Phosphorylation of caldesmon in arterial smooth muscle.
We have isolated caldesmon (Mr = 145,000), by immunoprecipitation, from [32P]orthophosphate-loaded porcine carotid arteries. In resting muscles, caldesmon was phosphorylated to 0.45 mol of PO4/mol protein, while the 20,000-dalton myosin regulatory light chain (LC20) was phosphorylated to less than 0.05 mol/mol. After stimulation by KCl (110 mM) for 75 min and phorbol 12,13-dibutyrate (PDBu, 1 microM) for 60 min, caldesmon phosphorylation levels rose to 0.96 and 1.1 mol/mol, respectively. LC20 phosphorylation increased to 0.49 mol/mol at 1 min of stimulation by KCl and decreased to 0.17 mol/mol at 60 min. With PDBu, phosphate incorporation into LC20 rose only slightly, reaching 0.09 mol/mol after 90 min. Muscles contracted with histamine (10 microM) or ouabain (1 microM) also demonstrated elevated levels of phosphate incorporation into caldesmon. In these muscles, LC20 phosphorylation levels were less than 0.05 mol/mol. Three major phosphopeptides of indistinguishable mobility were identified on maps of caldesmon from resting, KCl-stimulated, and PDBu-stimulated muscles. There was, however, little similarity between the phosphopeptide maps of caldesmon phosphorylated in intact tissue and maps of purified caldesmon phosphorylated in vitro by protein kinase C (Ca2+/phospholipid-dependent enzyme) or Ca2+/calmodulin kinase II.


Paranodal vascular spread in breast cancer with axillary node involvement.
The presence of tumour cells in the efferent paranodal vessels of tumour-bearing axillary lymph nodes from patients with operable breast carcinoma was associated with a significant reduction in survival time at 5 yr compared to cases with node involvement in which these vessels did not contain tumour cells.


Narrowing down the conditions for extinction of Pavlovian feature-positive discriminations in humans.
The aim of this study was to delineate the minimal conditions for extinction of Pavlovian modulation in humans. Previous experiments at our lab showed that, after X-- A+/A- acquisition training, X- trials did not extinguish differential X-- A+/A- responding, while X-- A- trials did. Additionally, X-- A- extinction training seemed only to extinguish differential X-- A+/A- responding, while leaving differential responding on a concurrently trained Y [Symbol: see text] B+/B- discrimination intact. It thus seemed that the X-- A+/A- discrimination can only be extinguished by X-- A- extinction trials. (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986), on the other hand, found that the minimal conditions for extinction were broader in pigeons: Namely, he found that an acquired X-- A+/A- discrimination could be extinguished by presenting the original feature X in combination with a different target (B) that was minimally trained as an exciter. We thus wanted to examine whether this was also the case in humans. We found that nonreinforced X-- B- presentations did not abolish discriminative X-- A/A responding when target B was a nonreinforced stimulus. Nonreinforced X-- B- trials did extinguish the X-- A+/A- discrimination when target B had previously been trained as a target for modulation (X-- B+/B- or Y [Symbol: see text] B+/B- training) or as a reinforced exciter (B+). Our results thusf parallel and extend those in nonhuman animals (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986).


Is there a pathophysiological and therapeutic link between panic disorder and epilepsy?
Relations between panic disorder (PD) and epilepsy (E) have repeatedly been discussed. Three patients with juvenile E who had been free of seizures under anticonvulsant medication for many years and developed PD are presented. Increasing anticonvulsant medication resulted in complete and stable remission of PD. It is hypothesized that, in a subgroup of patients with PD, there is a pathophysiological relation to E. Further research into the usefulness of anticonvulsants in the treatment of PD, especially in therapy-refractory cases, is suggested.


Comparison between dexmedetomidine and midazolam as a sedation agent with local anesthesia in inguinal hernia repair: randomized controlled trial.
In Japan, inguinal hernia repair is widely performed with local anesthesia. The objective of this study was to evaluate safety and efficacy of intravenous dexmedetomidine as a sedation agent with local anesthesia in inguinal hernia repair. We performed this randomized, single-blind study for 200 patients who were scheduled to undergo inguinal hernia repair with local anesthesia. Patients were randomly divided into two groups (dexmedetomidine group: Group D, midazolam group: Group M). The primary outcome was to evaluate the safety of intravenous dexmedetomidine. Secondary outcomes were to analyze results of operators' surveys and patients' questionnaires and evaluate implementation of conscious sedation. Incidence of respiratory depression was significantly higher in Group M than Group D (p = 0.03). Other adverse events examined did not differ significantly. All three operators' questionnaires indicated that results were better in Group D than Group M. More than 70% of patients in both groups were satisfied with the surgery. More than 80% of Group D patients and 74% of Group M patients achieved a state of conscious sedation. This study demonstrated that intravenous dexmedetomidine during hernia repair with local anesthesia is safe and the results were satisfactory to both operators and patients.


Utilizing a high fundamental frequency quartz crystal resonator as a biosensor in a digital microfluidic platform.
We demonstrate the operation of a digital microfluidic lab-on-a-chip system utilizing Electro Wetting on Dielectrics (EWOD) as the actuation principle and a High Fundamental Frequency (HFF; 50 MHz) quartz crystal microbalance (QCM) resonator as a mass-sensitive sensor. In a first experiment we have tested the reversible formation of a phosphor-lipid monolayer of phospholipid vesicles out of an aqueous buffer suspension onto a bio-functionalized integrated QCM sensor. A binding of bio-molecules results in an altered mass load of the resonant sensor and a shift of the resonance frequency can be measured. In the second part of the experiment, the formation of a protein multilayer composed of the biomolecule streptavidin and biotinylated immunoglobulin G was monitored. Additionally, the macroscopic contact angle was optically measured in order to verify the bio-specific binding and to test the implications onto the balance of the surface tensions. Using these sample applications, we were able to demonstrate and to verify the feasibility of integrating a mass-sensitive QCM sensor into a digital microfluidic chip.


Surgical technique for closure of difficult abdomen.
Abdominal dehiscence reported to occur with a frequency of one per cent even under the best circumstances, is a dreaded complication. Closure of the dehisced abdominal wall under adverse conditions like local infection and wound edge retraction may be difficult. We describe a new technique which is a modification of classical retention sutures for the abdominal wall closure.


Recognizing and treating atypical Parkinson disorders.
Though less common than Parkinson's disease (PD), the atypical Parkinson disorders such as such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration are increasingly recognized and important to distinguish from PD. Atypical or "Parkinson-plus" disorders are multisystem disorders and generally progress more rapidly and respond poorly to current therapies compared to PD. Recent advances in our understanding of the pathophysiology of these disorders, however, have generated new interest in the development of novel diagnostics and disease-modifying therapeutics aimed at identifying and treating these disorders. In this review we discuss the clinical approach to the atypical Parkinson disorders and the recent developments in diagnostic and research criteria that take into account the phenotypic heterogeneity and advances in our understanding of the pathophysiology of these disorders.


Torque expression of self-ligating brackets.
The labiolingual inclination of maxillary and mandibular incisors is considered by many orthodontists to be an important determinant of pleasing dental esthetics and ideal stable occlusion. In contemporary fixed appliances, attaching a rectangular orthodontic archwire to a bracket with a rectangular slot makes third-order control possible. The purpose of this study was to measure the difference in third-order moments that can be delivered by engaging 0.019 x 0.025-in stainless steel archwires to 2 active self-ligating brackets (In-Ovation, GAC, Bohemia, NY; Speed, Strite Industries, Cambridge, Ontario, Canada) and 2 passive self-ligating brackets (Damon2, Ormco, Orange, Calif; Smart Clip, 3M Unitek, Monrovia, Calif). A bracket/wire assembly torsion device was developed. This novel apparatus can apply torsion to the wire while maintaining perfect vertical and horizontal alignment between the wire and the bracket. A multi-axis force/torque transducer was used to measure the moment of the couple (torque), and a digital inclinometer was used to measure the torsion angle. Fifty maxillary right central incisor brackets from each of the 4 manufacturers were tested. There was a significant difference in the engagement angle between the 2 types of brackets; on average, torque started to be expressed at 7.5 degrees of torsion for the active self-ligating brackets and at 15 degrees of torsion for the passive self-ligating brackets. The torque expression was higher for the active self-ligating brackets up to 35 degrees of torsion. Torsion of the wire past this point resulted in a linear increase of the measured torque for the Damon2, the Smart Clip, and the In-Ovation brackets. The torque was relatively constant past 35 degrees of torsion for the Speed bracket. We conclude that active self-ligating brackets are more effective in torque expression than passive self-ligating brackets.


A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency.
Numerous syndromic forms of intellectual disability have been described including those with abnormal sweating pattern. To describe the clinical and molecular analysis of a large multiplex consanguineous Saudi family with an unusual constellation of severe intellectual disability, hypohidrosis, abnormal teeth, and acquired microcephaly. Clinical evaluation, autozygosity mapping, exome sequencing, and expression analysis. Autozygosity mapping revealed a single critical locus corresponding to chr13:39 338 062-40 857 430. Exome sequencing uncovered a deep intronic (NM_020751.2:c.1167-24A>G) variant in COG6 that largely replaces the consensus acceptor site, resulting in pronounced reduction of the normal transcript and consequent deficiency of COG6 protein. Patient cells also exhibited pronounced deficiency of STX6, consistent with the established stabilising effect of COG6 on STX6. Four additional patients representing two families of the same tribal origin as the original family were found to have the same mutation, confirming a founder effect. Remarkably, none of the patients displayed any detectable abnormality in the glycosylation pattern of transferrin, which contradicts a previously published report of a patient whose abnormal glycosylation pattern was presumed to be caused by a missense variant in COG6. Our data implicate COG6 in the pathogenesis of a novel hypohidrotic disorder in humans that is distinct from congenital disorders of glycosylation.


Tumour blood flow for prediction of human prostate cancer aggressiveness: a study with Rubidium-82 PET, MRI and Na+/K+-ATPase-density.
Tumour blood flow (TBF) is a crucial determinant of cancer growth. Recently, we validated Rubidium-82 (82Rb) positron emission tomography (PET) for TBF measurement in prostate cancer (PCa) and found TBF and cancer aggressiveness positively correlated. The aims of the present study were to determine the ability of TBF for separating significant from insignificant PCa and to examine the relation to underlying Na+/K+-ATPase density, which is relevant as 82Rb is transported intracellularly via the Na+/K+-ATPase. One hundred and two patients were included for pelvic 82Rb PET scan prior to magnetic resonance imaging (MRI)-guided prostate biopsy. Findings constituted 100 PCa lesions (86 patients) and 25 benign lesions (16 patients). Tumours were defined on MRI and transferred to 82Rb PET for TBF measurement. Immunohistochemical Na+/K+-ATPase staining was subsequently performed on biopsies. TBF was the superior predictor (rho = 0.68, p < 0.0001, inflammatory lesions excluded) of MRI-guided biopsy grade group (GG) over lowest apparent diffusion coefficient (ADC) value (rho = -0.23, p = 0.01), independent of ADC value and tumour volume (p < 0.0001). PET could separate GG-2-5 from GG-1 and benign lesions with an area under the curve (AUC), sensitivity, and specificity of 0.79, 96%, and 59%, respectively. For separating GG-3-5 from GG-1-2 and benign lesions the AUC, sensitivity, and specificity were 0.82, 95%, and 63%, respectively. Na+/K+-ATPase density per PCa cell profile was 38% lower compared with that of the benign prostate cell profiles. Neither cell density nor Na+/K+-ATPase density determined tumour 82Rb uptake. TBF is an independent predictor of PCa aggressiveness and deserves more attention, as it may be valuable in separating clinically significant from insignificant PCa.


How a university hospital improves its prevention performance: results of two biennial studies 2004-2006.
Prevention is a legal obligation for French hospitals and should be systematically assessed. To measure how a French University Hospital improved its prevention performance between two biennial prevention studies after incentives measures were applied. 45 medical, obstetrical or surgical units were included. A doctor-nurse pair was free to select inpatients at random. 14 preventive procedures were evaluated: blood pressure check, measures of weight, height and body mass index, screenings for diabetes, cervix and breast cancers, tetanus and influenza immunizations, serologies of viruses, research for a prostatic and cognitive disorder and evaluation of alcohol and tobacco consumptions and addictions. Incentives measures for prevention were enacted during the same time. In 2004 and in 2006, respectively 253 inpatients and 243 inpatients were respectively included. Tetanus immunization was checked in less than one tenth of cases in both the studies. Seven acts were performed more in 2006 and only body mass index was measured less. The results were encouraging but insufficient especially for tetanus immunization. Weight was measured more than body mass index, probably meaning that's weight and more precisely its variations are a better clinical sign. Bad results for tetanus immunization meant that incentive strategies only displayed within the hospital were ineffective. Lastly, two propositions were done to improve the questionnaire and the prevention performance: to add five preventive services and a medical file first page, common to all units, summing up all preventive procedures evaluated. The ability of this University Hospital to improve its prevention performance answering to local incentive measures was weak. Another solutions need to be found.


Fe-catalyzed multicomponent reactions: the regioselective alkoxy allylation of activated olefins and its application in sequential Fe catalysis.
We present herein a versatile and broadly applicable Fe-catalyzed regioselective alkoxy allylation of activated double bonds. Substituted allylic carbonates are converted into the corresponding σ-enyl Fe complexes by reaction with Bu(4)N[Fe(CO)(3)(NO)] (TBAFe) at 30 °C. The liberated alkoxide adds to an activated double bond with the generation of a C-nucleophile, which is trapped by the σ-enyl Fe complex in a regioselective manner. Alternatively, the alkoxide acts as a base in deprotonating an external pronucleophile, which undergoes Michael addition. The method is characterized by a broad functional group tolerance, mild reaction conditions, low catalyst loadings, and high regioselectivities in favor of the ipso-substitution product.


Effects of PS1 deficiency on membrane protein trafficking in neurons.
We have examined the trafficking and metabolism of the beta-amyloid precursor protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1. We report that PS1-deficient neurons fail to secrete Abeta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylation is severely compromised in neurons lacking PS1. We conclude that PS1 plays an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.


[The effect of Cu2+, Zn2+ cations and biogenic amines on the nuclear poly(ADP-ribose) polymerase activity in the rat brain].
Study of the effects of Cu2+, Zn2+ cations and polyamines, spermine and spermidine, on the nuclear poly(ADP-ribose)polymerase activity of rat brain was carried out. It was shown that low concentrations of Cu2+ stimulate the activity of purified poly(ADP-ribose)polymerase. The poly(ADP-ribose)polymerase activity was increased 1.4-fold at 5 microM Cu2+. A further increase of Cu2+ concentration inhibited the enzymatic activity; at 50 microM Cu2+ the polymerase activity appeared to be fully inhibited. It was shown that Zn2+ inhibited only the poly(ADP-ribose)polymerase activity. Zn2+ at a concentration of 125 microM fully inhibited the enzymatic activity. Spermine and spermidine stimulated the poly(ADP-ribose)polymerase activity of brain nuclei of newborn and old rats.


Improved methodology for analysis and quantitation of proteins on one-dimensional silver-stained slab gels.
A sodium dodecyl sulfate-discontinuous polyacrylamide gel electrophoresis system for separation and quantitation of low-molecular-weight (75 to 10K Da) proteins from single muscle fibers is described. Slab gels (0.75 mm thick) were stained using an improved silver-stain technique which does not require photographic fixers in order to achieve low-level background staining. The modified staining procedure uses continuous flow washing to minimize the handling of gels. The procedure has high sensitivity and gave a linear response between approximately 2 and 70 ng of protein per band. In addition, a convenient method for mounting slab gels for photography, scanning, and long-term storage has been developed.


Piltunines A-F from the Marine-Derived Fungus Penicillium piltunense KMM 4668.
Six new carotane sesquiterpenoids piltunines A-F (1-6) together with known compounds (7-9) were isolated from the marine-derived fungus Penicillium piltunense KMM 4668. Their structures were established using spectroscopic methods. The absolute configurations of 1-7 were determined based on circular dichroism (CD) and nuclear Overhauser spectroscopy (NOESY) data as well as biogenetic considerations. The cytotoxic activity of some of the isolated compounds and their effects on regulation of reactive oxygen species (ROS) and nitric oxide (NO) production in lipopolysaccharide-stimulated macrophages were examined.


Stimulation of Paramecium phagocytosis by phorbol ester and forskolin.
Phorbol ester (PMA) exerted a dose- and time- dependent stimulating effect on phagocytosis in axenic Paramecium aurelia. When cells were exposed to 200-800 nM PMA in the presence of latex beads, the phagocytic coefficient was enhanced 2.25 to 3.14 times, during 10 min of continuous treatment and then rapidly declined. A similar effect was observed when the cells were exposed to a forskolin treatment, which resulted in nearly a twofold increase in phagocytic activity after a 10 min pulse. Both PMA and forskolin strongly stimulated phagocytosis (i.e. fivefold and threefold, respectively) in cells in which such activity had been completely inhibited by pre-exposure to the beta-receptor antagonist 1-propranolol.


Noninvasive Administration of Inhaled Nitric Oxide and its Hemodynamic Effects in Patients With Acute Right Ventricular Dysfunction.
The authors aimed to assess the hemodynamic effects and demonstrate the feasibility of inhaled nitric oxide (iNO) in hemodynamically unstable patients with acute right ventricular (RV) dysfunction and to explore the safety profile of this approach. Retrospective cohort study. Intensive care unit (ICU) of 2 tertiary care centers between January 2013 and 2017. All patients with RV dysfunction in whom iNO was initiated without invasive mechanical ventilation. Noninvasive administration of iNO. Eighteen patients received the intervention during the study period; 8 of these patients had a pulmonary artery catheter and 2 had a pulse contour analysis device. Median (interquartile range) iNO concentration was 20 (20-20) ppm, and therapy duration was 24 (12-46) hours. Most patients received iNO through nasal prongs (66.7%) or a high-flow nasal cannula (27.8%). Within 1 hour, iNO reduced pulmonary vascular resistance from 219.1 to 165.4 dyn•s/cm5 (n = 7; p < 0.001), mean pulmonary artery pressure from 28.4 to 25.3 mmHg (n = 8; p = 0.01), and central venous pressure from 17.5 to 13.1 mmHg (n = 16; p = 0.001). Indexed cardiac output increased from 2.0 to 2.6 L/min/m2 (n = 9; p = 0.004). ICU mortality was 27.78%, and median ICU length of stay was 7 (5-9) days. Two significant bleeding episodes requiring intervention and 1 acute kidney injury occurred during iNO therapy. No headache was reported. Noninvasively administered iNO was associated with favorable hemodynamic effects in ICU patients with acute RV dysfunction. These results suggest the safety and feasibility of this therapy for which further prospective study is warranted.


Regulatory issues in the use of insect-cell culture.
The insect cell as host for protein production is relative new. Therefore few data are available. This creates a vicious circle because it makes the choice of insect cells as basis for a pharmaceutical process less attractive. There are three main issues when comparing insect-cells to "traditional" systems as mammalian and bacterial cells. First, since the expression vector is not incorporated in the cells, a virus stock similar to the cell bank system has to be laid down and tested. This will cost time and money. Secondly the vector is subject to mutation and therefore the decrease in infectivity has to be characterized and validated. Third, the post-translational modification of the protein may differ. None of the mentioned issues, however, forms an obstacle that can not be overcome.


Social support during delivery in rural central Ghana: a mixed methods study of women's preferences for and against inclusion of a lay companion in the delivery room.
This study aimed to explore pregnant women's attitudes towards the inclusion of a lay companion as a source of social support during labour and delivery in rural central Ghana. Quantitative demographic and pregnancy-related data were collected from 50 pregnant women presenting for antenatal care at a rural district hospital and analysed using STATA/IC 11.1. Qualitative attitudinal questions were collected from the same women through semi-structured interviews; data were analysed using NVivo 9.0. Twenty-nine out of 50 women (58%) preferred to have a lay companion during facility-based labour and delivery, whereas 21 (42%) preferred to deliver alone with the nurses in a facility. Women desiring a companion were younger, had more antenatal care visits, had greater educational attainment and were likely to be experiencing their first delivery. Women varied in the type of companion they prefer (male partner vs female relative). What was expected in terms of social support differed based upon the type of companion. Male companions were expected to provide emotional support and to 'witness her pain'. Female companions were expected to provide emotional support as well as instrumental, informational and appraisal support. Three qualitative themes were identified that run counter to the inclusion of a lay helper: fear of an evil-spirited companion, a companion not being necessary or helpful, and being 'too shy' of a companion. This research challenges the assumption of a unilateral desire for social support during labour and delivery, and suggests that women differ in the type of companion and type of support they prefer during facility deliveries. Future research is needed to determine the direction of the relationship--whether women desire certain types of support and thus choose companions they believe can meet those needs, or whether women desire a certain companion and adjust their expectations accordingly.


Geographic linkage and variation in Cryptosporidium hominis.
UK Cryptosporidium hominis isolates have previously shown slight PCR fragment length polymorphism at multiple loci. To further investigate transmission, we conducted a case-control study and sequenced the GP60 locus from 115 isolates. Nine subtypes were identified; IbA10G2 predominated. Having a non-IbA10G2 subtype was significantly linked to recent travel outside Europe.


Effects of Melandrium firmum methanolic extract on testosterone-induced benign prostatic hyperplasia in Wistar rats.
Benign prostatic hyperplasia (BPH) is an age-related disease of unknown aetiology characterized by prostatic enlargement coincident with distinct alterations in tissue histomorphology. Instead of therapeutic agents that can cause severe side effects, plant extracts are frequently used to treat BPH. In this study, we investigated whether the Melandrium firmum methanolic extract (MFME) improves BPH, using the testosterone propionate (TP)-induced BPH rat model. Castration was performed via the scrotal route under sodium pentobarbital anaesthesia. BPH in castrated rats was generated via daily subcutaneous injections of TP (3 mg kg(-1)) dissolved in corn oil, for 4 weeks. MFME was administered daily by oral gavage at a dose of 200 mg kg(-1) for 4 weeks, along with the TP injections. The control group received injections of corn oil subcutaneously. At the scheduled termination of the experiment, all rats were killed and their prostates weighed; the relative prostate weight (prostate/body weight ratio) was calculated, and histomorphological changes in the prostate were examined. Additionally, we measured the levels of testosterone and dihydrotestosterone (DHT) in the serum and the prostate. Experimentally induced BPH led to marked decreases in the relative prostate weight and the DHT levels in the serum and the prostate. Histologically, BPH was evident in the ventral lobe of the prostate, and MFME treatment suppressed the severity of the lesions. These results indicate that MFME effectively inhibits the development of BPH induced by testosterone in a rat model. Further studies will be needed to identify the compound(s) responsibility for inducing the protective effect against BPH and determine its mechanism of action.


[Contact behavior of elderly females living alone from the social psychologic viewpoint--an exploratory study. II: Social contact with children (close relations) and with other relatives (siblings, extended family)].
After a theoretical introduction, the authors present the results of an exploratory study on the social contacts between older women living alone and their children and other relatives, respectively. It seems to be of special importance for future examinations not to confine oneself to recording the quality and the quantity of such contacts. The necessity of a description of the social contacts in substance in the individual fields of contact is pointed out.


Silencing glypican-3 expression induces apoptosis in human hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is one of the most common internal malignant tumors. Glypican-3 (GPC3) is involved in the biological and molecular events in the tumorigenesis of HCC. We used RNA interference to evaluate the molecular effects of GPC3 suppression at the translational level and demonstrated for the first time that GPC3 silencing results in a significant elevation of the Bax/Bcl-2 ratio, the release of cytochrome c from mitochondria and the activation of caspase-3. The results suggest that GPC3 regulates cell proliferation by enhancing the resistance to apoptosis through the dysfunction of the Bax/Bcl-2/cytochrome c/caspase-3 signaling pathway and therefore plays a critical role in the tumorigenesis of HCC. Thus, the knockdown of GPC3 should be further investigated as an attractive novel approach for the targeted gene therapy of HCC.


Comparative evaluation of metoprolol degradation by UV/chlorine and UV/H2O2 processes.
The degradation of metoprolol (MTP), a β-blocker commonly used for cardiovascular diseases, by UV/chlorine and UV/H2O2 processes was comparatively evaluated. MTP direct photolysis at 254 nm could be neglected, but remarkable MTP degradation was observed in both the UV/chlorine and UV/H2O2 systems. Compared with UV/H2O2, UV/chlorine has a more pronounced MTP degradation efficiency. In addition to primary radicals (OH and Cl), secondary radicals (ClO and Cl2-) played a pivotal role in degrading MTP by UV/chlorine process. The relative contributions of hydroxyl radicals (OH) and reactive chlorine species (RCS) in the UV/chlorine system varied at different solution pH values (i.e., the contribution of RCS increased from 57.7% to 75.1% as the pH increased from 6 to 8). The degradation rate rose as the oxidant dosage increased in the UV/chlorine and UV/H2O2 processes. The presence of Cl- slightly affected MTP degradation in both processes, while the existence of HCO3- and HA inhibited MTP degradation to different extents in both processes. In terms of the overall cost of electrical energy, UV/chlorine is more cost efficient than UV/H2O2. The degradation products during the two processes were identified and compared, and the degradation pathways were proposed accordingly. Compared with the direct chlorination of MTP, pre-oxidation with UV/chlorine and UV/H2O2 significantly enhanced the formation of commonly known DBPs. Therefore, when using UV/chlorine and UV/H2O2 in real waters to remove organic pollutants, the possible risk of enhanced DBP formation resulting from the degradation of certain pollutants during post-chlorination should be carefully considered.


Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis.
The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients' peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.


Comparison of lidocaine hydrocarbonate, lidocaine hydrochloride and mepivacaine in the axillary block.
Axillary block was performed on 60 patients undergoing various types of surgical procedures on the upper limb. The patients were divided randomly into three equal groups of 20 and received lidocaine hydrocarbonate 1% or lidocaine hydrochloride 1% or mepivacaine 1%, each solution containing epinephrine 1/400,000. A double-blind design was used. Lidocaine hydrocarbonate and lidocaine hydrochloride were both found to have a shorter latency of analgesia than mepivacaine. Duration of analgesia, quality of the sensory and motor block were not found to be statistically different between the three groups.


Ganglioside GM1 effects on the expression of nerve growth factor (NGF), Trk-A receptor, proinflammatory cytokines and on autoimmune diabetes onset in non-obese diabetic (NOD) mice.
NOD (non-obese diabetic) mice develop type 1 diabetes mellitus spontaneously and with a strong similarity to the human disease. Differentiation and function of pancreas beta cells are regulated by a variety of hormones and growth factors, including the nerve growth factor (NGF). Gangliosides have multiple immunomodulatory activities with immunosuppressive properties, decreasing lymphoproliferative responses and modulating cytokine production. In the present study, serum, pancreas islets and spleen mononuclear cells from NOD mice treated with monosialic ganglioside GM1 (100 mg/kg/day) and the group control which received saline solution were isolated to investigate the proinflammatory cytokines (IL-1beta, IFN-gamma, IL-12, TNF-alpha), NGF and its high-affinity receptor TrkA, peri-islet Schwann cells components (GFAP, S100-beta) expression and the relationship with diabetes onset and morphological aspects. Our results suggest that GM1 administration to female NOD mice beginning at the 4th week of life is able to reduce the index of inflammatory infiltrate and consequently the expression of diabetes, modulating the expression of proinflammatory cytokines (IL-12, IFN-gamma, TNF-alpha and IL-1beta). Furthermore, GM1 increases GFAP, S-100beta and NGF in pancreas islets, factors involved in beta cell survival.


Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians.
Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity. Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized. Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE. Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity. NCT00340132.


Omega-3 Polyunsaturated Fatty Acids Protect Neurological Function After Traumatic Brain Injury by Suppressing Microglial Transformation to the Proinflammatory Phenotype and Activating Exosomal NGF/TrkA Signaling.
The transformation of microglia to a pro-inflammatory phenotype at the site of traumatic brain injury (TBI) drives the progression of secondary neurodegeneration and irreversible neurological impairment. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to suppress this phenotype transformation, thereby reducing neuroinflammation following TBI, but the molecular mechanisms are unknown. We found that Omega-3 PUFA suppressed the expression of disintegrin metalloproteinase (ADAM17), the enzyme required to convert tumor necrosis factor-α (TNF-α) to the soluble form, thereby inhibiting the TNF-α/NF-κB pathway both in vitro and in a mouse model of TBI. Omega-3 PUFA also prevented the reactive transformation of microglia and promoted the secretion of microglial exosomes containing nerve growth factor (NGF), activating the neuroprotective NGF/TrkA pathway both in culture and TBI model mice. Moreover, Omega-3 PUFA suppressed the pro-apoptotic NGF/P75NTR pathway at the TBI site and reduced apoptotic neuronal death, brain edema, and disruption of the blood-brain barrier. Finally, Omega-3 PUFA preserved sensory and motor function as assessed by two broad-spectrum test batteries. The beneficial effects of Omega-3 PUFA were blocked by an ADAM17 promotor and by a NGF inhibitor, confirming the pathogenic function of ADAM17 and the central neuroprotective role of NGF. Collectively, these findings provide a strong experimental basis for Omega-3 PUFA as a potential clinical treatment for TBI.


Reducing the viral load of SARS-CoV-2 in the saliva of patients with COVID-19.
To evaluate the reduction in the salivary viral load using oral antiseptic mouthwashes in patients testing positive for COVID-19. Sixty-three individuals were recruited after testing positive for COVID-19 by real-time RT-PCR assay and divided into 5 groups. Group 1 received sterile water, group 2 received 1.5% hydrogen peroxide solution (HP), group 3 received 0.12% chlorhexidine (CHX), group 4 received 0.1% sodium hypochlorite solution (NaClO), and group 5 received sequential rinses using CHX and HP. After collecting the initial saliva sample, individuals were asked to use the designated mouthwash for 1 min. Additional saliva samples were collected immediately after rinsing, 15, and 30 min after rinsing. Real-time RT-PCR assays for RNA detection of SARS-CoV-2 were performed on the saliva samples. There were no significant differences among the experimental groups and the control group in any period. Compared to the baseline values, there was a significant reduction in the number of copies of SARS-CoV-2 after 30 min in group 2 and immediately after the initial mouthwash in group 4. No experimental group demonstrated a significant reduction in the viral load compared to the control group.


Preventive effect of L-carnosine on changes in the thermal nociceptive threshold in streptozotocin-induced diabetic mice.
Sensory abnormality is one of the serious complications in diabetes. Since the effective therapeutic regimen to ameliorate the diabetic sensory abnormality is very few, the present study was then designed to investigate the effect of zinc L-carnosine on the changes of nociceptive threshold in diabetic mice. Zinc L-carnosine (75-300 mg/kg, p.o.) was administered once daily from 1 day after streptozotocin treatment. Diabetic mice showed shorter tail-flick latency at 1-4 weeks after streptozotocin treatment and longer tail-flick latency at 6-9 weeks after its treatment. The shortened tail-flick latency in early stage of diabetic mice was ameliorated by treatment with zinc L-carnosine. Moreover, zinc L-carnosine also slowed the onset of hypoalgesia in diabetic mice. Tail-flick latency in non-diabetic mice was not affected by the zinc L-carnosine treatment, indicating that zinc L-carnosine did not affect normal nociceptive transmission. Moreover, L-carnosine, but not zinc sulfate, ameliorated the abnormal sensory perception in diabetic mice. Interestingly, the ameliorative effect of zinc l-carnosine on the abnormal sensory perception in diabetic mice is much stronger than that of L-carnosine. These results provide the evidence of the ameliorative potential of zinc L-carnosine on the progressive diabetic neuropathy. Moreover, L-carnosine combined with zinc shows more potent amelioration of abnormal sensory perception in diabetic mice than by itself.


A non-mitotic CENP-E homolog in Dictyostelium discoideum with slow motor activity.
Kinesins are ATP-dependent molecular motors that mediate unidirectional intracellular transport along microtubules. Dictyostelium discoideum has 13 different kinesin isoforms including two members of the kinesin-7 family, Kif4 and Kif11. While Kif4 is structurally and functionally related to centromere-associated CENP-E proteins involved in the transport of chromosomes to the poles during mitosis, the function of the unusually short CENP-E variant Kif11 is unclear. Here we show that orthologs of short CENP-E variants are present in plants and fungi, and analyze functional properties of the Dictyostelium CENP-E version, Kif11. Gene knockout mutants reveal that Kif11 is not required for mitosis or development. Imaging of GFP-labeled Kif11 expressing Dictyostelium cells indicates that Kif11 is a plus-end directed motor that accumulates at microtubule plus ends. By multiple motor gliding assays, we show that Kif11 moves with an average velocity of 38nm/s, thus defining Kif11 as a very slow motor. The activity of the Kif11 motor appears to be modulated via interactions with the non-catalytic tail region. Our work highlights a subclass of kinesin-7-like motors that function outside of a role in mitosis.


Roll of stenosis severity, artery radius and blood fluid behavior on the flow velocity in the arteries: Application in biomedical engineering.
In this work, the Sisko model is involved for blood flow simulation in the arteries with triangular shapes of stenosis, which is different in severities of 20%, 30%, and 40%, respectively. Firstly, the effects of different severity of stenosis as much as 20%, 30%, and 40% are investigated in the velocity of blood while artery radius of 0.002 m and Sisko parameters of n = 0.639 and b = 0.1735 are constant. Then, stenosis with the severity of 40% remains, and the radius of the artery is varied from 0.002 m to 0.0035 m to investigate the effects of artery radius on the blood velocity. Finally, different types of blood fluids are employed by manipulation of Sisko parameters, and influences of blood fluid behaviors are investigated in velocity profiles. It is reported that influences of increasing severity of stenosis and reducing the radius of the artery cause blood velocity to be augmented due to the role of stenosis as an obstacle against blood flow and influences of artery radius in reducing cross-section area of the vessel. Maximum velocities are roundabout 0.15 m/s, 0.185 m/s of 0.235 m/s in order of stenosis of 20%, 30% and 40% respectively. Also, investigation in the effects of the behavior of different blood showed that blood fluid types could change maximum flow velocity as much as 0.025 m/s. Despite of roll of stenosis severity, artery radius, and blood fluid behavior in exacerbation of velocity deviation, it was concluded that their consequences for the human body healthy can be ignorable in the range of studied.


Extracorporeal photopheresis: how, when, and why.
Extracorporeal photopheresis (ECP) is a well-tolerated procedure that suppresses T-lymphocyte activity in a clonally-specific way. It is an effective therapy that has established indications in the management of cutaneous T-cell lymphoma, graft-versus-host disease and some scenarios of solid-organ transplant rejection. It is being used increasingly around the world. Its applications are evolving, including exploration of its potential for treating autoimmune diseases where cytotoxic T-cell-mediated mechanisms appear to be involved, such as Crohn's disease. This article reviews scientific insights into its mechanism of action on the immune system, details of the clinical procedure, its clinical applications in various diseases, and the current evidence for its efficacy and place in medical therapeutics.


Gilbert's syndrome--does it exist? A study of the prevalence of symptoms in Gilbert's syndrome.
Liver function tests and prevalence of different symptoms generally said to occur in Gilbert's syndrome were analysed in male conscripts and in male and female participants in two cross-sectional population studies in Göteborg, in total 2395 subjects. The serum bilirubin levels showed a skew distribution without bimodality. We observed no tendency to higher prevalence of symptoms in subjects with high serum bilirubin levels, but normal alkaline phosphatase and aminotransferase values compared to subjects with normal bilirubin. The findings contradict the existence of a disease entity named "Gilbert's syndrome".


The anti-adiposity effect of bitter melon seed oil is solely attributed to its fatty acid components.
Obesity is the leading chronic disease affecting people of all ages. The objective of this study was to optimize composition of a bitter melon seed oil (BMSO) product to maximize its anti-adiposity effect. Bleaching oil, saponifiables and non-saponifiables were prepared from BMSO, with α-eleostearic acid (α-ESA) content in BMSO maintained in bleaching oil and saponifiables. C57BL/6 J mice were allocated into five groups (n = 10/group) to receive diet C [30% soybean oil (SBO)], BM [25% SBO + 5% BMSO], BMS, BMNS or BMD. For the three latter diets, saponifiables (hydrolyzed fatty acids from BMSO), non-saponifiables (excluding fatty acids from BMSO) or bleaching oil (excluding pigments from BMSO), respectively, were added in amount equivalent to their content in 5% BMSO and SBO was added to bring total fat to 30%. After 14 wk., indices associated with adiposity and safety, as well as lipid metabolic signaling in white adipose tissue (WAT), were measured. The body fat percentage of mice in group BM, BMS, BMNS, and BMD were 90 ± 26, 76 ± 21, 115 ± 30 and 95 ± 17% of that in group C. Based on body fat percentage and plasma leptin concentrations, an anti-adiposity effect was evident in groups BM, BMS and BMD (greatest effect in BMS). Histologically, inguinal fat had smaller adipocytes in groups BM, BMS and BMD (P < 0.05), but not in group BMNS, relative to group C. There were no differences among groups in blood pressure or heart rate. Moreover, Sirt1 mRNA levels in inguinal fat were significantly greater in groups BM, BMS and BMD than group C. We concluded that the anti-adiposity function of BMSO was solely attributed to the fatty acid fraction, with the free fatty acid form having the greatest effect.


Isolation and characterization of the cyanogen bromide peptides from the B fragment of diphtheria toxin.
Homogeneous fragment B, obtained through nicking of diphtheria toxin with insoluble trypsin, was cleaved with cyanogen bromide in 70% formic acid. After citraconylation, the cleavage products were separated by gel filtration on Sephadex G--75 and purified by gel filtration, ion-exchange and thin-layer or paper chromatography. Six CNBr peptides were characterized, the composition of which account for the total amino acid content of fragment B. Their apparent molecular weights are: CB 1, 12 000; CB 2, 14 000; CB 3, 8000; CB 4a, 2400; CB 4b, 2200; CB 5, 2200. CB 4a is the NH2--terminal peptide; it contains the cysteine residue of the disulfide bridge linking fragment B to fragment A. CB 3 is the COOH--terminal peptide; it bears the disulfide bridge of fragment B. Characterization of two CNBr--derived overlapping peptides provided the positioning of CB 4b and CB 2 and allowed an alignment of the CNBr peptides of fragment B to be proposed.


Dual mini-fragment plating for midshaft clavicle fractures: a clinical and biomechanical investigation.
We sought to evaluate clinical and biomechanical outcomes of dual mini-fragment plate fixation for clavicle fractures. We hypothesized that this technique would produce an anatomical reduction with good clinical outcomes, be well tolerated by patients, and demonstrate equivalent biomechanics to single plating. Dual mini-fragment plating was performed for 17 isolated, displaced midshaft clavicle fractures. Functional outcomes and complications were retrospectively reviewed. A sawbones model compared dual plating biomechanics to a (1) superior 3.5-mm locking reconstruction plate, or (2) antero-inferior 3.5-mm locking reconstruction plate. On biomechanical testing, with anterior loading, dual plating was significantly more rigid than single locked anterior-plating (p = 0.02) but less rigid than single locked superior-plating (p = 0.001). With superior loading, dual plating trended toward higher rigidity versus single locked superior-plating (p = 0.07) but was less rigid than single locked anterior-plating (p = 0.03). No statistically significant differences in axial loading (p = 0.27) or torsion (p = 0.23) were detected. Average patient follow-up was 16.1 months (12-38). Anatomic reduction was achieved and maintained through final healing (average 14.7 weeks). No patient underwent hardware removal. Average 1-year DASH score was 4.0 (completed in 88 %). Displaced midshaft clavicle fractures can be effectively managed with dual mini-fragment plating. This technique results in high union rates and excellent clinical outcomes. Compared to single plating, dual plating is biomechanically equivalent in axial loading and torsion, yet offers better multi-planar bending stiffness despite the use of smaller plates. This technique may decrease the need for secondary surgery due to implant prominence and may aid in fracture reduction by buttressing butterfly fragments in two planes.


Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients.
Baseline cholesterol metabolism was hypothesized to regulate responses of cholesterol synthesis and absorption, and serum cholesterol lowering to hypolipidaemic treatment. Thus, serum cholesterol and non-cholesterol sterols were measured before and during long-term simvastatin treatment (inhibition of cholesterol synthesis) and subsequent combination of statin with plant stanol ester margarine (inhibition of cholesterol absorption) consumption in subjects with low (n=15) and high (n=15) absorption of cholesterol, defined by respective low and high baseline ratios of serum cholestanol to cholesterol. Cholesterol synthesis (defined by precursors of cholesterol) was markedly reduced by the long-term statin treatment in both groups, but more extensively in the low than high absorption group (P<0.05), yet the respective serum cholesterol reductions were similar. From among the absorption markers, sitosterol and cholestanol ratios were correspondingly increased more in the low than in the high absorption group. Plant stanol ester margarine consumption, combined with chronic statin treatment, further lowered the serum cholesterol level (P<0.001) only in the high absorption group. The sum of cholesterol absorption markers was reduced more (P<0.05) in the high than in the low absorption group, while the non-significant serum cholesterol reduction of the low absorption group was associated with relatively high increase of cholesterol synthesis. Thus, stanol ester margarine combined with chronic simvastatin treatment reduces cholesterol absorption and serum cholesterol more consistently in subjects with high than low baseline absorption of cholesterol. The profile of baseline cholesterol metabolism determines the changes in synthesis and absorption of cholesterol to hypolipidaemic treatments, but affects less differently serum cholesterol level.


Total intravenous anesthesia in horses.
Total intravenous anesthesia (TIVA) is the mainstay of short-term (up to 60 minutes) and field anesthesia in horses. This article discusses the pros and cons of TIVA, commonly used TIVA protocols, and their use, monitoring during, and recovery from, TIVA.


Developing an Awareness Campaign to Reduce Second Hand Smoke Among Disadvantaged Families-A Participatory M-Health Approach.
Children from disadvantaged families are particularly exposed to second hand smoke in their home environment. Using a mixed methods participatory approach, we aimed at identifying suitable media channels and appropriate content for a campaign increasing caregivers' knowledge about the risks of second hand smoke (SHS) exposure for their children and appropriate measures for exposure reduction. In the first phase of the mixed method design, we evaluated knowledge and norms about children's SHS and perceived barriers for avoiding it. To this end, we conducted 26 one-to-one interviews with smoking caregivers of children below the age of six years. Subsequently, we developed and illustrated core messages and identified appropriate communication channels. These were evaluated in focus group discussions by 20 of the 26 interview participants. After a final revision, 121 caregivers evaluated the campaign via an online questionnaire. Online social networks were identified as the most suitable media channel. For these, we developed animated photos with voiceovers addressing the potential consequences of SHS for children. The overall rating of the campaign messages was promising. Participants confirmed that it was important to address the issue in social media. However, sharing the pictures was considered unlikely due to the sensitive topic of the campaign, while the importance of doctors or scientists being recognizable as a source was highlighted. Employing a participatory approach, we developed an m-health campaign, which can now be disseminated in social networks to reach the target population. The effectiveness of the campaign should be evaluated.


Prognosis of patients with non-malignant chronic intestinal failure receiving long-term home parenteral nutrition. Gastroenterology 1995; 108:1005-10.
Long-term survival of patients with intestinal failure requiring home parenteral nutrition (HPN) has not been clearly shown. The authors describe the survival of these patients and explore the prognostic factors. A total of 217 non-cancer non-AIDS adult patients presenting with chronic intestinal failure enrolled from January 1980 to December 1989 in approved HPN programs in Belgium and France. Data were updated in March 1991; not one of the patients was lost for follow up. The prognosis factors for survival are explored using multivariate analysis. During the survey 73 patients died, and the mortality rate related to HPN complications accounted for 11% of deaths. Probabilities of survival at 1, 3 and 5 years were 91%, 70%, and 62% respectively. Three independent variables were associated with a decreased risk of death: age of patients younger than 40 years, start of HPN after 1987, and absence of chronic intestinal obstruction. In patients younger than 60 years, included after 1983 and with a very short bowel (< or = 50 cm), (who could represent suitable candidates for small bowel transplantation) the 2-year survival rate was 90%, a prognosis that compares favourably with recent reports on survival after small bowel transplantation. In conclusion, HPN prognosis compares favourably with recent reports of survival after small bowel transplantation.


Infant temperament predicts life span in female rats that develop spontaneous tumors.
In a recent study, we found that male rats that minimally explored a novel environment as infants died significantly faster than their more exploratory brothers. At death, these males had various complex pathologies, precluding identification of specific hormonal mechanisms underlying adult disease progression and mortality. To minimize the variance of disease processes at the end of life, we conducted a longitudinal study with female Sprague-Dawley rats prone to high rates of spontaneous mammary and pituitary tumors. For females that developed either mammary or pituitary tumors, those that had been neophobic (least exploratory) as infants died approximately 6 months earlier than their neophilic (most exploratory) sisters. In the case of mammary tumors, both benign and malignant, neophobic females developed palpable tumors earlier than neophilic females, whereas the interval between first palpation and death was the same for all females, indicating psychosocial regulation of early rather than later stages of the disease. Neophobic females' ovarian function aged more rapidly than their neophilic sisters. Concomitantly, they had lower corticosterone responses to restraint in late adulthood, ruling out high estrogen or corticosterone levels during senescence as causal factors in their accelerated mortality. During puberty, when mammary tissue is proliferating and differentiating, neophobic females experienced more irregular cycles with prolonged "luteal" phases, suggesting a role for prolactin, prolonged progesterone and fewer estrogen surges during this sensitive period for mammary tumor risk. Thus, we identified prolactin, estrogen, progesterone and possibly corticosterone dynamics as candidates for neuroendocrine mechanisms linking infant temperament with onset of adult neoplastic disease.


Hydrothorax, a complication of the insertion of central venous cannulae.
Hydrothorax developing in a patient after insertion of a central venous cannula is described. The cannula appeared to be in the superior vena cava on chest X-ray, and the condition only became apparent 48 hours after insertion.


Unequal twins: probability distributions do not determine everything.
It is the common lore to assume that knowing the equation for the probability distribution function (PDF) of a stochastic model as a function of time tells the whole picture defining all other characteristics of the model. We show that this is not the case by comparing two exactly solvable models of anomalous diffusion due to geometric constraints: the comb model and the random walk on a random walk. We show that though the two models have exactly the same PDFs, they differ in other respects, like their first passage time distributions, their autocorrelation functions, and their aging properties.


Convexity constraints on linear background models for electron energy-loss spectra.
In this paper convexity constraints are derived for a background model of electron energy loss spectra (EELS) that is linear in the fitting parameters. The model outperforms a power-law both on experimental and simulated backgrounds, especially for wide energy ranges, and thus improves elemental quantification results. Owing to the model's linearity, the constraints can be imposed through fitting by quadratic programming. This has important advantages over conventional nonlinear power-law fitting such as high speed and a guaranteed unique solution without need for initial parameters. As such, the need for user input is significantly reduced, which is essential for unsupervised treatment of large datasets. This is demonstrated on a demanding spectrum image of a semiconductor device sample with a high number of elements over a wide energy range.


Evaluating the Prevalence of Regret With the Decision to Proceed With a Hysterectomy in Women Younger than Age 35.
This study sought to evaluate prevalence of regret with the decision to undergo a hysterectomy at a young age. A retrospective cohort study was performed at two centres and included patients who underwent an elective hysterectomy for benign indications under age 35, between January 1, 2008 and December 31, 2015. Eligible patients were contacted and completed a validated decision regret survey and patient health questionnaire. A total of 189 patients met the study criteria. Of the 95 patients who could be contacted, 71 consented to participate (response rate, 75%). The most common indications for surgery were menorrhagia (35.2%), uterine fibroids (22.5%), endometriosis (19.7%), and pain (15.5%). Overall, 91.5% of patients agreed that having this surgery was the right decision for them, and 90% said that they would make the same choice in the future. A total of 2.8% regretted the choice that they made, and 14% responded that this caused them harm. Over 95% of patients reported that the decision was either mostly patient driven or shared with the physician. This is the first evaluation of regret after hysterectomy specifically examining a younger patient population. The study results suggest that patients who are appropriately counselled do not regret their decision to proceed with hysterectomy.


Coexistence of ecologically similar colonising species III. Drosophila aldrichi and D. buzzatii: larval performance on, and adult preference for, three Opuntia cactus species.
Two Drosophila species, D. buzzatti and D. aldrichi, coexist on several species of Opuntia cacti in Australia, primarily on O. tomentosa and O. streptacantha in the northern part of the cactus distribution, and on O. stricta in the south. Thorax length of field-collected adults was less, and the variance in length greater, than that for flies reared on simulated rots in the laboratory, indicating that these species are affected by crowding in nature. A larval performance index, measured on simulated cactus rots at low, moderate and high densities in single-species cultures, and at moderate and high densities in mixed-species cultures, was used to compare the relative intensity of intra- and interspecific competition at the same total larval density per 5 g necrotic cactus. Larval performance of both fly species was greatest on O. streptacantha, intermediate on O. tomentosa, and least on O. stricta in both single-species and mixed-species cultures. On O. stricta, the performances of D. aldrichi and D. buzzatii were not different when in single-species cultures, but that of D. aldrichi decreased significantly in mixed-species cultures. On the other two cactus species, the performances of D. aldrichi and D. buzzattii were not different in mixed-species cultures. The order of preferences by adult females for the cacti differed from that for larval performance, with females of both species prefering O. stricta. Analysis of microbial numbers growing on the cacti showed little difference among cacti at the rot age used for testing adult preference, but later growth was greater on O. tomentosa and O. streptacantha, the cacti that best supported larvae. Differential larval performance on O. stricta may contribute to the rare presence of D. aldrichi in the southern part of the cactus distribution, while the superior quality of O. tomentosa and O. streptacantha (larger rot size and higher microbial concentration) may reduce competition and facilitate cocxistence of the fly species in the north.


Investigation on toxicity mechanism of halogenated aromatic disinfection by-products to zebrafish based on molecular docking and QSAR model.
Halogenated aromatic disinfection by-products (DBPs) are a new type of DBPs that have been detected in various water bodies. Previous studies have shown that most of them can induce in vivo toxicity in aquatic organisms. In this study, in order to further investigate the toxic effects and mechanisms of aromatic DBPs, the toxicity and ecological risks of 10 halogenated aromatic DBPs were assessed using the model organism zebrafish. It was found that the toxicity of DBPs was related to the number, type, and position of halogen and the type of substituent, and the 24 h-toxicity value of DBPs in this experiment could replace their 96 h-toxicity value to reduce the test time and save the test cost. Halogenated phenol and halogenated nitrophenol were more toxic, but the current ecological risks of DBPs were relatively low. In addition, the toxicity mechanism of DBPs was analyzed based on molecular docking and quantitative structure-activity relationship (QSAR) models. The molecular docking results showed that all 10 DBPs could bind to zebrafish's catalase (CAT), cytochrome P450 (CYP450), p53, and acetylcholinesterase (AChE), thereby affecting their normal life activities. QSAR models indicated that the toxicity of halogenated aromatic DBPs to zebrafish mainly depended on their hydrophobicity (log D), the interaction with CAT (ECAT), and hydrogen bonding acidity (A).


Cross-talk between lung cancer and bones results in neutrophils that promote tumor progression.
Lung cancer is the leading cause of cancer mortality around the world. The lack of detailed understanding of the cellular and molecular mechanisms participating in the lung tumor progression restrains the development of efficient treatments. Recently, by using state-of-the-art technologies, including in vivo sophisticated Cre/loxP technologies in combination with lung tumor models, it was revealed that osteoblasts activate neutrophils that promote tumor growth in the lung. Strikingly, genetic ablation of osteoblasts abolished lung tumor progression via interruption of SiglecFhigh-expressing neutrophils supply to the tumor microenvironment. Interestingly, SiglecFhigh neutrophil signature was associated with worse lung adenocarcinoma patients outcome. This study identifies novel cellular targets for lung cancer treatment. Here, we summarize and evaluate recent advances in our understanding of lung tumor microenvironment.


The jugular foramen: a comparative radioanatomic study.
Advances in microsurgical techniques made possible the removal of advanced jugular foramen (JF) lesions, which once had been accepted as unoperable. However, successful surgery requires detailed knowledge of the JF anatomy. Sixteen jugular foramina in eight formalin-preserved adult cadavers were scanned with axial and coronal high resolution computed tomography (HRCT) prior to dissection. After craniectomy and removal of brain tissue, the relationships of the neurovascular structures in the JF were determined by drilling the temporal bones from superior to inferior on planes parallel to the skull base. No bony partition of the JF was observed. A dural band consistently divided the JF into two parts. Anterior to it was the glossopharyngeal nerve (IX) while the vagus (X) and accessory (XI) nerves were located posteriorly. There was a notch in which the IX nerve entered the JF. It was also identified on the CT scans and defined as the glossopharyngeal recess. The IX nerve made a genu within the JF in all specimens. Then, it ran inferiorly through a bony canal in three specimens (18.75%), and through an incomplete bony canal in two (12.5%), which were also defined on the CT images. The inferior petrosal sinus ran through a sulcus anteromedial to the glossopharyngeal recess. The posterior meningeal artery was found to be located between the X and XI nerves within the JF. This study revealed a complex and highly variable pattern of the relationships of the neurovascular structures in the JF, and their HRCT images correlated well with the anatomic microdissections.


Inhibition of hepatic fatty acid oxidation by bezafibrate and bezafibroyl CoA.
The acute effect of the hypolipidemic agent bezafibrate on fatty acid oxidation was studied in rat hepatocytes and mitochondria. Bezafibrate caused a concentration-related inhibition of oleate oxidation in liver cells. In mitochondria bezafibrate inhibited the oxidation of palmitoyl CoA but had no effect on palmitoylcarnitine oxidation, suggesting the site of inhibition was the formation of the carnitine derivative. Bezafibrate and bezafibroyl CoA inhibited the overt carnitine palmitoyltransferase (I) in rat liver mitochondria with comparable potency but with distinct kinetics. The inhibition caused by bezafibrate was not prevented by omission of Mg++-ATP from the assay mixture, indicating activation of bezafibrate to bezafibroyl CoA was not required for inhibition. The data demonstrate that bezafibrate, like several other peroxisome proliferating agents, inhibits mitochondrial fatty acid oxidation in rat liver. The inhibition may be relevant to the mechanism of peroxisome proliferation.


Successful diagnosis and surgical treatment of single ventricle, truncus arteriosus.
The association of single ventricle and truncus arteriosus is rare. We present the successful surgical palliation of a patient who echocardiographically and angiographically has a truncus arteriosus type I and single left ventricle. At operation, the main pulmonary artery was dissected off the truncus arteriosus, and a 4-mm polytetrafluoroethylene graft was placed from the ascending aorta to the left pulmonary artery. The patient is currently 13 months old and growing well.


A Longitudinal Study of the Mini-Mental State Examination in Late Nonagenarians and Its Relationship with Dementia, Mortality, and Education.
To examine level of and change in cognitive status using the Mini-Mental State Examination (MMSE) in relation to dementia, mortality, education, and sex in late nonagenarians. Three-year longitudinal study with examinations at ages 97, 99, and 100. Trained psychiatric research nurses examined participants at their place of living. A representative population-based sample of 97-year-old Swedes (N = 591; 107 men, 484 women) living in Gothenburg, Sweden. A Swedish version of the MMSE was used to measure cognitive status. Geriatric psychiatrists diagnosed dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Mixed models were fitted to the data to model the longitudinal relationship between MMSE score and explanatory variables. Individuals with dementia between age 97 and 100 had lower mean MMSE scores than those without dementia. Those who died during the 3-year follow-up had lower MMSE scores than those who survived. MMSE scores at baseline did not differ between those without dementia and those who developed dementia during the 3-year follow-up. Participants with more education had higher MMSE scores, but there was no association between education and linear change. MMSE score is associated with dementia and subsequent mortality even in very old individuals, although the preclinical phase of dementia may be short in older age. Level of education is positively associated with MMSE score but not rate of decline in individuals approaching age 100.


Age-related differential mRNA expression of T cell cytokines in NZB/NZW F1 mice.
The mRNA expression of interleukin (IL)-2, IL-2 receptor-alpha-chain (IL-2R alpha), IL-4 and interferon-gamma (IFN-gamma) in spleen cells from NZB/NZW F1) mice following the stimulation with concanavalin A (Con A) was examined by Northern blot analysis. Kinetic patterns of the mRNA expression after the stimulation were not different between 2-month-old and 6 to 8-month-old B/W F1 mice. However, relative mRNA expression of IL-2 to a cytoskeletal protein, alpha-Tubulin was lower in 6 to 8-month-old B/W F1 mice than in 2-month-old mice. Similar but not significant tendency was observed in IL-2R mRNA expression. In contrast, Relative IL-4 mRNA expression in 6 to 8-month-old B/W F1 mice was significantly higher than that in 2-month-old animals. On the other hand, no apparent change was observed in IFN-gamma mRNA expression. Flow cytometric analysis indicated that there was no apparent difference in proportion of L3T4 positive T cells in spleen cells from 2 and 6 to 8-month-old B/W F1 mice. These results suggest that mRNA expression of IL-2 and IL-4 differentially changes with aging in autoimmune B/W F1 mice.


Microbial conversion of vanillin from ferulic acid extracted from raw coir pith.
Coir pith, an agro-industrial residue, is resistant to natural degradation, and its accumulation causes environmental pollution. Ferulic acid, a precursor of vanillin, was extracted from the raw coir pith by chemical pre-treatment such as alkaline hydrolysis, acidification, and liquid-liquid extraction method. The obtained ferulic acid (1.2 g/50 g) was analysed using high-performance liquid chromatography (HPLC) and used as a substrate for biotransformation by Aspergillus niger to vanillic acid, which, in turn, was fermented by using Phanerochaete chrysosporium to vanillin. The quantity of vanillic acid detected by HPLC on the third day of incubation was 0.773 g/L, while the optimal yield of vanillin on the subsequent third day of incubation was 0.628 g/L. Thus, the chemical extraction of ferulic acid from coir pith ensued bioconversion into vanillin. These products are highly valuable and economical to be used in industries such as pharmaceuticals, health, cosmetics, and neutraceuticals.


TeaPVs: a comprehensive genomic variation database for tea plant (Camellia sinensis).
Genome variation not only plays an important role in plant phenotypic modeling and adaptive evolution, but also enhances population genetic diversity and regulates gene expression. The tea tree (Camellia sinensis) has a large genome (~ 3.0 Gb), making the identification of genome-wide variants time-consuming and expensive. With the continuous publication of a large number of different types of population sequencing data, there is a lack of an open platform to integrate these data and identify variants in the tea plant genome.To integrate the genetic variation confidence in the tea plant population genome, 238 whole-genome resequencing, 213 transcriptome sequencing, and 96 hybrid F1 individuals with a total of more than 20 Tb were collected for mutation site identification. Based on these variations information, we constructed the first tea tree variation web service database TeaPVs ( http://22.214.171.124:8025/ and http://liushang.top:8025/ ). It supports users to search all SNP, Indel, SV mutations and SSR/Polymorphic SSR sequences by location or gene ID. Furthermore, the website also provides the functions of gene expression search of different transcriptome, sequence blast, sequence extraction of CDS and mutation loci, etc.The features of the TeaPVs database make it a comprehensive tea plant genetic variation bioinformatics platform for researchers, and will also be helpful for revealing new functional mutations in the tea plant genome and molecular marker-assisted breeding.


Application of 15N tracing and bioinformatics for estimating microbial-mediated nitrogen cycle processes in oil-contaminated soils.
Crude oil pollution can profoundly alter the nitrogen (N) cycle in the soil. Here, a 30-day incubation with 15N tracer approach was performed to assess the impacts of crude oil concentrations (medium: 10,000 mg kg-1; heavy: 50,000 mg kg-1) on soil N cycling based on a numerical model. Results showed that crude oil pollution significantly increased the gross N-transformation rates, but the rates of oxidation of recalcitrant organic N, the immbolization of NO3- and the adsorption of NH4+ changed differently as a function of hydrocarbon concentrations. There was no significant difference of the oxidation rate of recalcitrant organic N between the medium and heavy oil-contaminated soils (medium: 0.1149 mmol N kg-1 d-1; heavy: 0.1299 mmol N kg-1 d-1), but the rates of NO3- immobilization (0.1135 mmol N kg-1 d-1) and NH4+ adsorption were the highest (0.1148 mmol N kg-1 d-1) in the moderately oil-contaminated soils than those in the heavy polluted soil (0.0849 mmol N kg-1 d-1 and 0.0034 mmol N kg-1 d-1, respectively). The NO3- immobilization rate was 2.5-fold higher than its reduction rate, indicating that NO3- immobilization played a more important role during the process of NO3- transformation. Microbial community structure analysis indicated that phyla of Actinobacteria and Ascomycota respectively promoted the immobilization of NO3- to recalcitrant organic N and the reduction of NO3- to NH4+. The genus of Aspergillus was related to net NH4+ production, and the genera of Penicillium and Acremonium were responsible for oxidation of recalcitrant organic N to NO3-.


Role and control of X chromosome dosage in mammalian development.
Many species have evolved sex chromosomes with highly divergent gene content, such as the X and Y chromosomes in mammals. As most non sex-specific genes probably need to be expressed at similar levels in males and females, dosage compensation mechanisms are in place to equalize the gene dosage between the sexes, and possibly also between sex chromosomes and autosomes. In mammals, one out of two X chromosomes is inactivated early during development in a process called X-chromosome inactivation that has been investigated intensively in the 50 years since it was discovered. Less is known about the potential functional roles of X-linked gene dosage, for example in controlling development in a sex-specific manner. In this review, we discuss the evolution of dosage compensation and how it is controlled during embryogenesis of mammals. In addition we will summarize evidence on the potential role of X chromosome number during early development.


The measurement of subnanosecond fluorescence decay of flavins using time-correlated photon counting and a mode-locked Ar ion laser.
A system is described consisting of a mode-locked Ar ion laser and time-resolved photon-counting electronics. The system is capable of measuring fluorescence lifetimes in the subnanosecond time domain. The Ar ion laser is suitable for the excitation of flavins, since the available laser wavelengths encompass the first absorption band of the yellow chromophore. Due to the high radiation density and the short pulse, both the time and wavelength resolution of the fluorescence of very weakly emitting compounds can be measured. Experiments have been described for flavin models exhibiting single and multiple modes of decay. In these examples lifetimes were determined both from deconvolved decay curves and from direct analysis of the tail of the curve, where no interference of the exciting pulse is encountered. Both determinations showed very good agreement. Due to the highly polarized laser light the decay of the emission anisotropy could be measured directly after the exciting pulse. In principle, fast rotational motions might be detected. An anisotropy measurement conducted with a flavoprotein with a noncovalently attached FAD is presented.


Determination of the microscopic rate constants for the hydrolysis of diuron in soil/water mixture.
A kinetic equation for the analysis of the degradation reaction of xenobiotic molecules in the soil/water mixture has been derived. By means of this equation we have evaluated the microscopic rate constant for the abiotic hydrolysis of the herbicide diuron in the water phase of a soil/water mixture assuming that the reaction occurs only in the water phase and that diuron is reversibly adsorbed by the soil with a higher rate. The soil catalytic capacity on the hydrolysis of diuron was evaluated.


Glutathione transport in the endo/sarcoplasmic reticulum.
Glutathione transport through the endo/sarcoplasmic reticulum (ER/SR) membrane might play a role in the maintenance of the thiol redox potential difference between the lumen and the cytosol. The transport of glutathione (both GSH and glutathione disulfide, GSSG) is entirely different in the ER and SR membranes. The transport measurements based on either rapid filtration or light scattering techniques revealed that the SR membrane transports glutathione much faster than the hepatic ER membrane or microsomal membranes prepared from heart or brain. The fastest transport has been measured in the membrane of muscle terminal cisternae, which is enriched in ryanodine receptor type 1 (RyR1). All the studied membranes have been found to be equally impermeable to various hydrophilic substances of similar size to glutathione, thus the glutathione transport in muscle microsomes and terminal cysternae as well as the correlation between the rate of glutathione transport and the abundance of RyR1 are specific. In both muscle microsomes and terminal cysternae, glutathione influx can be either inhibited or activated by antagonists and agonists of the ryanodine receptor, respectively, while these agents do not influence the transport of other small permeant molecules. These findings strongly suggest that the ryanodine receptor channel activity is directly associated with glutathione transport activity in the skeletal muscle sarcoplasmic reticulum membrane.


Hodgkin's lymphoma in a pregnant patient with acquired immunodeficiency syndrome.
The occurrence of Hodgkin's lymphoma in pregnancy is unusual; its management poses not only medical but also ethical problems. We report the case history of a pregnant patient with acquired immunodeficiency syndrome and Hodgkin's lymphoma. Combination chemotherapy was given, with a favourable outcome for the foetus. From a review of some of the available literature, the management considerations are discussed.


Pediatric neurotology.
Pediatric neurotology is a subspecialty encompassing the medical and surgical treatment of conditions involving the middle ear, inner ear and lateral skull base. Multiple otologic and neurotologic diseases exist. In the pediatric patient the most common neurotologic conditions are vertigo, complications of otitis media, cholesteatoma, hearing loss and facial paralysis. Vertigo is differentiated into peripheral and central vestibular abnormalities. Peripheral vestibular causes include Meniere's disease, benign paroxysmal positional vertigo, vestibular neuronitis, otitis media and labyrinthitis. The predominant lesions in our field causing central vestibular disorders are brainstem and posterior fossa tumors. Mastoiditis, meningitis, petrositis, sigmoid sinus thrombosis, extradural abscess, brain abscess, otitic hydrocephalus, cholesteatoma and cholesterol granuloma are complications of otitis media and middle ear disease. Sensorineural hearing loss is now readily treated with cochlear implantation. Facial nerve paralysis may result from infectious and other etiologies.


Exploring anticancer efficiency of mitochondria-targeted cyclometalated iridium(III) complexes.
We prepared and characterized new iridium(III) complexes: [Ir(NC)2(MPPIP)](PF6) (N-C = 2-phenylpyridine 1; benzo[h]quinolone 2; 1-phenylisoquinolone, 3, MPPIP = 2-(4-(4'-methylpiperazin-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline). MTT (MTT = 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide) method was used to assay anticancer activities of the complexes 1-3 toward SGC-7901, HeLa, A549, BEL-7402, mouse embryonic fibroblast NIH3T3 cell lines. Complexes 1, 2, 3 are sensitive to A549 cells and display a relatively low IC50 value of 5.4 ± 0.3, 4.2 ± 0.03 and 3.8 ± 0.2 μM, respectively. The apoptotic efficiency was investigated and the number of apoptotic cells induced by 1, 2 and 3 is 9.92%, 11.30% and 16.00%. The complexes are able to increase intracellular ROS content and lessen the mitochondrial membrane potential. Besides, anti-tumor activity in vivo reveals that complex 3 exhibits moderate effect on inhibiting the tumor growth, and complex 3 has no influence on liver, brain, kidney, lung and heart.


Restructuring of titanium oxide overlayers over nickel nanoparticles during catalysis.
Reducible supports can affect the performance of metal catalysts by the formation of suboxide overlayers upon reduction, a process referred to as the strong metal-support interaction (SMSI). A combination of operando electron microscopy and vibrational spectroscopy revealed that thin TiOx overlayers formed on nickel/titanium dioxide catalysts during 400°C reduction were completely removed under carbon dioxide hydrogenation conditions. Conversely, after 600°C reduction, exposure to carbon dioxide hydrogenation reaction conditions led to only partial reexposure of nickel, forming interfacial sites in contact with TiOx and favoring carbon-carbon coupling by providing a carbon species reservoir. Our findings challenge the conventional understanding of SMSIs and call for more-detailed operando investigations of nanocatalysts at the single-particle level to revisit static models of structure-activity relationships.


Cerebellar effects after consumption of edible morels (Morchella conica, Morchella esculenta).
Morchella esculenta and Morchella conica are well known edible morels, which seldom induce clinical symptoms. We report six persons who developed cerebellar effects 6-12 hours after consumption of these mushrooms. The symptoms were self-limited and disappeared after one day.


Approach to the mechanism of Zajdela's hepatoma cell growth inhibition induced by concanavalin A and phytohaemagglutinin.
Cell growth of tumour ascites cells was inhibited by concanavalin A, phytohaemagglutinin and Ricinus lectin at 2-100 micrograms/ml. As expected, the Ricinus lectin inhibited the protein synthesis estimated by leucine incorporation and decreased thymidine incorporation, whereas concanavalin A and phytohaemagglutinin stimulate the uptake and the incorporation of both leucine and thymidine, and thus, synthesis of protein and DNA. These results suggest that different mechanisms are involved in the hepatoma cell growth inhibition by the lectins. This difference was not related to the kinetic characteristics of the lectin interactions with the cells which represent a first and necessary step. It was showed that concanavalin A and phytohaemagglutinin as well as chloroquine inhibited the 14C-labelled asialofetuin degradation. We can conclude that Ricinus lectin present a toxic effect whereas both concanavalin A and phytohaemagglutinin show an anti-protease activity.


Lack of effect of withdrawal from cigarette smoking on theophylline pharmacokinetics.
The intravenous disposition of theophylline was determined in 12 healthy young male smokers during periods of smoking and short-term withdrawal (24 to 36 hours), using a crossover design. Median half-life, clearance, volume of distribution, hepatic extraction, and intrinsic clearance of theophylline during withdrawal were within +/- 5% of the corresponding median control (smoking) parameters and were normal in comparison with values published for smokers. The lack of change in the pharmacokinetic profile of theophylline indicates that adjustment of the dosage regimen should not be necessary immediately after smoking withdrawal.


The spectrum of neutrophilic dermatoses associated with monoclonal gammopathy: Association with IgA isotype and inflammatory profile.
Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome. We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg. We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules. This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1. This is a retrospective study from a single institution with a limited number of participants. Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.


Management of brain and spine injuries.
For both SCI and TBI, physicians are unable to affect reversal of the cellular injuries suffered at the time of trauma directly. Unfortunately, understanding such processes is just on the horizon. Physicians do, however, have significant influence on recovery through the avoidance of secondary insults to the injured nervous system. In keeping with trauma in general, the mechanism for this is focused and coordinated multi-disciplinary care originating at the earliest contact and continuing through acute care. Aggressive and pre-emptive attention to the ABC(D)s with attention to the needs of the injured nervous system, appropriate monitoring in all patients, meticulous medical management, and prompt surgical intervention when indicated have made marked improvements in outcome, particularly in TBI. Focusing on the basics and strict attention to detail appear to be the major roles played in the care of CNS trauma.


[Clinical picture of Herpesviridae infections among immunocompromised patients: bone marrow and solid organ transplants recipients].
The human herpes virus (HHV) family (herpesviridae) are large DNA viruses containing eight important, ubiquitous human pathogens. This group of viruses encompasses: herpes simplex virus (HSV types 1 and 2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, HHV-7 (cause roseola or exanthema subitum in children) and Kaposi sarcoma herpes virus--(KSHV). The outstanding property of herpes viruses is lifelong persistence of infection and potential periodic reactivation, particularly often among immunocompromised patients. Herpesvirus infections are associated with a wide spectrum of diseases ranging from local ulceration to serious systemic illnessess or malignancies. These infections are one of the major cause of morbidity and mortality in the immunocompromised patients.


Epidemiology, molecular characterization, and drug resistance of IncHI5 plasmids from Enterobacteriaceae.
The increasingly frequent occurence of IncHI5 plasmids has attracted worldwide attention. The aim of this study was to perform an in-depth bioinformatics analysis to determine the genetic characteristics and global distribution of all IncHI5 plasmids. The geographic distribution and epidemiology of all IncHI5 plasmids from GenBank were analyzed based on relevant literature reports and background information from the National Center for Biotechnology Information (NCBI). Detailed annotation of antibiotic resistance genes was performed. A total of 65 IncHI5 plasmid genomes were collected in GenBank. All IncHI5 plasmids were carried by Enterobacteriaceae, of which Klebsiella pneumoniae accounted for the largest proportion (50%, 33/65). The host bacterium of IncHI5 plasmids was mainly isolated from Homo Sapiens (81%, 53/65). All strains carrying IncHI5 plasmids were mainly distributed in China (83%, 54/65). Evolutionary analysis can divide IncHI5 plasmids into two groups, namely Groups I/II, of which Group II was more widely distributed worldwide. This study showed that Enterobacteriaceae, especially Klebsiella, was the main host for IncHI5 plasmid. Almost all IncHI5 plasmids carried multiple types of antibiotic resistance genes, related to Tn1696 or Tn6535. The IncHI5 plasmids should be of continuing interest as good repositories for antibiotic resistance genes.


Association between polymorphisms of interleukin 12 and rheumatoid arthritis associated biomarkers in a Chinese population.
The aim of the present study was to examine the association between polymorphisms of interleukin 12 (IL-12) and rheumatoid arthritis (RA) associated biomarkers in a Chinese population. We studied IL-12A rs2243115 T/G and IL-12B rs3212227 A/C polymorphisms in 615 RA patients and 839 controls in a Chinese population. Genotyping was done by a custom-by-design 48-Plex SNPscan™ Kit. The plasma level of IL-12 was measured by an enzyme-linked immune-sorbent assay in 90 RA patients and 90 controls. Clinical data with other potential diagnostic value were provided by the physicians. A significantly increased risk for RA associated with the IL-12A rs2243115 GG (GG versus TT: OR=4.81, 95% CI 1.33-17.36, P=0.017; and GG versus TG+TT: OR=4.55, 95% CI 1.27-16.36, P=0.020) genotype was evident among rheumatoid factor (RF) negative patients, and with the IL-12B rs3212227 AC (AC versus AA) and AC+CC (AC+CC versus AA) genotypes were evident among older patients (OR=1.48, 95% CI 1.06-2.06, P=0.020), RF positive patients (OR=1.35, 95% CI 1.04-1.75, P=0.026) and anti-cyclic citrullinated peptide antibodies (ACPA) negative patients (OR=1.53, 95% CI 1.11-2.10, P=0.009). The plasma level of IL-12 was significantly higher in RA patients (P<0.001). IL-12 plasma level of IL-12A rs2243115 TT (P<0.001) and IL-12B rs3212227 C allele (P<0.001) were significantly higher in RA patients than controls respectively. The plasma level of IL-12 of RF positive RA patients was significantly higher than RF negative patients (P=0.008), especially in rs3212227 AC patients (P=0.01). These findings suggested that the functional single nucleotide polymorphism (SNP) IL-12A rs2243115 GG genotype may increase the risk of RA in RF negative patients, and the IL-12B rs3212227 AC and AC+CC genotypes are associated with RA risk in older patients, RF positive patients and ACPA negative patients. The IL-12A rs2243115 T/G and IL-12B rs3212227 A/C allele might also impact the inflammatory reaction of IL-12 in patients with RA.


Effect of allergen-specific immunotherapy with purified Alt a1 on AMP responsiveness, exhaled nitric oxide and exhaled breath condensate pH: a randomized double blind study.
Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air. This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered. The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 μg/mL (0.03-0.11) at baseline to 1.21 μg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 μg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 μg/mL (0.06-0.12) at baseline to 0.13 μg/mL (0.07-0.18) at 6 months and to 0.11 μg/mL (0.07-0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups. Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy-induced increase in IgG4 levels and its effect on airway responsiveness and inflammation.


An integrated interval-valued intuitionistic fuzzy technique for resumption risk assessment amid COVID-19 prevention.
Currently, China has achieved a remarkable achievement on the containment of COVID-19, which creates a favorable condition for the gradual resumption of normal life. However, COVID-19 infections continue to rise in many nations and some sporadic cases occur from time to time in China, which still poses some risks to the resumption. Hence, it is imperative to develop some reasonable techniques to assess the resumption risk. This paper aims to investigate an integrated interval-valued intuitionistic fuzzy (IVIF) technique to adroitly assess the resumption risk based on DEMATEL (decision making trial and evaluation laboratory), BWM (best-worst method) and SPA (set pair analysis). This integrated technique is called IVIF-DBWM-SPA, where the IVIF-DBWM (combined by the IVIF-DEMATEL and IVIF-BWM) is used to determine the global criteria weights and the IVIF-SPA is employed to generate the ranking order of the alternatives. The IVIF-DEMATEL and IVIF-BWM are used to determine the weights of dimensions and the weights of criteria under each dimension, respectively. In this IVIF-BWM, two bi-objective programming models are constructed by regarding experts' pessimistic and optimistic attitudes, respectively. Combined experts' intrapersonal and interpersonal uncertainties simultaneously, a bi-objective programming model is proposed to derive the dynamic weights of experts. Based on the determined weights of experts and criteria, an IVIF-SPA is developed to assess the risk levels of all alternatives. The validity of the proposed technique is demonstrated with a real case of college resumption risk assessment amid COVID-19. Some sensitivity and comparison analyses are provided to show the merits of the proposed technique.


CT demonstration of a rapidly growing transitional cell carcinoma of the ureter and renal pelvis.
Transitional cell carcinoma (TCC) is the most common urothelial malignancy. We present a case of an exceptionally aggressive TCC involving the renal pelvis and ureter. To our knowledge, an upper tract TCC of such rapid growth has not been reported.