Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.
Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.


Microalgae: A Promising Source of Bioactive Phycobiliproteins.
Phycobiliproteins are photosynthetic light-harvesting pigments isolated from microalgae with fluorescent, colorimetric and biological properties, making them a potential commodity in the pharmaceutical, cosmetic and food industries. Hence, improving their metabolic yield is of great interest. In this regard, the present review aimed, first, to provide a detailed and thorough overview of the optimization of culture media elements, as well as various physical parameters, to improve the large-scale manufacturing of such bioactive molecules. The second section of the review offers systematic, deep and detailed data about the current main features of phycobiliproteins. In the ultimate section, the health and nutritional claims related to these bioactive pigments, explaining their noticeable potential for biotechnological uses in various fields, are examined.


Biochemical requirements for the formation of clathrin- and COP-coated transport vesicles.
Clathrin-coated vesicles and COP-coated vesicles constitute two major classes of functionally and structurally distinct transport vesicles. Cell-free assays that directly measure the formation of either class of vesicle are revealing important similarities and differences in the biochemical requirements for transport vesicle formation.


Interictal, circulating sphingolipids in women with episodic migraine: A case-control study.
To evaluate interictal, circulating sphingolipids in women migraineurs. In the fasting state, serum samples were obtained pain-free from 88 women with episodic migraine (EM; n=52) and from controls (n=36). Sphingolipids were detected and quantified by high-performance liquid chromatography coupled with tandem mass spectrometry using multiple reaction monitoring. Multivariate logistic regression was used to examine the association between serum sphingolipids and EM odds. A recursive partitioning decision tree based on the serum concentrations of 10 sphingolipids was used to determine the presence or absence of EM in a subset of participants. Total ceramide (EM 6,502.9 ng/mL vs controls 10,518.5 ng/mL; p<0.0001) and dihydroceramide (EM 39.3 ng/mL vs controls 63.1 ng/mL; p<0.0001) levels were decreased in those with EM as compared with controls. Using multivariate logistic regression, each SD increase in total ceramide (odds ratio [OR] 0.07; 95% confidence interval [CI]: 0.02, 0.22; p<0.001) and total dihydroceramide (OR 0.05; 95% CI: 0.01, 0.21; p<0.001) levels was associated with more than 92% reduced odds of migraine. Although crude sphingomyelin levels were not different in EM compared with controls, after adjustments, every SD increase in the sphingomyelin species C18:0 (OR 4.28; 95% CI: 1.87, 9.81; p=0.001) and C18:1 (OR 2.93; 95% CI: 1.55, 5.54; p=0.001) was associated with an increased odds of migraine. Recursive portioning models correctly classified 14 of 14 randomly selected participants as EM or control. These results suggest that sphingolipid metabolism is altered in women with EM and that serum sphingolipid panels may have potential to differentiate EM presence or absence. This study provides Class III evidence that serum sphingolipid panels accurately distinguish women with migraine from women without migraine.


Superoxide dismutase induces differentiation in microplasmodia of the slime mold Physarum polycephalum.
Evidence is presented that supports a role for the enzyme superoxide dismutase (SOD) in the differentiation of the slime mold, Physarum polycephalum. SOD activity increases 46-fold during differentiation. A strain of Physarum that does not differentiate exhibits no change in SOD activity. Addition of SOD, via liposomes, to the nondifferentiating strain induces differentiation; this effect is enhanced by an inhibitor of glutathione synthesis. Other antioxidants selected for study failed to induce differentiation. Conversely, oxidative treatments including introduction of D-amino acid oxidase, via liposomes, induced differentiation. Cellular oxidation is the probable cause of the SOD effect.


(+)-Morphine attenuates the (-)-morphine-produced conditioned place preference and the mu-opioid receptor-mediated dopamine increase in the posterior nucleus accumbens of the rat.
An unbiased conditioned place preference paradigm and the microdialysis technique was used to evaluate the effect of (+)-morphine pretreatment on the conditioned place preference produced by (-)-morphine and the increased release of the dopamine produced by mu-opioid ligand endomorphin-1, respectively, in the posterior nucleus accumbens shell of the male CD rat. (-)-Morphine (2.5-10 microg) microinjected into the posterior nucleus accumbens shell dose-dependently produced the conditioned place preference. Pretreatment with (+)-morphine (0.1-10 pg) given into the posterior accumbens shell for 45 min dose-dependently attenuated the conditioned place preference produced by (-)-morphine (5 microg) given into the same posterior accumbens shell. However, higher doses of (+)-morphine (0.1 and 1 ng) were less effective in attenuating the (-)-morphine-produced conditioned place preference. Thus, like given systemically, (+)-morphine given into the posterior nucleus accumbens shell also induces a U-shaped dose-response curve for attenuating the (-)-morphine-produced conditioned place preference. Microinjection of mu-opioid agonist endomorphin-1 (1-10 microg) given into the ventral tegmental area dose-dependently increased the release of the extracellular dopamine in the posterior nucleus accumbens shell in the urethane-anesthetized rats. The increased dopamine caused by endomorphin-1 (10 microg) was completed blocked by the (+)-morphine (10 pg) pretreatment given into ventral tegmental area. It is concluded that (+)-morphine attenuates the (-)-morphine-produced conditioned place preference and the mu-opioid receptor-mediated increase of extracellular dopamine in the posterior nucleus accumbens shell of the rat.


Integrating host transcriptomic signatures for distinguishing autoimmune encephalitis in cerebrospinal fluid by metagenomic sequencing.
The early accurate diagnoses for autoimmune encephalitis (AE) and infectious encephalitis (IE) are essential since the treatments for them are different. This study aims to discover some specific and sensitive biomarkers to distinguish AE from IE at early stage to give specific treatments for good outcomes. We compared the host gene expression profiles and microbial diversities of cerebrospinal fluid (CSF) from 41 patients with IE and 18 patients with AE through meta-transcriptomic sequencing. Significant differences were found in host gene expression profiles and microbial diversities in CSF between patients with AE and patients with IE. The most significantly upregulated genes in patients with IE were enriched in pathways related with immune response such as neutrophil degranulation, antigen processing and presentation and adaptive immune system. In contrast, those upregulated genes in patients with AE were mainly involved in sensory organ development such as olfactory transduction, as well as synaptic transmission and signaling. Based on the differentially expressed genes, a classifier consisting of 5 host genes showed outstanding performance with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.95. This study provides a promising classifier and is the first to investigate transcriptomic signatures for differentiating AE from IE by using meta-transcriptomic next-generation sequencing technology.


Pilot-scale testing of a leachbed for anaerobic digestion of livestock residues on-farm.
A leachbed is a relatively simple anaerobic digester suitable for high-solids residues and on-farm applications. However, performance characteristics and optimal configuration of leachbeds are not well-understood. In this study, two 200 L pilot-scale leachbeds fed with spent straw bedding from pigs/swine (methane potential, B0 = 195-218 L CH4 kg(-1) VS fed) were used to assess the effects of leachate recirculation mode (trickling vs. flood-and-drain) on the digestion performance. Results showed comparable substrate solubilisation extents (30-45% of total chemical oxygen demand fed) and methane conversion (50% of the B0) for the trickling and flood-and-drain modes, indicating that digestion performance was insensitive to the mode of leachate flow. However, the flood-and-drain leachbed mobilised more particulates into the leachate than the trickling leachbed, an undesirable outcome, because these particulates were mostly non-biodegradable. Inoculation with solid residues from a previous leachbed (inoculum-to-substrate ratio of 0.22 on a VS basis) hastened the leachbed start-up, but methane recovery remained at 50% of the B0 regardless of the leachate recirculation mode. Post-digestion testing indicated that the leachbeds may have been limited by microbial activity/inhibition. The high residual methane potential of leachate from the trickling (residual Bo = 732 ± 7 L CH4 kg(-1) VS fed) and flood-and-drain leachbeds (582 ± 8 L CH4 kg(-1) VS fed) indicated an opportunity for further processing of leachate via a separate methanogenic step. Overall, a trickling leachbed appeared to be more favourable than the flood-and-drain leachbed for treating spent bedding at farm-scale due to easier operation.


Transrectal ultrasound screening for prostatic adenocarcinoma with histopathological correlation. Factors affecting specificity.
Ultrasound (US) is increasingly used for the detection of prostatic cancer, yet its specificity is low when used alone. A study was undertaken to examine the factors affecting the specificity of prostatic US. Thirty-five intact prostates obtained at autopsy were studied in vitro by US, and the findings were correlated with those in histologic sections. US abnormalities were noted in 24 cases, but prostatic adenocarcinoma was diagnosed by US in only 5 of 12 proven cases. It appears that the US diagnosis of tumor is determined more by location than by size. Anterior and central tumors often are missed by US. Benign prostatic hyperplasia, which affects the transition zone, contributed to a false-positive or false-negative diagnosis of tumor in 10 of 35 cases. Other findings associated with abnormal US include abscesses, infarcts, and seminal vesicles embedded in the prostate. The specificity of prostatic US is low; it should not be used as an isolated test in screening the prostate for tumors.


Cell-diffusion precipitin analysis of mixed IgM-IgG cryoglobulins. An unusual kappa-chain determinant of the IgM component.
Antigenic features of monoclonal IgM kappa components of three mixed IgM-IgG cryoglobulins were studied by gel-diffusion precipitin analysis. An unusual kappa-chain determinant was revealed in the IgM components but not in other monoclonal immunoglobulins (IgM kappa, BJ kappa) or normal IgG. Antibodies to this determinant were found not only in anti-kappa, but also in anti-lambda sera, and in antisera to hidden determinants of L-chains.


Sister-chromatid exchange in spleenic lymphocytes of mice after exposure to nifurtimox or benznidazole.
The induction of sister-chromatid exchange (SCE) was analyzed in spleenic lymphocytes of mouse after exposure to nifurtimox (NFX) or benznidazole (BZ). Lymphocytes from Swiss mice treated "in vivo" with 1200 and 2000 mg/kg NFX (p.o.) and then incubated "in vitro" with bromo-2'-deoxyuridine showed an increased frequency of SCE. No significant differences were observed in mice treated with 2000 mg/kg BZ (p.o.). The present and previous results obtained in this and other laboratories suggest that the effects observed should warn against the potential risk of NFX treatment in humans receiving this chemotherapeutic agent as a treatment for Chagas' disease.


Low frequency of parental mosaicism in de novo COL4A5 mutations in X-linked Alport syndrome.
Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in the COL4A5 gene encoding the α5-chain of type-IV collagen. The proportion of de novo COL4A5 sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies. In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleterious COL4A5 sequence variants in these patients were previously assumed to be de novo, based on Sanger sequencing of the parents. A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic. These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to be de novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.


Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity.
A series of KRAS G12C-targeting PROTACs (PROteolysis TArgeting Chimeras) were designed and synthesized based on KRas G12C-IN-3 (a KRAS G12C inhibitor) and pomalidomide as degraders of KRAS G12C with a molecular weight of < 900. Among them, compound KP-14 (m.w. = 852.16; tPSA = 174.53) showed the highest KRAS G12C-degrading capability in NCI-H358 cancer cells (DC50≈1.25 μM). KP-14 bound to KRAS G12C through the acrylamide warhead and recruited the E3 ligase CRBN, causing rapid and sustained KRAS G12C degradation which led to suppression of MAPK signaling pathway in NCI-H358 cells. In addition, KP-14 selectively induced the degradation of KRAS G12C but not other KRAS isoforms such as G13D via PROTAC mechanism. Furthermore, KP-14 exhibited potent antiproliferative activity against NCI-H358 cancer cells and was able to suppress the formation of NCI-H358 tumor colonies. Collectively, this work suggests that KP-14 may serve as a tool compound for exploring the degradation of KRAS G12C by PROTAC strategy and deserve further investigation as a potential anticancer agent.


Tetracycline photolysis in natural waters: loss of antibacterial activity.
Previous work has shown that tetracycline undergoes direct photolysis in the presence of sunlight, with the decomposition rate highly dependent on conditions such as water hardness and pH. The purpose of this study was to examine the potential long-term significance of photoproducts formed when tetracycline undergoes photodegradation under a range of environmentally relevant conditions. Tetracycline was photolyzed in nine different natural and artificial water samples using simulated sunlight. The pH values of the samples ranged from 5 to 9. Total hardness values (combined Ca(2+) and Mg(2+) concentrations) varied from 30 to 450 ppm. Assays based on growth inhibition of two bacterial strains, Escherichia coli DH5α and Vibrio fischeri, were used to determine the antibacterial activity of tetracycline's photoproducts in these water samples. In all tested conditions, it was determined that the photoproducts retain no significant antibacterial activity; all observed growth inhibition was attributable to residual tetracycline. This suggests that tetracycline photoproducts formed under a wide range of pH and water hardness conditions will not contribute to the selection of antibiotic-resistant bacteria in environmental systems.


Uveal vs. cutaneous melanoma. Origins and causes of the differences.
Melanoma is a malignant tumour derived from melanocytes (dendritic cells originated from the neural crest and capable to produce melanin synthesis) that could be established on the skin or less frequently on the uvea. The cellular origin from both kind of melanoma seems to be the same but the melanocytes migrates to the epithelia for cutaneous melanoma, while for uveal melanoma, they migrate to mesodermic tissues. Despite the common origin, both melanomas show extreme differences in their metastatic potential, clinical response to treatments, immune response and genetic alterations. We will describe some of those differences in this review.


Glow discharge plasma stabilization of azo dye on PMMA polymer.
The effects of argon gas glow discharge plasma on the surface of DR1 dye-loaded PMMA polymer films are examined in this work. Plasma immobilizes the dye on the surface of polymer without using stabilizers. Argon plasma activates the surface through breaking some bonds and generation of radical sites. It affects the acrylate groups of PMMA leading to covalent bonds between dye and surface of polymer. In addition, plasma treatment and contact with ambient air may result in the creation of new polar components, such as carbonyl and carboxyl compounds and links that enhance the dye attachment to the polymer matrix. Besides, the dye adsorption on the polymer film is impacted by changes in surface topography. Furthermore, plasma modifies the dye conformation, which affects the adherence of the dye to the polymer surface through bringing the dye to the higher energy state. The chemical and topographical modification of dye-loaded PMMA films by plasma are investigated by spectroscopic and AFM methods. Furthermore, aging process was used to confirm dye retention on the polymer film after plasma modification as opposed to dye-loaded polymer film that was left untreated as a reference sample. Finally, investigated method suggests a novel and very affordable technique for fabrication of poly(MMA-co-DR1) copolymer in the form of a homogeneous surface layer.


Factors Predicting Patient Dissatisfaction 2 Years After Discectomy for Lumbar Disc Herniation in a Chinese Older Cohort: A Prospective Study of 843 Cases at a Single Institution.
We aim to identify factors predicting patient dissatisfaction 2 years after discectomy for lumbar disc herniation (LDH) in a Chinese older cohort. Preoperative and 2-year follow-up data for 843 patients were analyzed. After 2 years of discectomy, the patients rated their satisfaction by Patient Satisfaction Index (PSI), with response of 1 or 2 defining satisfaction and a PSI response of 3 or 4 defining dissatisfaction. Associations between perioperative variables and satisfaction with the results of surgery were examined in univariate and multivariate analysis. Six hundred fifty-seven patients had a PSI of 1 or 2 and were enrolled as satisfied group, 186 patients had a PSI of 3 or 4 and were enrolled as dissatisfied group. At baseline, no significant differences were found between the 2 groups in age, occupation, Oswestry Disability Index (ODI), Visual Analog Scale (VAS)-leg, and VAS-back. Compared to satisfied group, dissatisfied group had a significantly higher BMI and a higher incidence of depression. Two years after discectomy, no significant differences were found between the 2 groups in decrease of ODI, decrease of VAS-back, decrease of VAS-leg, surgery complications. Compared to satisfied group, dissatisfied group experienced higher incidence of symptom recurrence and depression. Logistic regression analysis showed that obesity, pre- and postoperative depression, symptom recurrence were independently associated with patient dissatisfaction 2 years after discectomy.I n conclusion, more than 70% patients expressed satisfaction with discectomy for LDH. Two factors could predict patient dissatisfaction and be assessed before surgery: obesity and preoperative depression. Symptom recurrence and postoperative depression are also associated with diminished patient satisfaction.


Exercise testing.
In the athletic horse, an exercise test may be required to measure the adaptation of the animal to a specific training program; to modify the training program in response to the progress achieved; to investigate the reasons for failure to perform at the expected level; and to form part of an overall clinical examination of a horse with a specific disability. This article includes information on the scope and form of an exercise test, the parameters measured during the test and their interpretation, treadmill and track tests, and the clinical applications of exercise tests.


Diagnostic, Prognostic, and Therapeutic Value of miR-148b in Human Cancers.
MicroRNAs (miRs) is a class of conserved, small, noncoding RNA molecules that modulate gene expression post-transcriptionally. miR-148b is a member of miR- 148/152 family generally known to be a tumor suppressor via its effect on different signaling pathways and regulatory genes. Aberrant expression of miR-148b has recently been shown to be responsible for tumorigenesis of several different cancer types. This review discusses the current evidence regarding the involvement of miR-148b expression in human cancers and its potential clinical importance for tumor diagnosis, prognosis, and therapeutics.


Structural and mechanical characterisation of the peri-prosthetic tissue surrounding loosened hip prostheses. An explorative study.
Very little is known about the structure and properties of peri-prosthetic fibrous tissue that is found around loose orthopaedic implants. We describe a method for characterizing the structural organisation (histology, confocal microscopy) as well as the nano- and micro-scale mechanical behaviour (atomic force microscopy, nanoindentation) of peri-prosthetic fibrous tissue. The tissue was collected from 11 patients undergoing revision surgery due to aseptic loosening. Sirius Red and Movat histological staining procedures indicated that the tissue mainly consists of collagen fibres and ground substance. However, large inter- and intra-patient variations in the relative proportions of these tissue components were found, as well as in collagen fibre orientation and possibly also maturation. The nano-scale Young׳s moduli ranged from 0-950kPa, but showed large inter-patient variability. When the results per sample were presented in a probability density function, we could roughly discriminate one peak in the 0-100kPa range and/or one peak in the 100-500Pa range. These nano-scale moduli seem to respectively present the mechanical properties of glycosaminoglycan (GAG) and collagen molecules. The majority of the micro-scale Young׳s moduli ranged between 0.5 and 2.0kPa for all samples. This explorative study provides new insights in (the variations of) structural organisation and mechanical properties of peri-prosthetic tissue.


The reactivity of the sulphydryl groups of chorismate mutase/prephenate dehydratase--a bifunctional enzyme of phenylalanine biosynthesis in Escherichia coli K12.
The reaction of N-ethylmaleimide with chorismate mutase/prephenate dehydratase (chorismate pyruvatemutase/prephenate hydrolyase (decarboxylating) EC 220.127.116.11/EC 184.108.40.206) from Escherichia coli K12, which leads to the preferential inactivation of the prephenate dehydratase activity (Gething, M-J.H. and Davidson, B.E. (1977) Eur. J. Biochem. 78, 111-117), was found to involve only the sulphydryl groups of the enzyme. Determination of the reactivities of the four different cysteine residues indicated that the reaction was not specific for a single residue, although two residues (Cys-216 and Cys-374) were more reactive than the others. The amount of inhibition of the prephenate dehydratase activity approximated in extent to the sum of the stoichiometries of the individual reactions of N-ethylmaleimide with these two cysteine residues. In the presence of either phenylpyruvate, the product of the prephenate dehydratase activity, or cis-aconitate, a competitive inhibitor with respect to prephenate, the prephenate dehydratase activity was substantially protected from inactivation. This protection was concomitant with a significant decline in the reactivities of both Cys-216 and Cys-374. These results are interpreted as indicating that both of these cysteine residues are at, or near to, the prephenate dehydratase active site and are possibly essential for the prephenate dehydratase activity of the enzyme.


Acute graft-versus-host disease of the intestine. A surgical perspective.
The general surgeon may be involved in assessment and treatment of intestinal complications in patients who have undergone bone marrow transplantation. It is important to recognize the major causes of intestinal morbidity in these patients and to be aware of the cause and natural progression of the entity of acute graft-versus-host disease. Of 89 patients who underwent allogeneic bone marrow transplantation over a 6 year period, acute intestinal graft versus host disease developed in 29 (33 percent). Although surgical consultation for abdominal pain and peritonism was requested for 15 of these patients, intestinal perforation did not occur, and only two patients underwent laparotomy, both for obstruction (and hemorrhage in one case). Patients who require operation tend to be in the end stages of the disease, and the chance for salvage appears to be remote.


Effect of fresh egg white addition on the quality characteristics and protein aggregation of oat noodles.
The influence of fresh egg white (EW) addition on the quality characteristics and protein aggregation in oat noodles containing wheat flour and gluten was studied. EW addition decreased cooking loss and increased cooking time of 70% oat noodles. The hardness, chewiness, tensile force and tensile distance improved significantly. A smooth surface and continuous protein network were observed by scanning electron microscopy (SEM) after adding EW. After cooking, the peak area in SE-HPLC profile of 70% oat noodles with EW decreased obviously. The extractabilities of protein in sodium dodecyl sulfate containing medium (SDSEP) of cooked wheat and oat noodles under non-reducing condition were lower than those of samples under reducing condition. The protein bands changes in SDS-PAGE profiles showed that EW could induce disulfide cross-linking of proteins in noodles. EW addition promoted proteins interaction and improved the cooking and texture properties of oat noodles.


Echinococcus granulosus: specificity of amino acid transport systems in protoscoleces.
Protoscoleces of Echinococcus granulosus absorb the L-amino acids proline, methionine, leucine, alanine, serine, phenylalanine, lysine and glutamic acid by a combination of mediated transport and diffusion. All eight amino acids were accumulated against a concentration gradient. Comparison of Kt and Vmax values suggests that a low affinity for a particular compound is compensated for by a relatively larger number of transport sites for that compound. Four systems serve for the transport of the eight substrates studied: 2 for neutral (EgN1, EgN2) and 1 each for acidic (EgA) and basic (EgB) amino acids. All eight amino acids are incorporated into protein to varying degrees and substantial portions of absorbed L-alanine and L-methionine are metabolized into other compounds.


Complaints of reduced cognitive functioning during perimenopause: a cross-sectional analysis of the Japan Nurses' Health Study.
Many women experience various symptoms during the period of menopausal transition, including complaints of reduced cognitive functioning. However, these complaints are not necessarily recognized as core menopausal symptoms. In this study, we sought to characterize subjective complaints of reduced cognitive functioning by analyzing cross-sectional data from the Japan Nurses' Health Study (JNHS). The JNHS 4-year follow-up questionnaire containing a 21-item climacteric symptom checklist, which included a question about "poor memory or forgetfulness", was mailed between 2005 and 2011 to all JNHS participants, regardless of their age at the time of the survey. We estimated the prevalence of slight and severe complaints in 5-year age-groups. We used principal component analysis to explore the underlying factors among the 21 symptoms during the menopausal transition period in women aged 45-54 years at the time of the survey. We also examined risk factors for complaints using multivariable modified Poisson regression analysis. In total, 12,507 women responded to the 4-year survey. The mean age at the time of the 4-year survey was 46.5 years (range 27-82). "Poor memory or forgetfulness" showed a peak prevalence of 81.7% (severe 27.9%; slight 53.8%) at 50-54 years, and gradually decreased after 55 years. Principal component analysis indicated that "poor memory or forgetfulness" belonged to somatic symptoms and was close to psychological symptoms in women aged 45-54 years. In women aged 45-54 years, the complaint was also significantly associated with hot flashes and sweats. Multivariable modified Poisson regression analysis showed that menopausal status (uncertain and postmenopausal), less sleep (sleep of < 5 h and sleep of 5- < 6 h), night-shift work, and severe vasomotor symptoms (VMS) were significantly associated with the prevalence of severe complaints of reduced cognitive functioning in women aged 45-54 years. We found that prevalence of "poor memory or forgetfulness" was highest during the menopausal transition period and among perimenopausal women. This subjective complaint was associated with somatic, psychological complaints and VMS. It may be useful for women with cognitive problems in the transition period to consider management of comorbid menopausal symptoms.


Deaf individuals use compensatory strategies to estimate visual time events.
Temporal perception is so profoundly linked to hearing that congenitally and early deaf individuals appear to experience visual temporal impairments. However, most studies investigated visual temporal perception in deaf individuals using static stimuli, while ecological objects with which we interact in everyday life often move across space and time. Given that deafness does not impact spatial metric representations, we hypothesize that, while the temporal perception of static stimuli is altered after early hearing loss, it can be enhanced by providing additional, ecologically relevant information. To evaluate our hypothesis, deaf and hearing participants were tested using an oddball-like visual temporal task. In such a task, participants had to temporally discriminate a Target embedded in a series of static stimuli, whose spatiotemporal structure was dynamically manipulated during the presentation. Our results highlighted that deaf participants could not successfully discriminate the Target's duration when only temporal information was manipulated, while their temporal sensitivity significantly improved when coherent spatiotemporal information was displayed. Our findings suggest that deaf individuals might develop compensatory strategies based on other visual, non-temporal features to estimate external time events.


[Influence of non-alcoholic fatty liver disease on cardiovascular disease].
Non-alcoholic fatty liver disease encompasses a spectrum ranging from simple steatosis to steatohepatitis without excess alcohol intake and is considered to be the hepatic manifestation of metabolic syndrome. Recent studies indicate that non-alcoholic fatty liver disease is closely related to cardiovascular disease, especially to thickening of the intima-media layer of the carotid artery, as the morphostructural manifestation of the presence of subclinical atheromatosis. Therefore, the correct management of non-alcoholic fatty liver disease would allow the natural history of both the liver disease and the atherosclerosis to be modified.


Foreign accent syndrome: an organic disorder?
This paper reports the case of a 32-year-old Dutch speaking woman who presented with foreign accent syndrome (FAS). There are good reasons to believe that the speech disturbance in this patient was of psychogenic origin. This case suggests that attested brain damage is not a prerequisite for a speech disorder to qualify as FAS and that FAS is not necessarily linked to another neurogenic speech disorder. It is argued that FAS is not a syndrome in its own right but only exists in the ears of the beholder. LEARNING OUTCOME: Readers will be able to describe the features that are believed to be typical of the foreign accent syndrome. Readers will be able to summarize the arguments that can be adduced to consider the foreign accent syndrome as an epiphenomenona.


Factors influencing naming performance in aphasia: a review of the literature.
The naming performance of aphasic patients may vary substantially, depending upon linguistic factors associated with the target words, characteristics of the referent (real or pictured), the manner in which the response is elicited, and the particular situation in which the naming response is produced. Furthermore, the specific influence of certain of these factors on naming performance appears to vary with type of aphasia. This article reviews and evaluates the literature pertaining to factors that influence adult aphasics' naming performances. Implications for future research are discussed.


Recent progress in therapeutic natural product biosynthesis using Escherichia coli.
E. coli has become a common host for the heterologous biosynthesis of natural products that demonstrate therapeutic value but suffer from access challenges posed by native production hosts. This review will highlight recent examples of heterologous products produced using E. coli. An emphasis will be placed on tools at the cellular and process levels to enable, improve, and alter production efforts. At the cellular scale, summaries of the process to enable heterologous biosynthesis will be supplemented with strategies (synthetic biology and metabolic engineering) to improve production levels. Process engineering strategies such as precursor-directed biosynthesis will also be highlighted in analog formation cases. In summary, the article will provide a recent overview of heterologous production efforts using E. coli and the relationship of the products produced to therapeutic applications.


Analytical comparability demonstrated for an IgG4 molecule, inclacumab, following transfer of manufacturing responsibility from Roche to Global Blood Therapeutics.
Inclacumab is a recombinant, fully human, immunoglobulin IgG4 monoclonal antibody that selectively binds to P-selectin. Initially discovered and developed by Roche through phase 2 clinical studies in peripheral arterial disease and coronary artery disease, inclacumab has been in-licensed by Global Blood Therapeutics (GBT) as a potential treatment to reduce the frequency of vaso-occlusive crises in individuals with sickle cell disease. GBT sought to demonstrate the analytical comparability between material produced by Roche and material produced by GBT to ensure that no meaningful differences in identity, safety, purity, potency, or bioavailability exist between the GBT and Roche lots. Inclacumab samples produced by GBT were found to be comparable to the Roche v0.2 inclacumab samples based on (1) comparable primary and higher-order structures; (2) comparable purity profiles; (3) comparable potency, in vitro functional activities, and in vivo plasma exposures and pharmacokinetic profiles; and (4) comparable degradation patterns and kinetics under forced degradation conditions. Based on the design of this comparability study and the results obtained, the US Food and Drug Administration approved the changes to the manufacturing process and gave clearance for GBT to proceed with phase 3 clinical trials.


Urethral stricture assessment: a prospective study evaluating urethral ultrasonography and conventional radiological studies.
To evaluate the accuracy of urethral ultrasonography (sono-urethrography, SUG) in determining the length of anterior urethral strictures, and for predicting the degree of spongiofibrosis. In all, 52 patients with anterior urethral strictures detected on retrograde urethrography (RUG) were also examined using SUG, to assess the stricture location, length and degree of spongiofibrosis. The findings of both procedures were then compared with the operative findings. The mean (sd) stricture length on RUG, SUG and at surgery was 2 (0.8), 3.8 (1.4) and 3.5 (1.6) cm, respectively. The mean length on SUG was closer to that at surgery. Spongiofibrosis was detected by SUG with an overall accuracy of 42%, 56% and 83% for mild, moderate and severe degrees of fibrosis, respectively. There were no significant complications during the procedure. SUG is more accurate for evaluating the length of anterior urethral strictures than RUG, and gives additional information about spongiofibrosis.


Blood pressure, plasma and pituitary prolactin responses to bromocriptine in New Zealand genetically hypertensive and normotensive rats.
1. The effects on blood pressure (BP), plasma and pituitary prolactin (PRL) of a 13 day intraperitoneal infusion of bromocriptine (BRC) delivered by osmotic minipump were investigated in genetically hypertensive rats (GHR) and their normotensive (NT) controls. 2. In the GHR, the mean BP in the BRC-treated group over the 13 day period of study was significantly lower than in the vehicle-treated group. In the NT rats, the mean BP in the BRC-treated group over the 13 day period was also significantly lower than in the vehicle-treated group. 3. Mean plasma PRL concentration in the GHR and NT rats were comparable. In the GHR, the mean plasma PRL concentration taken on day 13 was significantly lower in the BRC-treated group than in the vehicle-treated group. In the NT rats, the mean plasma PRL concentration taken on day 13 in the BRC-treated group was, however, not significantly different from that in the vehicle-treated group. 4. The mean pituitary PRL content was not significantly different in the GH and NT rats. There was a greater suppression of pituitary PRL content in the BRC-treated GHR than in the BRC-treated NT rats compared with their respective vehicle-treated groups. 5. The results raise the possibility that PRL may have an indirect role in the pathogenesis of the hypertension of the GHR.


The arbuscular mycorrhizal fungus Funneliformis mosseae induces changes and increases the concentration of volatile organic compounds in Vitis vinifera cv. Sangiovese leaf tissue.
Arbuscular mycorrhizal fungi (AMF) are beneficial obligate symbionts of plant roots. Volatile organic compounds (VOCs) participate in plant communication and defence. The aim of this study was to analyse the effects of the arbuscular mycorrhizal fungus Funneliformis mosseae IMA1 on VOCs in Vitis vinifera cv. Sangiovese leaf tissue. Grapevine plants inoculated with F. mosseae IMA1 were incubated for 23 weeks. VOCs were extracted from leaves and identified using headspace solid-phase microextraction (HS-SPME) coupled to GC-MS. VOCs in leaf tissue were strongly enhanced (85%) by F. mosseae IMA1. The mycorrhizal fungus IMA1 modified the levels of specific VOCs synthesised in different anabolic pathways. An increase in volatiles that have been related to plant defences under pathogen/herbivore attack or linked to water stress, such as (E)-2-hexenal, 3-hexenal, geraniol, benzaldehyde and methyl salicylate, was observed in mycorrhizal plants. In contrast, some C13-norisoprenoids decreased strongly in mycorrhizal plants. The study of the effects of AMF on VOCs in grapevine plants may provide useful information to establish sustainable viticultural practices.


Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A.
Renal allograft survival is related directly to cell senescence. In the transplantation scenario many cellular events - participating as immunological and non-immunological factors - could contribute to accelerate this biological process, responsible for the ultimate fate of the graft. Mechanisms concerned in tolerance versus rejection are paramount in this outcome. For this reason, immunosuppressive treatment constitutes an extremely important decision to prevent organ dysfunction and, finally, graft loss. This study was conducted to document the proportion of CD4(+) /interleukin (IL)-17A(+) -, CD16(+) /indoleamine 2, 3-dioxygenase (IDO(+) )-, forkhead box protein P3 (FoxP3(+))-expressing cells, senescent cells (p16(INK) (4α)) and the percentage of interstitial fibrosis (IF) in graft biopsies of kidney transplant recipients participating in the BENEFIT (Bristol-Myers Squibb IM103008) study. CD4(+) /IL-17A(+) , CD16(+) /IDO(+), FoxP3(+) and p16(INK) (4α+) cells were evaluated by immunohistochemistry, and the percentage of IF by morphometry on graft biopsies obtained at time 0 (pre-implantation) and at 12 months post-transplant. Senescent cells and CD4(+) /IL-17A(+) cells were increased among graft biopsies in subjects receiving cyclosporin A (CsA) compared to those under belatacept treatment. Meanwhile, CD16(+) /IDO(+) and FoxP3(+) -expressing cells were lower in biopsies from CsA treatment compared to patients treated with Belatacept. Histological morphometric analyses disclosed more IF in 12-month CsA-treated patients in comparison to pre-implantation biopsy findings. Summing up, renal biopsies from patients receiving belatacept showed greater amounts of FoxP3(+) cells and lower amounts of CD4(+) /IL-17A(+) and senescent cells compared to patients under CsA treatment. Along with these findings, an increase in IF in annual CsA-treated-patients biopsies compared to pre-implantation and belatacept-treated patients were observed.


[The quality of dried fruit, especially figs, based on results of food surveillance and our own research].
The legal controls of dried fruits put forward by the state control laboratories show that contamination by insects, especially mites, is often a reason for complaints. This is evidently due to the rural conditions of production. Because hygiene is of great importance, a much stronger control should be achieved in the producing countries as well as in the importing countries.


New approaches to the antibiotic treatment of brucellosis.
The global burden of human brucellosis remains enormous, yet its optimal treatment remains based on traditional combinations of doxycycline with either rifampicin or streptomycin. Of the currently existing alternative regimens, only the combination of doxycycline with gentamicin can be considered therapeutically adequate and cost effective, the latter factor being a major obstacle in the utilisation of quinolones for brucellosis. Newer antibiotics, most notably tigecycline, may help in achieving monotherapy or shorter treatment duration. Alternatively, modification of the acidic intracellular environment where Brucellae reside may allow for enhanced effectiveness of existing antibiotics.


Heart allograft acceptance induced by anti-CD3 antibody in high-responder rats: effect on foxp3 and cytokine expression and graft infiltration.
The ability of anti-T cell monoclonal antibody G4.18 and polyclonal anti-lymphocyte serum (ALS) to induce long-term graft survival was examined in a high-responder rat heart transplant model. Heterotopic heart allografts were performed from PVG rat strain donors to high-responder Lewis recipients. Immunosuppressive properties of G4.18 and ALS were investigated by immunohistochemistry and PCR analysis. Untreated graft rejection was 8.5 days while treatment with 1 ml ALS prolonged survival to 11.5 days (p=0.01). Treatment with 7 mg/kg G4.18 on days 1 and 3 prolonged survival to >100 days (p=0.002 vs. control and p=0.002 vs. ALS) but did not induce tolerance. Acceptance was associated with marked inhibition of cellular infiltration and inflammatory cytokine expression and only a brief, slight increase in Foxp3:T cell ratio in the graft and no increase in the spleen. In conclusion, G4.18 treatment led to long-term heart transplant survival associated with marked inhibition of early inflammation. Failure to develop tolerance was associated with a lack of early accumulation of Foxp3 cells in the graft or spleen.


The thrombolytic effect of miniplasmin in a canine model of femoral artery thrombosis.
Miniplasmin was a des-kringle variant of plasminogen with potential pharmacological application. We investigated the thrombolytic effect of miniplasmin in a canine model of femoral artery thrombosis. In anesthetized dogs, a stable occlusive thrombus was formed by mechanical and electrolytic injury of the vessel wall, that the animals were later injected with miniplasmin (0.75 mg/kg, 1.5 mg/kg and 3.0 mg/kg, i.a.) and rt-PA (0.5 mg/kg, i.a.) intra-arterially. Hemodynamic parameters and hemorrhage status were monitored for 2 h. Thrombin time, activated partial thromboplastin time, prothrombin time and fibrinogen concentration were tested at 2 h after administration. Fibrin degradation product and D-dimer concentration were tested by ELISA. The incidence of reperfusion in the miniplasmin (3.0 and 1.5 mg/kg) groups was 100%, and time to reperfusion was (3.3+/-1.0) and (7.0+/-2.3) min, which was shorter than rt-PA. After reperfusion, none of the vessels in the miniplasmin (1.5 and 3.0 mg/kg) groups reoccluded, whereas 20% of vessels reoccluded in the rt-PA group. Rudimental thrombus mass in the miniplasmin (1.5 and 3.0 mg/kg) groups were smaller than rt-PA. The operative wounds in all miniplasmin groups had no hemorrhage within 2 h. There were no significant differences in thrombin time, activated partial thromboplastin time and prothrombin time. Fibrinogen concentration in the miniplasmin (3.0 mg/kg) group reduced significantly as compared with baseline and thrombosis values, whereas these values in the miniplasmin (1.5 and 0.75 mg/kg) groups were unchanged. Fibrin degradation product and D-dimer concentration increased significantly after thrombolysis. The results suggest that miniplasmin may be useful for the treatment of thrombosis and without complication of hemorrhage. This is in contrast to rt-PA, which intrinsically has a higher risk of occurring the hemorrhage risk.


Edema in the upper airway in patients with obstructive sleep apnea syndrome.
The purpose of this study was to investigate the histologic alterations in the upper airway in patients with obstructive sleep apnea syndrome. Surgical specimens were obtained during non-laser-assisted uvulopalatopharyngoplasty from 5 adult patients (4 male and 1 female) with polysomnographically confirmed obstructive sleep apnea syndrome. In all of the specimens, interstitial edema was present with mild inflammatory reaction. Fat was not at all prominent. It is confirmed histologically that there is edema present in the upper airway in patients with obstructive sleep apnea syndrome. It is uncertain whether this edema is one of the causative mechanisms of the obstruction or a consequence of the syndrome.


Synthesis of the four isomers of 5-hydroxy-PGI1.
We wish to report here the syntheses of (5S, 6R)-5-hydroxy-, (5R, 6R)-5-hydroxy-, (5R, 6S)-5-hydroxy-, and (5S, 6S)-5-hydroxy-PGI1 and their methyl ester derivatives. Treatment of (5R, 6S)-epoxy- and (5S, 6R)-epoxy-PGF1alpha methyl esters with acid washed silica gel afforded (5R, 6R)-5-hydroxy- and (5S, 6S)-5-hydroxy-PGI1 methyl esters; correspondingly, silica promoted cyclization of (5S, 6S)-epoxy- and (5R, 6R)-epoxy-PGF1alpha methyl esters yielded (5S, 6R)-5-hydroxy- and (5R, 6S)-5-hydroxy-PGI1 methyl esters. Alternatively, the 5-hydroxyl group was introduced into the PGI1 skeleton via reaction of the 5-mercuric halides with sodium borohydride in the presence of oxygen. Stereochemical assignments were based on their mode of synthesis and 1H nmr shift differences.


Helmet ventilation and carbon dioxide rebreathing: effects of adding a leak at the helmet ports.
We examined whether additional helmet flow obtained by a single-circuit and a modified plateau valve applied at the helmet expiratory port (open-circuit ventilators) improves CO(2) wash-out by increasing helmet airflow. Randomized physiological study in a university research laboratory. Ten healthy volunteers. Helmet continuous positive airway pressure and pressure support ventilation delivered by an ICU ventilator (closed-circuit ventilator) and two open-circuit ventilators equipped with a plateau valve placed either at the inspiratory or at the helmet expiratory port. We measured helmet air leaks, breathing pattern, helmet minute ventilation (Eh)), minute ventilation washing the helmet (Ewh)), CO(2) wash-out, and ventilator inspiratory assistance. Air leaks were small and similar in all conditions. Breathing pattern was similar among the different ventilators. Inspiratory and end-tidal CO(2) were lower, while (Eh) and (Ewh) were higher only using open-circuit ventilators with the plateau valve placed at the helmet expiratory port. This occurred notwithstanding these ventilators delivered a lower inspiratory assistance. Additional helmet flow provided by open-circuit ventilators can lower helmet CO(2) rebreathing. However, inspiratory pressure assistance significantly decreases using open-circuit ventilators, still casting doubts on the choice of the optimal helmet ventilation setup.


Impact of high self-perceived burden to others with preferences for end-of-life care and its determinants for terminally ill cancer patients: a prospective cohort study.
Self-perceived burden to others (SPB) is a major concern of terminally ill cancer patients and is frequently factored into end-of-life (EOL) care decision-making. However, changes in and determinants of SPB and its longitudinal impact on preferences for EOL care over the dying process have not been investigated. Our study was aimed at filling this gap in knowledge. A convenience sample of 325 cancer patients was followed until death. High SPB was identified as scoring >20 on the Self-perceived Burden Scale. Preferences for EOL care included EOL-care goals, life-sustaining treatments, and hospice care. Factors potentially precipitating/minimizing patients' high SPB included demographics, disease characteristics and burden, and social support and were examined by multivariate logistic regression modeling with the generalized estimating equation. Prevalence of high SPB increased as death approached (51.78%, 58.26%, 62.66%, and 65.38% for 181-365, 91-180, 31-90, and 1-30 days before death, respectively). High SPB was precipitated by women, younger age, having inadequate financial resources, without religious affiliation, and suffering from severe symptom distress and heavy functional dependence but was independent of time proximity to patient death, disease characteristics, and social support. Furthermore, high SPB was not associated with EOL-care preferences, whether aggressive life-sustaining treatments or hospice care. High SPB was prevalent among terminally ill cancer patients but independent of preferences for EOL care. Cancer patients' SPB may be lessened by adequate symptom relief to facilitate functional independence. These strategies to ease SPB may improve the quality of death and dying. Copyright © 2016 John Wiley & Sons, Ltd.


Temporal correlation between two channels EEG of bipolar lead in the head midline is associated with sleep-wake stages.
Whether the temporal correlation between inter-leads Electroencephalogram (EEG) that located on the boundary between left and right brain hemispheres is associated with sleep stages or not is still unknown. The purpose of this paper is to evaluate the role of correlation coefficients between EEG leads Fpz-Cz and Pz-Oz for automatic classification of sleep stages. A total number of 39 EEG recordings (about 20 h each) were selected from the expanded sleep database in European data format for temporal correlation analysis. Original waveform of EEG was decomposed into sub-bands δ (1-4 Hz), θ (4-8 Hz), α (8-13 Hz) and β (13-30 Hz). The correlation coefficient between original EEG leads Fpz-Cz and Pz-Oz within frequency band 0.5-30 Hz was defined as r(EEG) and was calculated every 30 s, while that between the two leads EEG in sub-bands δ, θ, α and β were defined as r(δ), r(θ), r(α) and r(β), respectively. Classification of wakefulness and sleep was processed by fixed threshold that derived from the probability density function of correlation coefficients. There was no correlation between EEG leads Fpz-Cz and Pz-Oz during wakefulness (|r| < 0.1 for r(θ), r(α) and r(β), while 0.3 > r > 0.1 for r(EEG) and r(δ)), while low correlation existed during sleep (r ≈ -0.4 for r(EEG), r(δ), r(θ), r(α) and r(β)). There were significant differences (analysis of variance, P < 0.001) for r(EEG), r(δ), r(θ), r(α) and r(β) during sleep when in comparison with that during wakefulness, respectively. The accuracy for distinguishing states between wakefulness and sleep was 94.2, 93.4, 89.4, 85.2 and 91.4% in terms of r(EEG), r(δ), r(θ), r(α) and r(β), respectively. However, no correlation index between EEG leads Fpz-Cz and Pz-Oz could distinguish all five types of wakefulness, rapid eye movement (REM) sleep, N1 sleep, N2 sleep and N3 sleep. In conclusion, the temporal correlation between EEG bipolar leads Fpz-Cz and Pz-Oz are highly associated with sleep-wake stages. Moreover, high accuracy of sleep-wake classification could be achieved by the temporal correlation within frequency band 0.5-30 Hz between EEG leads Fpz-Cz and Pz-Oz.


Heavy metals and metalloid in aquatic invertebrates: A review of single/mixed forms, combination with other pollutants, and environmental factors.
Heavy metals (HMs) and metalloid occur naturally and are found throughout the Earth's crust but they are discharged into aquatic environments at high concentrations by human activities, increasing heavy metal pollution. HMs can bioaccumulate in higher organisms through the food web and consequently affect humans. In an aquatic environment, various HMs mixtures can be present. Furthermore, HMs adsorb on other environmental pollutants, such as microplastics and persistent organic pollutants, causing a synergistic or antagonistic effect on aquatic organisms. Therefore, to understand the biological and physiological effects of HMs on aquatic organisms, it is important to evaluate the effects of exposure to combinations of complex HM mixtures and/or pollutants and other environmental factors. Aquatic invertebrates occupy an important niche in the aquatic food chain as the main energy link between higher and lower organisms. The distribution of heavy metals and the resulting toxic effects in aquatic invertebrates have been extensively studied, but few reports have dealt with the relationship between HMs, pollutants, and environmental factors in biological systems with regard to biological availability and toxicity. This review describes the overall properties of individual HM and their effects on aquatic invertebrates and comprehensively reviews physiological and biochemical endpoints in aquatic invertebrates depending on interactions among HMs, other pollutants, and environmental factors.


The impact of global budgeting on health service utilization, health care expenditures, and quality of care among patients with pneumonia in Taiwan.
This study evaluated the effect of global budgeting on health service utilization, health care expenditures, and the quality of care among patients with pneumonia in Taiwan. The National Health Insurance Research Database (NHIRD) was used for analysis. Data on patients diagnosed with pneumonia during 2000-2001 (the prebudget group) were used as the baseline data, and data on patients diagnosed with pneumonia during 2004-2005 (the postbudget group) were used as the postintervention data. The length of stay (LOS), diagnostic costs, drug costs, therapy costs, total costs, risk of readmission within 14 days, and risk of revisiting the Emergency Department (ED) within 3 days of discharge before and after implementing the global budget system were analyzed and compared. Data on 32,535 patients with pneumonia were analyzed. The mean LOS increased from 6.36 ± 0.07 to 10.78 ± 0.09 days after implementing the global budget system. The mean total costs in the prebudget and postbudget groups were 22,697.82 ± 542.40 and 62,016.7 ± 793.19 New Taiwan dollars (NT$), respectively. The mean rate of revisiting the ED within 3 days decreased from 5.5 ± 0.2 % to 4.6 ± 0.1 % in the prebudget and postbudget groups, respectively. The mean rates of readmission within 14 days before were 6.1 ± 0.2 % and 8.2 ± 0.2 % in the prebudget and postbudget groups, respectively. Global budgeting is associated with a significantly longer LOS, higher health care costs, and poorer quality of care among patients with pneumonia.


Role of sFlt-1/PlGF ratio and feto-maternal Doppler for the prediction of adverse perinatal outcome in late-onset pre-eclampsia.
The sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio and uterine artery Doppler have shown to be helpful in the diagnosis of pre-eclampsia (PE). The predictive value of the cerebroplacental ratio (CPR) regarding adverse perinatal outcome (APO) in low-risk pregnancies is intensively discussed. We evaluated the extent to which sFlt-1/PlGF ratio and feto-maternal Doppler may be useful in predicting APO in singleton pregnancies complicated by late-onset PE and/or HELLP syndrome. This is a retrospective study from 2010 to 2018 consisting of singleton pregnancies with confirmed diagnosis of late-onset (lo ≥ 34 weeks) PE/HELLP syndrome in which sFlt-1/PlGF ratio and feto-maternal Doppler (mUtA-PI: mean uterine artery pulsatility index and CPR) were determined. The ability of sFlt-1/PlGF ratio, mUtA-PI, CPR and their combination to predict APO or SGA was evaluated using receiver operating characteristic (ROC) curves. 67 patients were included in the final analysis. Of these, sFlt-1/PlGF was > 110 (defining angiogenic lo PE) in 40.3% (27/67), mUtA-PI was above the 95th centile in 34.3% (23/67) patients and CPR was lower than the 5th centile in 10.4% (7/67). Abnormal sFlt-1/PlGF and mUtA-PI as well as CPR were associated with a lower birth weight (BW). Late-preterm birth (< 37 weeks) as well as postnatal diagnosis of small for gestational age (SGA: BW < 3rd centile) was significantly more often in angiogenic lo PE cases. Neither sFlt-1/PIGF nor CPR or mUtA-PI were APO predictors. Only for sFlt-1/PlGF, ROC analysis revealed a significant predictive value for postnatal SGA (AUC = 0.856, p = 0.001, 95% CI 0.75-0.97). There was no statistical added value of combined SGA predictors as compared to sFlt-1/PlGF alone. In patients with lo PE, adding sFlt-1/PlGF ratio to routine antepartum fetal surveillance may be useful to identify cases of postnatal SGA. However, further prospective studies are warranted to define the role of feto-maternal Doppler and sFlt-1/PlGF ratio as outcome predictors.


Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles.
To evaluate the effects of cholesteryl ester transfer protein (CETP) on apoB-containing lipoproteins, we analyzed plasma lipoproteins from three different lines of human CETP transgenic mice, with plasma CETP concentration ranging from low (1.5 microgram/ml) to high levels (8.5 micrograms/ml). With increasing CETP concentration, very low density lipoprotein and low density lipoprotein (LDL) cholesteryl ester (CE) and apoB were progressively increased, and high density lipoprotein CE was decreased. To investigate the mechanism of accumulation of lipoproteins containing apoB (lipoprotein B), the abundance of hepatic LDL receptor mRNA was determined. LDL receptor mRNA was reduced as a result of CETP expression, with maximum repression to about 48% of the level of non-transgenic mice. Among the different lines of CETP transgenic mice there was an inverse relationship between plasma CETP concentration and hepatic LDL receptor mRNA abundance (r = -0.94, p < 0.01). CETP expression also led to increased cholesterol and cholesteryl ester content in liver and to decreased abundance of mRNAs encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase and 7-alpha-hydroxylase. Thus, CETP expression results in increased cholesteryl ester concentration in very low density lipoprotein and LDL, probably reflecting both CE transfer from high density lipoprotein and accumulation of lipoprotein B particles. The accumulation of lipoprotein B particles results from CETP-mediated down-regulation of liver LDL receptors, possibly due to enhanced return of cholesterol to the liver.


Effect of restoration thickness on the sealing ability of TERM.
An in vitro study was done using a fluid filtration device to compare microleakage of Temporary Endodontic Restorative Material (TERM) at various thicknesses. Forty-four extracted mandibular molars had their roots removed at the cementoenamel junction, occlusal table flattened, and a standardized endodontic access made in the crown. The teeth were restored with TERM in thicknesses of 1, 2, 3, and 4 mm, and quantitatively measured for leakage (microliters/min) at intervals of 1 and 24 h and 1, 3, and 5 wk. Thermocycling was accomplished at the 5-wk interval. Positive controls received 4-mm-thick IRM or gutta-percha restorations and were measured at 24 h only. Repeated measures of analysis of variance found no significant difference (p < 0.05) in leakage values in any group over time or between any of the different thicknesses. Positive controls showed significantly more leakage than all other groups. TERM maintained as tight a seal at 1-, 2-, and 3-mm thicknesses as it did at 4 mm and may be suited for clinical situations where less than 4 mm of restorative space exists.


Sticking of hydrocarbon radicals on different amorphous hydrogenated carbon surfaces: a molecular dynamics study.
In this study we investigate how the hydrogen flux administered to amorphous hydrogenated carbon (a-C : H) samples influences the sticking probability of hydrocarbon radicals on these samples. We bombard a-C : H samples that were previously subjected to different hydrogen fluxes with hydrocarbon radicals. The energy of the radicals is 10 eV. The sample temperatures are 700 and 1000 K. The results show that the sticking probability is larger on samples pre-irradiated with a higher hydrogen flux caused by the higher sp(2) fraction in the sample. This suggests that redeposition can contribute to the observed flux dependency of the carbon erosion yield.


Complications of surgery for thoracic outlet syndrome.
Having read through the previous litany of potential disasters and complications, one could ask the obvious question, "Why would anyone want to do this kind of surgery?" The answer is that most people elect not to! Nevertheless, for those who decide to venture into this field, there is the tremendous reward of being able to help patients who would otherwise continue to live with extremely disabling and disheartening symptoms. A sound knowledge of the regional anatomy and tutelage by those knowledgeable in particular areas of surgery that may not have been a part of the individual surgeon's prior training is essential. The author was fortunate to have the help of a very accomplished and generous vascular surgeon, Dr. William Abbott of the Massachusetts General Hospital for many months when I began on what I have considered a fascinating and intellectually rewarding odyssey.


Peripheral blood and bone marrow abnormalities in patients with HIV related disease.
Between February 1983 and April 1986 we studied peripheral blood and bone marrow samples from 20 patients with human immunodeficiency virus (HIV) related disease. 14 patients had AIDS, three had ARC, two had PGL and one had ITP as a sole manifestation of HIV related disease. Peripheral blood abnormalities included marked anisocytosis and poikilocytosis, rouleaux formation, neutropenia, lymphopenia, monocytopenia, a left shift in the granulocyte series and, in the patients with AIDS, vacuolated monocytes. The most frequent bone marrow abnormalities were reticuloendothelial iron block, dyserythropoiesis, megaloblastic change and erythroid hypoplasia. Excess histiocytes were noted in four marrows, one exhibiting haemophagocytosis. None of the bone marrows showed lymphopenia. Eight of the 20 marrows were difficult or impossible to aspirate. None of the trephine biopsies showed increased reticulin. The causes of these abnormalities are probably multiple and include opportunistic infections, drug therapy, immune mechanisms and possibly direct insult by the HIV virus.


Gender specificity of body adiposity and circulating adiponectin, visfatin, insulin, and insulin growth factor-I at term birth: relation to prenatal growth.
Fetal development is thought to be gender specific for adiposity and circulating insulin and IGF-I but not adipokinemia, as judged by serum visfatin and adiponectin at term birth. We studied the potential relationship between these gender specificities and fetal growth. The study was conducted at a university hospital. Subjects included 96 strictly matched neonates born appropriate for gestational age (AGA; 24 girls, 24 boys) or small for gestational age (SGA; 24 girls, 24 boys). Outcomes included serum insulin, IGF-I, visfatin, total and high-molecular-weight (HMW) adiponectin, osteocalcin at term birth, and neonatal body composition by absorptiometry. Cord insulin and IGF-I levels were higher in girls than boys (P < or = 0.01), in both the AGA and SGA subpopulation. In AGA newborns, fat and lean mass were each gender specific (P < 0.0001), whereas visfatin and total and HMW adiponectin were not. Conversely, in SGA newborns, visfatin and HMW adiponectin were gender specific (higher levels in girls), whereas body adiposity was not. In SGA fetuses, the distribution of adiponectin isoforms was in both genders shifted toward HMW (P < 0.005 vs. AGA). Cord osteocalcin did not differ by either gender or birth weight. At term birth, the gender specificity of adiposity and circulating visfatin and HMW adiponectin appeared to depend on prenatal growth, whereas the gender specificity of insulin and IGF-I levels did not. The fetal shift in adiponectin isoforms may contribute to explain why SGA newborns tend to be hypersensitive to insulin.


GATA1-mediated transcriptional regulation of the γ-secretase activating protein increases Aβ formation in Down syndrome.
Because of an extra copy of the Aβ precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Aβ peptides and Alzheimer disease-like brain amyloidosis early in life. Here we show that the γ-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Aβ-lowering therapeutic strategy for this disorder.


Prediction of suicidal ideation in shift workers compared to non-shift workers using machine learning techniques.
Shift work can affect sleep and increase the risk of suicide. This study attempted to predict suicidal ideation according to shift work by using machine learning techniques. We analyzed a total of 43,095 data conducted by using the 10-year Korean National Health and Nutrition Examination Survey (KHANES). Shift workers and daytime workers were categorized and analyzed using random forest (RF) and decision tree (DT) techniques of machine learning techniques. Shift workers were more than twice as likely to have suicidal ideation as daytime workers. The RF model showed an accuracy of 91.6% for shift workers and 98% for daytime workers. In the DT technique, the rate of suicidal ideation was the highest among shift workers (82.7%) when they were depressed and had an EuroQol-5 Dimension (EQ-5D) score of less than 0.71. Shift work type was evaluated questionnaire and based on screening data, it was not possible to reflect recent changes in the work type and we evaluated for only suicidal ideation for suicide risk factors. The variables influencing the suicide risk of shift workers and daytime workers differ. In the case of shift workers, negative factors such as depression and low quality of life are risk factors for suicide. Efforts are needed to reduce risk factors through administrative and policy interventions to manage workers' health by early screening.


Regulators of genetic risk of breast cancer identified by integrative network analysis.
Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.


Mechanical stress-activated immune response genes via Sirtuin 1 expression in human periodontal ligament cells.
Recently, Sirtuin 1 (SIRT1) has been implicated in the molecular control of ageing and immune response. Although the remodelling of periodontal ligament (PDL) in response to mechanical stress (MS) is mediated by several host factors, including cytokines and chemokines, the transmission of mechanical stimuli into specific cellular activity is still not understood fully. This study aimed to investigate the effects of MS, particularly cyclic strain, on immune response genes, as well as SIRT1 and its signal transduction pathways, in human PDL cells. MS up-regulated the expression of SIRT1 and immune response genes encoding cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-1β], chemokines [IL-8, monocyte cheoattractant protein (CCL)-20], defensins [human β-defensin (hBD)-2, hBD-3] and Toll-like receptors (TLR-2 and TLR-4) in a force- and time-dependent manner. The SIRT1 inducers resveratrol and isonicotinamide attenuated MS-induced cytokine and chemokine expression, but enhanced the expression of defensins and TLRs. Blockade of SIRT1 activity by the SIRT1 inhibitors sirtinol and nicotinamide and down-regulation of SIRT1 expression by SIRT1 siRNA reduced the stimulatory effects of MS on defensins and TLRs, but increased its effects on cytokines and chemokines. MS induced activation of protein kinase B (Akt), protein kinase C (PKC), nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Treatment with the anti-oxidants N-acetylcysteine and glutathione inhibited MS-induced reactive oxygen species production and expression of cytokines, chemokines, defensins and TLRs. These results suggest that MS activates human PDL cells to express immune/defence genes encoding cytokines, chemokines, defensins and TLRs via a SIRT1 pathway.


The shifting sands of serials bibliography: titles using the term "peptide".
A commentary on the confusing nomenclature and bibliography of serial publications which use the term "peptide" in their titles is given, with guidance on citation.


Association Between Hip Bone Mineral Density and Mortality Risk After Hip Fracture: A Prospective Cohort Study.
Factors related to mortality after osteoporotic hip fracture (HF) have been investigated intensively, except for proximal femoral bone mineral density (BMD), which is also the primary cause of osteoporosis. In this study, we aimed to investigate the association of hip BMD with mortality risk after HF. Four hundred and eleven elderly patients with HF in Beijing, China, were included and prospectively followed up with a median time of 3 years. At baseline, quantitative CT technique (QCT) was used to measure areal BMD (aBMD) of the unaffected hip. Areal BMDs of the total hip (TH), femoral neck (FN), trochanter (TR), and intertrochanter were analyzed with postoperative mortality as the primary outcome. A total of 394 patients (78.59 ± 7.59 years, 75.4% female) were included in our final analysis, with 86 (82.23 ± 7.00 years, 81.4% female) dead. All hip bone densities demonstrated a significant association with mortality risks in the unadjusted model, but only TR aBMD remained significantly correlated after adjusting for all covariates. Compared to the lower TR aBMD group, the higher TR aBMD group yielded significantly lower death risks (HR 0.21 95% CI 0.05-0.9, P = 0.036). Higher survival probabilities were observed for higher TH and TR aBMD in survival analysis (P < 0.001). Hip BMD, especially TR BMD assessed by QCT, is an independent risk factor for postoperative mortality following HF. QCT may present a promising avenue for opportunistic analysis in immobilized patients, providing valuable information for early detection and personalized interventions to enhance patient outcomes.


[Time trends of occupational differences in smoking behaviour of employed men and women in Germany : Results of the 1999-2013 microcensus].
Studies show that people with a low occupational status are more likely to smoke than those with a high occupational status. Against the background of a general decline in tobacco consumption, time trends of occupational differences in smoking behaviour of employed men and women in Germany were examined. The analyses were based on the last five waves of the German microcensus that included questions about smoking (1999, 2003, 2005, 2009 and 2013), taking only employed men and women aged 18-64 years into account (n = 688,746). Information on occupational position was summarised using international classifications of occupation (ISEI-08 and ISCO-08). Raw and model-based standardized prevalence estimates of current smoking were calculated. Between 1999 and 2013, the proportion of smokers in the working population fell from 39.9 to 34.4% (men) and from 30.6 to 26.8% (women). Differences between occupational status groups increased significantly: while the prevalence of smoking among employees with high occupational status decreased, it remained largely stable in the low status group. In 2013, the occupations with the highest proportion of smokers were waste disposal workers, cleaning staff, unskilled workers, truck and bus drivers, salespeople and cashiers, and employees in the catering industry. Since the beginning of the 2000s, the prevalence of smoking in the working population has declined. The strengthened tobacco control policy - e. g. the establishment of smoke-free workplace laws - might have contributed to this trend. In the context of workplace health promotion, tobacco prevention and cessation measures should be targeted at those professions in which smoking is still particularly common.


Comparisons of activity measurements with radionuclide calibrators-A tool for quality assessment and improvement in nuclear medicine.
A national program of ongoing comparisons for assaying gamma-emitting radiopharmaceuticals for amount of radioactivity using radionuclide calibrators was begun in 2000. Nuclides of the most wide-spread use in Cuban nuclear medicine, 131I, 201Tl and (99m)Tc, as well as two measurement geometries, glass vials and plastic syringes, were employed. In this paper, the participants' performance is assessed by mean of a statistical analysis of the reported data. Performance tables have been obtained and a chi2 statistic is calculated from observed and expected frequencies, with the aim of testing the hypothesis about the independence of some characteristics of the comparison results, at a significance level alpha=0.05. The proportion of satisfactory results in the years 2002-2004 were found to be at the same level, but higher than in 2000. It reveals an improvement of the measurement quality since 2002. The causes of improvement were investigated using the statistical treatment of several data available as supplementary information.


Energy state of the myocardium during long-term cold storage and subsequent reperfusion.
Long-term preservation of dog hearts was performed over 24 h using Bretschneider-HTK cardioplegia and cold storage. Preservation was assessed in terms of conservation of myocardial tissue levels of high-energy phosphates (HEP) and functional outcome after cardiac transplantation. Serial left ventricular biopsies were taken and analysed for ATP, ADP, AMP, adenosine, inosine, hypoxanthine, xanthine and creatine phosphate. Myocardial structure was studied by electron microscopical examination of a similar biopsy specimen. Cardiac performance was measured before and after cardiac transplantation. Several techniques of cardioplegic arrest were studied: single dose cardioplegia, multidose cardioplegia and continuous perfusion with the cardioplegic solution. In all groups, the hearts were stored at 0.5 degree C for 24 h. In the group of single dose Bretschneider-HTK cardioplegia, myocardial ATP content after 24 h of cold storage was only 25% of control. The total sum of nucleotides at that time interval was however 65% of the control value. Reperfusion of these hearts using a support dog (whole blood reperfusion) did not result in any recovery of ATP. Creatinine phosphate however showed an overshoot. Accumulated nucleosides were washed out. The hearts showed electrical activity but were severely arrhythmic. Contractility was poor. In the group of multidose Bretschneider-HTK cardioplegia, HEP preservation was better than after single dose cardioplegia. ATP content was about 50% of control. The total sum of nucleotides was 85% of control. Ultrastructural assessment of the myocytes revealed only slight ischaemic damage to the mitochondria. Reperfusion on cardiopulmonary bypass after cardiac transplantation did not show any restoration of ATP, but a steady catabolism of HEP. The nucleosides adenosine and inosine were not washed out upon reperfusion. After cardiac transplantation, none of these hearts could be weaned from cardiopulmonary bypass due to irreversible low cardiac output. Histological examination demonstrated irreversible myocardial tissue damage. In the group of continuous cold Bretschneider cardioplegia, HEP content was completely preserved throughout the 24 h of perfusion. Ultrastructure of the myocytes was normal. Reperfusion of the transplanted hearts showed a mild breakdown of ATP to 70% of control values accompanied by a slight accumulation of nucleosides. Haemodynamic recovery however was perfect and none of the hearts needed positive inotropic support. Myocytes after reperfusion had a normal subcellular appearance.(ABSTRACT TRUNCATED AT 400 WORDS)


Persulfate activation by naturally occurring trace minerals.
The potential for 13 naturally occurring minerals to mediate the decomposition of persulfate and generate a range of reactive oxygen species was investigated to provide fundamental information on activation mechanisms when persulfate is used for in situ chemical oxidation (ISCO). Only four of the minerals (cobaltite, ilmenite, pyrite, and siderite) promoted the decomposition of persulfate more rapidly than persulfate-deionized water control systems. The other nine minerals decomposed persulfate at the same rate or more slowly than the control systems. Mineral-mediated persulfate activation was conducted with the addition of one of three probe compounds to detect the generation of reactive oxygen species: anisole (sulfate+hydroxyl radical), nitrobenzene (hydroxyl radical), and hexachloroethane (reductants and nucleophiles). The reduced mineral pyrite promoted rapid generation of sulfate+hydroxyl radical. However, the remainder of the minerals provided minimal potential for the generation of reactive oxygen species. The results of this research demonstrate that the majority of naturally occurring trace minerals do not activate persulfate to generate reactive oxygen species, and other mechanisms of activation are necessary to promote contaminant destruction in the subsurface during persulfate ISCO.


Ophthalmic changes in hydrocephalus. A follow-up examination of 50 patients treated with shunts.
Fifty children shunted for hydrocephalus aged 5-17 years underwent a later ophthalmological examination. Corrected vision of 0.9 or less was found in 45 out of 93 eyes; in 21 patients this was the vision of both eyes. Corrected vision 0.3 or less was found in 7 eyes; in 3 patients this was the vision of both eyes. Hyperopia greater than or equal to +2.0 D was found in 20%, myopia greater than or equal to -0.5 D in 13% and astigmatism greater than or equal to 1.0 D in 25.5% of 98 eyes. Clear nystagmus was present in 18% of patients. Heterophoria was found in 20% and manifest horizontal strabismus in 33%, but no paretic squint. The optic disc was considered normal in 36 out of 100 eyes on ophthalmoscopy and in 35 out of 78 eyes on colour photography. Retinal nerve fibre layer photographs showed normal nerve fibres in 49 out of 71 eyes. The Friedmann field was in the normal range in 33 out of 53 eyes, and the Goldmann field was normal in 37 out of 44 eyes. Right homonymous hemianopia was discovered in 2 patients. The Harrington-Flocks field was normal in 17 out of 24 eyes, and 1 patient had left homonymous hemianopia. The HRR test showed a red-green disturbance in 22 out of 71 eyes. The Farnsworth panel D-15 desaturated test was entirely normal in only 4 out of 65 eyes, but the errors were only slight in 48 cases.


Pulmonary disease caused by a newly identified mycobacterium: Mycolicibacterium toneyamachuris: a case report.
Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.


Enhanced-contrast two-photon optogenetic pH sensing and pH-resolved brain imaging.
We present experiments on cell cultures and brain slices that demonstrate two-photon optogenetic pH sensing and pH-resolved brain imaging using a laser driver whose spectrum is carefully tailored to provide the maximum contrast of a ratiometric two-photon fluorescence readout from a high-brightness genetically encoded yellow-fluorescent-protein-based sensor, SypHer3s. Two spectrally isolated components of this laser field are set to induce two-photon-excited fluorescence (2PEF) by driving SypHer3s through one of two excitation pathways-via either the protonated or deprotonated states of its chromophore. With the spectrum of the laser field accurately adjusted for a maximum contrast of these two 2PEF signals, the ratio of their intensities is shown to provide a remarkably broad dynamic range for pH measurements, enabling high-contrast optogenetic deep-brain pH sensing and pH-resolved 2PEF imaging within a vast class of biological systems, ranging from cell cultures to the living brain.


Preliminary antifungal and cytotoxicity studies of extracts of Ritchiea capparoides var. longipedicellata.
Crude extracts obtained from the leaves, stem bark and roots of Ritchiea capparoides var. longipedicellata were screened for in vitro antifungal activity using the agar tube dilution method. The leaf hexane, leaf methanol, stem bark methanol and root methanol extracts were tested using ten clinical strains of fungi at a concentration of 200 and 400 microg/ml, respectively. At 400 microg/ml, all four extracts inhibited the growth of six of the ten test fungi used in the study. Inhibition of the growth of Aspergillus niger by the extracts was also seen but the activity was low and the leaf hexane and root methanol extracts inhibited the growth of Drechslera rostrata. Only the leaf hexane extract was active against Curvularia lunata, while the growth of Candida albicans was not inhibited by any of the extracts. The inhibition of growth of almost all the microorganisms decreased at 200 microg, griseofulvin was included as a reference compound and methanol as the control. Preliminary cytotoxicity tests were done with the four extracts using the larvae of the brine shrimp, Artemia saline. The extracts were however found to be relatively non-toxic as each extract had an LD50 value greater than 1000 microg/ml.


Contextualized stress, global stress, and depression in well-educated, pregnant, African-American women.
Well-educated, pregnant, African-American women are disproportionately at risk for adverse birth outcomes and depression linked to stress has been established as a significant contributor to poor birth outcomes. Since racial and gendered stress have been identified as threats to birth outcomes, a cross-sectional study was conducted that utilized the Jackson, Hogue, Phillips Contextualized Stress Measure (JHP), a measurement of racial and gendered stress, and the Perceived Stress Scale (PSS), an assessment of global stress, to detect their associations and predictions for depression as measured by the Beck Depression Inventory II (BDI-II). We recruited 101 pregnant, well-educated, African-American women from ob-gyn offices who were administered the JHP, the PSS, and the BDI-II. Correlational, chi-square, and stepwise regression analyses were conducted with the measures and the demographic variables of relationship status, the presence of other children, and annual household income. The results revealed significant linear and covariate associations for the JHP, PSS, and BDI-II. Correspondingly, chi-square analysis found significant associations for the JHP and the BDI-II and the presence of other children, relationship status, and annual household income. Results from the regression models found that the contextualized and global stress measures were both predictive of depression. Demographic characteristics did not predict depression. The results argue for prenatal depression and stress screening. Furthermore, the link between contextualized stress and depression alerts health care providers and local communities to be responsive to the particular stressors that pose risks for pregnant African-American women and their babies.


Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT.
In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.


The clinical value of procalcitonin in the prediction of infected necrosis in acute pancreatitis.
Infection of pancreatic necrosis (IN) has a major impact on management and outcome in acute pancreatitis (AP). Currently, guided fine-needle aspiration (FNA) is the only means for an accurate diagnosis of IN. Procalcitonin (PCT), a 116 amino acid pro-peptide of calcitonin has been found in high concentrations in patients with sepsis. In the present study we analyzed the clinical value of serum PCT for predicting IN in AP and compared the results to guided FNA. Clinical study. A collaborative study between the Departments of General Surgery and Clinical Chemistry/ Pathobiochemistry of the University of Ulm, Germany. 61 patients with AP entered this study and were stratified into three groups according to morphological and bacteriological data: I. 22 patients with edematous pancreatitis (AIP), II. 18 patients with sterile necrosis (SN), III. 21 patients with IN. During an observation period of 14 days PCT was measured by immunoluminometry, CRP was determined by lasernephelometry on a routine base. In patients with IN overall PCT concentrations were significantly higher than in those with SN, whereas CRP levels did not differ in both groups. In contrast, only low concentrations of both parameters were found in patients with AIP. By ROC analysis the best PCT cut-off level for predicting IN or persisting pancreatic sepsis was obtained at > or =1.8 ng/ml. If this cut-off was reached on at least two consecutive days, IN could be predicted with a sensitivity of 95%, a specificity, of 88%, and an accuracy of 90%. Guided FNA achieved a sensitivity, specificity, and accuracy of 91%. 79%, and 84% in differentiating IN from SN, respectively. After surgical treatment of IN median PCT values continued to be significantly higher in patients with persisting pancreatic sepsis (n=12) compared to those with an uneventful postoperative course (n=7). Our results demonstrate that monitoring of serum PCT could serve as a noninvasive and accurate method to predict IN in AP as well as to select patients with persisting septic complications after surgical debridement.


The effect of DHEA complementary treatment on heroin addicts participating in a rehabilitation program: a preliminary study.
We evaluated the effect of DHEA complementary treatment in opiate addicts undergoing detoxification. DHEA (100 mg/day) or placebo was added to the routine medication protocol in a randomized, double blind controlled study. Follow-up for 12 months was conducted. Two separate DHEA-treated subgroups were identified by the Fuzzy clustering method: one showed statistically significant improvement in the severity of withdrawal symptoms, depression and anxiety scores (n=34; p<0.001 for all) and the other subgroup deteriorated in all measures (n=15). DHEA at the end of the detoxification program showed a tendency towards correlation with the duration of abstinence (r=0.6843; p>0.05; n=6), while a negative correlation was obtained with the cortisol level (r=-0.900; p=0.005, n=8). The completion-rate of the DHEA-improved subgroup was greater than in the DHEA-deteriorated subgroup (64.7% vs. 33.3%, respectively). The influence of supplementary DHEA treatment was mostly effective in heroin addicts who had not previously used either cocaine or benzodiazepines and who had experienced only few withdrawal programs.


Interactions with the protein binding of 7-hydroxy-methotrexate in human serum in vitro.
7-Hydroxy-methotrexate (7-OH-MTX), the major extracellular methotrexate (MTX) metabolite, is 90-95% bound in human serum, with albumin (HSA) as the major binding protein. Reports of an interaction with concomitantly administered non-steroidal antiinflammatory drugs (NSAIDs) during MTX therapy led us to investigate whether these compounds could reduce the binding of 7-OH-MTX in vitro. Equilibrium dialysis experiments demonstrated that naproxen and indomethacin concentration dependently reduced the binding of 1 microM 7-OH-MTX. After ingestion of 1000 mg naproxen, per cent unbound 7-OH-MTX in sera from volunteers increased 2-3-fold in vitro, positively correlated to naproxen concentrations (P less than 0.00015). In addition, etacrynic acid, bilirubin, sulphamethizole and acetylsalicylic acid displaced 7-OH-MTX from its binding protein(s) in a competitive manner. The data suggest that 7-OH-MTX interacts with several exogenous and endogenous substances associated with HSA in human serum. Displacement of 7-OH-MTX from HSA may contribute to the interaction between NSAIDs and MTX.


Role of soluble epoxide hydrolase phosphatase activity in the metabolism of lysophosphatidic acids.
The EPXH2 gene encodes for the soluble epoxide hydrolase (sEH), which has two distinct enzyme activities: epoxide hydrolase (Cterm-EH) and phosphatase (Nterm-phos). The Cterm-EH is involved in the metabolism of epoxides from arachidonic acid and other unsaturated fatty acids, endogenous chemical mediators that play important roles in blood pressure regulation, cell growth, inflammation and pain. While recent findings suggested complementary biological roles for Nterm-phos, its mode of action is not well understood. Herein, we demonstrate that lysophosphatidic acids are excellent substrates for Nterm-phos. We also showed that sEH phosphatase activity represents a significant (20-60%) part of LPA cellular hydrolysis, especially in the cytosol. This possible role of sEH on LPA hydrolysis could explain some of the biology previously associated with the Nterm-phos. These findings also underline possible cellular mechanisms by which both activities of sEH (EH and phosphatase) may have complementary or opposite roles.