease.
The case of a 57-year-old male with a history significant for myeloproliferative disease, chronic renal failure, hypertension, and prostate cancer is described. His complete blood count was remarkable for neutrophilia and, notably, eosinophilia. Subsequent to two syncopal episodes, a transthoracic echocardiogram was performed as part of the workup, which showed an unusual calcified mass in the left ventricular apical region but separate from the apical myocardium, with normal left ventricular systolic function. A transesophageal echocardiogram and computed tomography of the chest confirmed the presence of extensive calcification in the left ventricle of unusual location and shape. This patient probably had Loeffler endocarditis related to myeloproliferative disorder, complicated by calcification of the endocardial sclerotic lesions.


Effect of cholesterol feeding and fasting on sterol synthesis in seventeen tissues of the rat.
Rates of sterol synthesis were measured in 17 tissues of the rat, and the responsiveness of these rates to cholesterol feeding and to fasting was determined. The liver and gastrointestinal tract together account for 90% of synthetic activity of the whole body. After the rats had been fed cholesterol or fasted, liver synthesis was markedly decreased, whereas synthetic rates in all other organs tested were essentially unaffected (this conclusion applies to synthesis of cholesterol and of five other digitonin-precipitable tissue sterols). Consequently, the highest rate of cholesterogenesis in the cholesterol-fed or fasted rat is found in the gastrointestinal tract.


Somatostatin and octreotide in gastroenterology.
Somatostatin and octreotide have a definitive role in the management of symptomatic gut neuroendocrine tumours, particularly VIPomas and carcinoid. They probably also have a role in variceal bleeding, but this needs further confirmatory randomized trials. At present there is a potential role in the management of short bowel syndrome, dumping syndrome and gastrointestinal fistulae, but randomized clinical studies are needed. Possibly there is a role in AIDS-related diarrhoea and 'idiopathic' secretory diarrhoea, but more evidence is required. They have no role in acute pancreatitis and peptic ulcer bleeding. Irritable bowel syndrome remains unexplored but unlikely to benefit.


Metabolic Effects of Metformin in Humans.
Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes. Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.


Immunological characteristics of umbilical cord blood cells: phenotypic and functional analysis.
The purpose of this study was to phenotype and assay immunological function on cord blood from 70 samples. Immunophenotyping indicated similar numbers of CD2, 3, and 8-positive cells as in adult bone marrow. CD4-positive cells were increased and CD19, 20, and CD56-positive cells were decreased in numbers. Proliferative responses to nonspecific mitogens were lower in cord blood cells than in adult cells, as was NK activity and spontaneous secretion of IL-6 and TNF-alpha. This study confirms the relative immaturity of cord blood cells even when some functional assays appear normal.


Biology of male fertility control: an overview of various male contraceptive approaches.
The population of our planet continues to grow at an alarming rate. If the growth continues at the present rate, the estimated current world population of about seven billion is expected to double in the next forty years. Accumulated data from surveys by the United Nations Population Control Division suggest that a majority of today's young men in many countries are willing to have fewer children than their parents did. However, the contraceptive options available to them have not changed in several decades. In spite of the general agreement that men, like women, must take full responsibility of their fertility, the availability of safe, reversible and affordable contraceptives for men have lagged behind because of the complexity of the science of the male reproductive system. Thus, the contraceptive needs of millions of men/couples go unmet every single day and results in millions of unwanted pregnancies. In this article, we intend to discuss new hormonal and non-hormonal contraceptive approaches that are at various stages of research and development and may someday provide new contraceptives for men. In addition, we intend to discuss many details of three safe, effective, affordable and reversible vas-based approaches that are inching closer to being approved for use by millions of men in multiple countries. Finally, our intention is to discuss the male contraceptive pill that will soon be available to men only in Indonesia. The availability of these male contraceptives will allow both men and women to take full control of their fertility and participate in slowing down the growth of world population.


Use of Health Information Exchange in the Continuity of Care as Viewed by Patients and Nurses: A Cross-Sectional Study.
Patients' attitudes toward sharing their personal health information are critical for implementation of health information exchange. Nurses contribute significantly to information sharing within the care continuum in hospitals and community. This study aimed to examine the awareness and readiness of patients with chronic illness and nurses to the use health information exchange. A cross-sectional study was conducted among 314 inpatients with a chronic illness, 110 nurses working in internal wards, and 55 contact nurses working in a large health maintenance organization. The findings showed that the mean level of awareness was low across all three groups. Contact nurses expressed more positive attitudes than internal ward nurses or patients and were more willing than patients to share information with healthcare workers. Knowledge, attitudes, and being a nurse predicted the intention to share information with medical healthcare providers and with agents not involved in direct care. Before implementation of a health information exchange system, it is important to raise awareness, readiness, and intention to use it among the public, nurses, and other medical staff. Policy makers should organize national campaigns under the auspices of the Ministry of Health to present the advantages and provide detailed information about the system.


Patients benefit from using own CD4 T-cells.
HIV researchers continue to explore novel ways to fight the disease and enhance the benefits of antiretroviral therapy. One new approach involves the transferring activated autologous CD4 T-cells into HIV-infected patients with the goal of augmenting natural immunity to HIV infection. Reconstituting CD4 helper cell activity, along with decreasing CCR5 expression, may augment natural immunity to HIV infection, according to a newly published study.


Regional adjuvant chemotherapy after partial hepatectomy for metastatic colorectal carcinoma.
The prognostic factors after hepatic resection for metastases from colorectal carcinoma were examined, and the results of adjuvant hepatic arterial chemotherapy are presented. Hepatic resection was undertaken in 57 patients with metastatic liver tumor from colorectal cancer. Adjuvant hepatic arterial chemotherapy using 5-fluorouracil, doxorubicin or epirubicin, and mitomycin C was administered to 31 patients. The 3- and 5-year survival rates for the 57 patients were 53% and 23%, respectively. The significant prognostic factors were solitary liver tumor and metachronous liver tumor. However, type of hepatectomy, surgical margin, site of the primary tumor, and histologic differentiation of the carcinoma did not relate to the prognosis. The 3- and 5-year survival rates for the patients given adjuvant arterial chemotherapy were 57% and 57%, respectively, indicating a significantly better survival rate than in the nontreated patients. These results suggest that hepatic arterial chemotherapy is effective treatment in patients with hepatic resection for metastases from colorectal carcinoma. However, recurrence in the lung is relatively high. Further improvement might be achieved by administering hepatic arterial chemotherapy as well as effective systemic chemotherapy.


Adrenal myelolipoma. 6 cases and a review of the literature.
Adrenal myelolipoma is an uncommon, benign and hormonally inactive tumor. Most lesions are asymptomatic and usually are discovered incidentally at autopsy studies. Authors report on 6 patients (5 women, 1 man) with adrenal myelolipomas (5 right, 1 left), analyze their morphological findings and association with an adrenal hormonal overproduction. Five of the patients underwent surgery because of tumor size, in 3 of them histological evaluation confirmed myelolipoma and in 2 cases an adrenocortical adenoma with foci of myelolipoma. All the patients were asymptomatic and in 4 cases hormonal overproduction was not found. One female patient has oveproduction of dehydroepiandrosteron-sulphate (DHEAS) indicating a 3beta hydroxylase deficiency in this tumor and 1 patient has primary aldosteronism with a histological finding of an association of adrenocortical adenoma with foci of myelolipoma. Neither Cushings syndrome nor congenital adrenal hyperplasia were present in our group of patients.


Studies on the novel antiallergic agent HSR-609: its penetration into the central nervous system in mice and guinea pigs and its selectivity for the histamine H1-receptor.
We studied the pharmacological characteristics of HSR-609 (3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11- ylidene)- piperidino]propionic acid dihydrate), a novel amphoteric antiallergic agent, on the central nervous system (CNS). Its selectivity for the histamine H1-receptor and its ability to penetrate into the CNS were compared with those of typical antiallergic agents and the nonamphoteric basic compound PY-608 (8-fluoro-5,11-dihydro-11-(1-methyl-4-piperidylidene)benz[b]oxe pino- [4,3-b]pyridine), which has a chemical structure similar to that of HSR-609. In the in vitro study, HSR-609 had a high affinity for H1-receptors in the guinea pig cerebral cortex in comparison to affinities for muscarinic and serotonin 5-HT2-receptors in the rat cerebral cortex, while the selectivity of PY-608 for the H1-receptor was low. The inhibitory effects of these antiallergic agents on histamine-induced increase of vascular permeability in mice (ED50) were compared with the displacement of [3H]mepyramine binding to H1-receptors in mouse brain ex vivo (ID50). The ID50/ED50 ratio of HSR-609 was much larger than those of cyproheptadine, ketotifen and PY-608 and larger than those of terfenadine and cetirizine. HSR-609 was found to display selective displacement of the [3H]mepyramine binding to H1-receptors for lung vs cerebral cortex as found with terfenadine in guinea pigs ex vivo. These findings suggest that HSR-609 has high selectivity for the H1-receptor and poor ability to penetrate into the CNS in mice and guinea pigs due to its amphoteric chemical structure.


Gender differences in depression and chronic pain conditions in a national epidemiologic survey.
The authors explored gender differences in the prevalence of depression in four chronic pain conditions and pain severity indices in a national database. In 131,535 adults, the prevalence of depression in women (9.1%) was almost twice that of men (5%). One-third (32.8%) had a chronic pain condition (fibromyalgia, arthritis/rheumatism, back problems, and migraine headaches). The prevalence of depression in individuals with chronic pain conditions was 11.3%, versus 5.3% in those without. Women reported higher rates of chronic pain conditions and depression and higher pain severity than men. Depression and chronic pain conditions represent significant sources of disability, especially for women.


A longitudinal study of the relationship between financial compensation and symptoms after treated mild traumatic brain injury.
Demographic, injury-related, and symptom variables at intake, 3 months, and 12 months postinjury were compared between 50 treated adults with mild traumatic brain injury (MTBI) who were not seeking or receiving financial compensation at any time and 18 who were at each time. Compensation seekers/receivers reported symptom incidence and severity as approximately 1 SD higher at each time. The level of difference between the groups did not significantly differ across time. No demographic variables distinguished the groups. No injury-related variable other than more immediate postinjury prescription medication use was predictive of the greater symptom complaints for the patients seeking or receiving compensation. However, this medication effect did not explain away the compensation effect when medication use was co-varied in an analysis. Our study appears to be the first to examine the relationship between financial compensation and symptom report in an MTBI sample specifically treated for their condition. Our results indicate that even highly patient-rated treatment is not adequate to wash out the strong relationship between financial compensation status and symptom report after MTBI.


Malignant Fibrohisticytoma of the Knee in a Patient with HIV.
This case report describes a patient presenting with anterior knee pain (extensor mechanism pain), a poorly studied complaint in the HIV population. The final diagnosis was malignant fibrohistiocytoma, a rare condition among knee pathologies, successfully treated with endoprosthesis after tumor resection. This article focuses on what the authors learned after treating this patient, particularly on the difficulty in making a correct diagnosis of this group of patients due to lack of adequate epidemiological characterization. By assuming that the pathology was related to long-term infection and treatment of HIV (knee hoffitis), the authors underestimated the gravity of the case, almost compromising the result of treatment.


[Detection of Leishmania infantum in an experimentally-infected hamster using immunohistochemistry].
visceral leishmaniasis is considered the most severe form of this disease and can be fatal if not properly treated. In Latin America, the infection is caused by Leishmania infantum (syn. Leishmania chagasi). The unequivocal diagnosis and the selection of a suitable experimental model are required to undertake studies on this biologic agent. to determine the advantages of immunohistochemistry in identifying Leishmania. hamsters were inoculated with Leishmania infantum promastigotes. The body weights of every animal were monitored, and the relative weights of their spleens and livers were estimated. For identification of amastigotes, Giemsa-stained imprints and an immunohistochemistry protocol in paraffin-embedded tissues were developed. the infection was reproduced in the experimental model. The immunohistochemistry was positive in infected animal sections and non-reactive for the control group. When compared with the Giemsa staining, this methodology facilitated the identification, particularly in organs infected with few parasites. immunohistochemistry is a specific tool for detection of Leishmania since it facilitates observation and eliminates any confusion in the identification of the parasite, thus improving the quality of diagnosis.


Non-alcoholic fatty liver disease: What's in our arsenal?
Lifestyle changes and metabolic syndrome management are the best interventions for NAFLD. Less clear is which agents to use for liver-directed pharmacotherapy.


Frequent epidural dosing as a marker for impending uterine rupture in patients who attempt vaginal birth after cesarean delivery.
The purpose of this study was to estimate the association between epidural dosing and the risk of uterine rupture in women who attempt vaginal birth after cesarean delivery (VBAC). A nested case-control study within a multicenter retrospective cohort of >25,000 women with previous cesarean delivery compared cases of uterine rupture with women without rupture (control subjects) while attempting VBAC with epidural anesthesia. Dose timing, frequency, and quantity were compared. Time-to-event analyses were performed to estimate the association between epidural dosing and risk for uterine rupture while accounting for labor duration. Of 804 women in the nested case-control study, 504 women (62.7%) had epidural anesthesia, with no statistical difference in epidural usage rates between cases and control subjects (70.4% vs 62.4%; P = .09). Cox-regression analysis revealed a dose-response relationship between the number of epidural doses and uterine rupture risk: 1 dose (hazard ratio, 2.8; 95% confidence interval [CI], 1.4-5.7), 2 doses (hazard ratio, 3.1; 95% CI, 2.2-6.2), 3 doses (hazard ratio, 6.7; 95% CI, 3.8-12.1), > or =4 doses (hazard ratio, 8.1; 95% CI, 5.4-18.2). Clinical suspicion for uterine rupture should be high in women who require frequent epidural dosing during a VBAC trial.


Use of Saccharomyces cerevisiae To Reduce the Bioaccessibility of Mercury from Food.
Food is the main pathway of exposure to inorganic mercury [Hg(II)] and methylmercury (CH3Hg). Intestinal absorption of these mercury species is influenced by their chemical form, the luminal pH, and the composition of the diet. In this regard, strategies have been proposed for reducing mercury absorption using dietary components. This study evaluates the capacity of Saccharomyces cerevisiae to reduce the amount of mercury solubilized after gastrointestinal digestion that is available for intestinal absorption (bioaccessibility). The results show that S. cerevisiae strains reduce mercury bioaccessibility from aqueous solutions of Hg(II) (89 ± 6%) and CH3Hg (83 ± 4%), and from mushrooms (19-77%), but not from seafood. The formation of mercury-cysteine or mercury-polypeptide complexes in the bioaccessible fraction may contribute to the reduced effect of yeasts on mercury bioaccessibility from seafood. Our study indicates that budding yeasts could be useful for reducing the extent of intestinal absorption of mercury present in water and some food matrices.


The role of postoperative irradiation in carcinoma of the breast.
Chest wall and regional nodal recurrences, and survival following postmastectomy radiation therapy, were analyzed in 352 patients. Patients with T1 and T2 central and medial breast lesions, negative axillary nodal findings, and no evidence of skin or chest wall extension received irradiation to the peripheral lymphatics alone. There were no chest wall recurrences among these patients. The remainder of the patients, including those with axillary nodal involvement, regardless of the site of the primary breast lesion received irradiation by a three-field technique directed to both chest wall and regional nodes. The chest wall recurrence rate was 1.9% when axillary nodes were negative for metastatic disease, 1.3% when the axillary nodes showed less than 50% positivity, and 14.2% when axillary nodes showed greater than 50% involvement. The overall chest wall recurrence rate was 5.1%. A possible mechanism of chest wall recurrence is discussed. Cumulative 5-year survival for stage I is 76%, for stage II, 79%, and for stage III, 57%. If chemotherapy proves to be effective in controlling distant microscopic disease local control may become an equally critical issue in long-term survival of patients with breast carcinoma.


The effect of cholecyst-derived extracellular matrix on the phenotypic behaviour of valvular endothelial and valvular interstitial cells.
Cholecyst-derived extracellular matrix (CEM) is a novel, proteinaceous biomaterial, derived from the porcine cholecyst, which may have potential applications as a scaffold in the area of heart valve tissue engineering. In this study the potential of CEM to support the proliferation of valvular endothelial cells (VECs) and valvular interstitial cells (VICs), while maintaining their phenotypic mRNA synthesis, protein expression and morphology was assessed by biochemical assays, electron microscopy, immunostaining and reverse-transcriptase polymerase chain reaction. VICs and VECs were isolated from the porcine aortic valve and techniques were developed for the isolation of CEM for cell culture. VECs and VICs cultured on CEM adhered and proliferated, maintaining their phenotypic morphology. VECs synthesised von Willebrand factor mRNA and endothelial nitric oxide synthase (eNOS) mRNA and expressed eNOS and VICs synthesised alpha-smooth muscle actin (alphaSMA) mRNA and expressed alphaSMA. Cellular area fraction of VICs expressing alphaSMA was 87.7+/-6.8% and cellular area fraction of VECs expressing eNOS was 93.8+/-9.3%. Findings of this study support the hypothesis that CEM is a potential biomaterial for tissue engineered heart valve scaffold design.


Paraoxonase and arylesterase activity in bladder cancer.
Oxidative stress is the main pathogenetic mechanism in bladder cancer among many other causes. We aimed to investigate whether a potential relationship exists between bladder cancer and the activities of paraoxonase (PON1) and arylesterase (ARE) enzymes. The study included 56 patients with bladder cancer, and 57 healthy individuals. The relationships between enzyme activity and tumour grade, stage, muscular invasion and tumour size were evaluated. For statistical analysis, One-Sample Kolmogorov-Smirnov, Independent-T, ANOVA and Post-Hoc Bonferroni tests were used. Serum levels of PON1 and ARE enzymes, and total cholesterol were significantly lower in bladder cancer group. While other lipid parameters were similar in both the patient and the control groups. Levels of ARE were positively correlated with lipid parameters except for HDL cholesterol. Our results showed that decreased serum PON1 and ARE enzyme activities are related with tumour load and recurrence. Further studies with larger samples are needed to confirm predictive role of enzymatic activities of PON1 and ARE in the diagnosis and prognosis of bladder cancer.


[Study on the water intake of rat during long-term inhalation of diesel exhaust].
To determine the chronic toxicity of diesel exhaust, F 344 rats were made to inhale various dilutions of exhaust under specific pathogen-free conditions for 16 hours a day, 6 days a week for 30 months. Five experimental groups of 240 rats each were set up, each consisting of equal numbers of rats of the both sexes of five weeks-old. During the experiment, they were housed in inhalation chambers, which were maintained at 23 +/- 2 degrees C and 55 +/- 10% relative humidity with artificial lighting 12 hours a day. Daily water intakes of all rats in inhalation chambers during the period of flow of fresh air with lights on and the period of inhalation of exhaust with lights off were measured with a drip meter fitted to automatic watering system in each inhalation chamber throughout the experiment. Result was that the mean daily water intake of the 0.5 mg/m3 (lowest particulate concentration level), 1.0 mg/m3, 1.8 mg/m3, and 3.7 mg/m3 (highest particulate concentration level) groups were 15%, 24%, 27%, and 39% less than that of the control group. Moreover, the groups also showed dose-dependent decrease in hourly water intake during the period of inhalation of diesel exhaust with lights off and dose-dependent increase in that during the period of flow of fresh air with lights on. This finding suggested that diesel exhaust might affect the circadian rhythm of the water intake in rats. These results showed that the measurement of the water intake of rat is an useful parameter to detect the biological effect on inhalation experiment.


Interferon-induced changes in the expression and topography of H-2 antigens and receptors for SRBC in tumour cells.
The expression of H-2 antigens has been investigated in methylcholanthrene-transformed C3H embryonic fibroblasts of clones 36 and 57. Private specificities H-2.23 and H-2.32, typical of the H-2k haplotype, were present on cells of the two clones but differed considerably in their expression. After interferon treatment, the expression of H-2 antigens increased in both clones, though more markedly in clone 57. Interferon treatment also affected the topography of H-2 antigenic determinants on the cell membrane. The blocking index for antigenic determinants coded by a single region of the H-2 complex increased in both clones. Between antigenic determinants controlled by two regions of H-2 the blocking index remained unaltered in clone 36 but decreased significantly in clone 57. Rosette formation with SRBC was consistent with the results of the blocking test between H-2K and H-2D antigenic determinants; rosette formation decreased slightly in clone 36 but increased in clone 57 after interferon treatment. All the results suggest that alterations in expression of H-2 antigens following interferon treatment are due to the rearrangement of the cell membrane rather than to the virtual increase in the number of H-2 antigenic determinants. Cells of clone 57 exhibiting more pronounced changes in the topography of H-2 antigens were more resistant to the inhibitory effect of interferon on cell growth.


Bridging the knowledge-resuscitation gap for children: Still a long way to go.
The American Heart Association, along with the International Liaison Committee on Resuscitation, recently made changes to the paediatric resuscitation guidelines.Knowledge translation (KT) is imperative, but there is a lack of sufficient evidence for appropriate methodologies for implementation of these guidelines. Paediatric resuscitation presents many challenges; cases happen infrequently, affording few opportunities for implementation of the new guidelines, and are highly stressful and filled with uncertainty. Some KT strategies have shown some success in causing a notable degree of change in behaviour, but none have shown a striking difference when used alone.Previous efforts to disseminate current guidelines centred on development of courses for health care providers and preparing paediatric residents and paediatricians for circumstances they could encounter with paediatric acute illness. None of the studies assessing these techniques measured direct patient outcomes, and only a few demonstrated some long-term knowledge acquisition among trainees. The purpose of the present review was to illuminate the challenges, offer future directions for KT and outline potentially more effective methodologies and strategies to overcome current barriers.


Kawasaki disease: State of the art.
Kawasaki disease is an acute febrile arteritis of childhood that can result in coronary artery aneurysms if untreated in the first 10 and ideally 7 days of illness. Kawasaki disease begins as a necrotizing arteritis with neutrophilic infiltrate, followed by subacute/chronic changes and luminal myofibroblastic proliferation that can cause coronary artery stenosis. Manifestations include the presence of ≥5 days of fever, together with clinical criteria of extremity changes, rash, conjunctivitis, oral changes, and unilateral cervical lymphadenopathy. Echocardiography should be performed at the time of diagnosis, then 1-2 weeks and 4-6 weeks later, with more frequent studies in individuals with coronary artery dilation or persistent fever. Coronary artery dimensions are characterized both as z-scores and absolute measurements, and coronary architecture evolves over time in children who have aneurysms in the first weeks of illness. Systematic follow-up and therapies are tailored to the degree of coronary disease and to coronary ischemia.


IL-2-mTORC1 signaling coordinates the STAT1/T-bet axis to ensure Th1 cell differentiation and anti-bacterial immune response in fish.
Utilization of specialized Th1 cells to resist intracellular pathogenic infection represents an important innovation of adaptive immunity. Although transcriptional evidence indicates the potential presence of Th1-like cells in some fish species, the existence of CD3+CD4+IFN-γ+ T cells, their detailed functions, and the mechanism determining their differentiation in these early vertebrates remain unclear. In the present study, we identified a population of CD3+CD4-1+IFN-γ+ (Th1) cells in Nile tilapia upon T-cell activation in vitro or Edwardsiella piscicida infection in vivo. By depleting CD4-1+ T cells or blocking IFN-γ, Th1 cells and their produced IFN-γ were found to be essential for tilapia to activate macrophages and resist the E. piscicida infection. Mechanistically, activated T cells of tilapia produce IL-2, which enhances the STAT5 and mTORC1 signaling that in turn trigger the STAT1/T-bet axis-controlled IFN-γ transcription and Th1 cell development. Additionally, mTORC1 regulates the differentiation of these cells by promoting the proliferation of CD3+CD4-1+ T cells. Moreover, IFN-γ binds to its receptors IFNγR1 and IFNγR2 and further initiates a STAT1/T-bet axis-mediated positive feedback loop to stabilize the Th1 cell polarization in tilapia. These findings demonstrate that, prior to the emergence of tetrapods, the bony fish Nile tilapia had already evolved Th1 cells to fight intracellular bacterial infection, and support the notion that IL-2-mTORC1 signaling coordinates the STAT1/T-bet axis to determine Th1 cell fate, which is an ancient mechanism that has been programmed early during vertebrate evolution. Our study is expected to provide novel perspectives into the evolution of adaptive immunity.


Pharmacokinetic parameters relevant to recovery from opioids.
Several recent studies have suggested that the terminal half-lives of many drugs do not predict the rate of washout of drug after the relatively short durations of infusions used in anesthesia. Many anesthetic drugs fit a three-compartment mamillary model, with three volumes of distribution (central [V1] and peripheral [V2 and V3]) and three clearances (elimination or metabolic [Cl1] and distribution [Cl2 and Cl3]). It has been suggested that a large V3:Cl3 ratio contributes to rapid recovery after infusion. We investigated the role of each of these primary pharmacokinetic parameters to determine values of each that would contribute to rapid recovery after various dosing schemes. Three sets of computer simulations were performed based on a three-compartment mamillary model for fentanyl, alfentanil, and sufentanil. Set I predicted the change in plasma concentration of each drug after a bolus if each pharmacokinetic parameter were independently increased by 5%. Set II predicted the time for an 80%, 50%, or 20% decrease in plasma concentration after infusions of varying duration (the 80%, 50%, and 20% decrement time, respectively) if each pharmacokinetic parameter were independently increased by 5%. Set III calculated the percent change in each pharmacokinetic parameter alone that would give a 30% shorter decrement time after infusions of varying duration. Set I demonstrated that after a bolus dose to obtain identical initial plasma concentrations, the drug with a larger V1 had a higher plasma concentration than did the parent drug at all subsequent times. The drug with a larger Cl1 had a lower plasma concentration than did the parent drug at all times. A larger V2, V3, Cl2, or Cl3 led to a lower plasma concentration at times soon after the bolus and subsequently to a higher plasma concentration than did the parent drug. Set II demonstrated that after an infusion, increasing V1 led to a longer decrement time and increasing Cl1 led to a shorter decrement time for infusions of all durations. Increasing V2, V3, Cl2, or Cl3 led to a shorter decrement time when the infusion had been short and when a small decrease in plasma concentration was desired. Increasing each of these four parameters led to a longer decrement time when the infusion had been long and when a larger decrease in plasma concentration was desired. Set III demonstrated that a smaller V1 or a larger Cl1 always led to a shorter decrement time. For infusions of short duration and for a small decrease in plasma concentration, a larger V2, V3, Cl2, or Cl3 led to the desired decrease in decrement time. For infusions of longer duration and for larger decreases in plasma concentration, a smaller V2, V3, Cl2, or Cl3 was able to decrease the decrement time by 30%. This study proposes qualitative guidelines for pharmacokinetic properties desirable in anesthetic drugs. If a rapid decrease in plasma concentration is desired after an infusion, it is always beneficial to have a small V1 and a large Cl1. For infusions of short duration, after which only a small decrease in plasma concentration is required, it is beneficial to have a larger V2, V3, Cl2, and Cl3. For infusions of longer duration, after which a large decrease in plasma concentration is desired, it is beneficial to have a smaller V2, V3, Cl2, and Cl3. These proposals may be beneficial for planning clinical trials of new drugs.


Driving performance in cold, warm, and thermoneutral environments.
Driving performance deteriorates at high ambient temperatures. Less is known about the effect of low ambient temperatures and the role of subjective aspects like thermal comfort and having control over the ambient temperature. Therefore, an experiment was constructed in which 50 subjects performed a road-tracking task in a cold (5 degrees C), a thermoneutral (20 degrees C) or a warm (35 degrees C) climate. All subjects had a heater/blower (H/B) which generated a fixed amount of heat/wind that could either be controlled or not controlled. In the cold climate, averaged leg skin temperature dropped to 18.5 degrees C and head skin temperature to 24.9 degrees C; the thermal comfort was rated between 'cold' and 'very cold'. In the warm climate, averaged leg skin temperature rose to 36.6 degrees C and head skin temperature to 30.8 degrees C; the thermal comfort was rated as 'hot'. Driving performance in the ambient temperature extremes decreased 16% in the cold environment and 13% in the warm situation. Having control over the local head temperature by adjusting a H/B affected neither thermal comfort nor driving performance. In agreement with the literature on priming effects, subjects who started with the no-control condition performed much better in all driving tasks because they were primed to focus on the driving task as such, rather than the complex combination of temperature controls and driving task. It can be concluded that a thermoneutral temperature in a car enhances driving performance and may thus positively affect safety. Using manual climatic controls in hot or cold cars may interfere with the driving task.


New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage.
The incidence of fungal infections has increased globally, and the introduction of the newer triazoles and echinocandin antifungals is a more-than-welcome and long overdue development. In this report, we review the clinical trials evaluating the therapeutic efficacy of these new antifungal agents and examine possible gaps in coverage. Voriconazole has become the primary treatment for most forms of invasive aspergillosis in a number of centers, posaconazole offers a broad antifungal spectrum, and echinocandins are fungicidal against most Candida species. Moreover, the new agents are active against some fungi that are resistant to amphotericin B, may have a role in the management of fever and neutropenia, and provide exciting options for combination antifungal therapy. However, significant questions remain, including the management of breakthrough infections and treatment failures and the efficacy of the new antifungal agents against less common fungi.


Anxiety as a personality dimension of short and long sleepers.
To clarify the interpretation of a difference in anxiety level that Hicks and Pellegrini (1977) had reported as being incongruent with Hartmann's (1973) clinical findings that consistent short sleepers tend to be non-worriers while consistent long sleepers tend to worry, groups of 25 short- and long-sleeping undergraduate students were administered the Hindi version of Sinha Anxiety Scale. Higher mean score was found in the short sleepers than in the long sleepers. The difference between these means was significant at the .001 level. These findings supported Hicks and Pellegrini's earlier results, which questioned the validity of the clinical observations that were the basis for Hartmann's conclusions.