Theory of mind and executive dysfunction in chronic inflammatory demyelinating polyneuropathy.
Although chronic inflammatory demyelinating polyneuropathy (CIDP) is understood as a disease affecting the peripheral nervous system, mild cognitive dysfunction, particularly in the executive domain, has been described to form part of the condition. Here our interest lay in CIDP-related theory of mind (ToM) capacities as an aspect of social cognition relevant for many aspects of everyday life. Twenty-nine patients with CIDP and 23 healthy controls participated in this study. They were subjected to overview cognitive testing, different executive function (EF) tasks, as well as to the Faux Pas Recognition Task (FPRT) for assessing cognitive ToM and the Reading the Mind in the Eyes Test (RMET) with respect to affective ToM. Persons with CIDP and controls did not differ with respect to their overall cognitive state. However, in the German verbal fluency standard, the digit span forward and the digit span backward tests used as EF tasks patients performed significantly worse than controls. Further, performance was abnormally low in the FPRT, whilst the groups did not differ with respect to RMET results. The FPRT and digit span backward results correlated with each other. Patients with CIDP showed deficits in cognitive ToM performance together with EF dysfunction, whilst affective ToM was preserved. Altogether, the results suggest that low cognitive ToM capacities in patients with CIDP arise as a particular aspect of disease-related executive dysfunction.


[Comparative double-blind study of the analgesic activity of fosfosal (UR-1521) in patients with musculoskeletal and articular pain (author's transl)].
Fosfosal or 2-phosphonoxybenzoic acid is a new analgesic drug, whose analgesic activity and side effects have been determined in a double blind clinical study in comparison with placebo. The study has been done with 60 outpatients, of both sexes, which suffered musculoskeletal and arthritic pains. Patients were treated with fosfosal or placebo for eight days. The daily dose of fosfosal was 1 gram three times a day, once every 6-8 hours. The results obtained show that fosfosal has a clear analgesic activity, statistically significant versus placebo in all the parameters that were measured: pain severity, activity impairment and insomnia. The overall evaluation of the group of patients treated with fosfosal showed a marked improvement with a difference statistically significant with respect to the control group treated with placebo (p less than 0.001). The distribution of results in the fosfosal treated group was as follows: poor, 1; regular, 8; good, 10 and excellent, 6. The distribution in the placebo group was as follows: poor, 15; regular, 3; good, 2 and excellent, 0. The marked analgesic activity, the absence of side effects and the excellent gastric tolerance suggest that fosfosal is a promising new analgesic drug useful for the treatment of painful syndromes of several etiologies.


Recent advances in understanding enteric pathogenic Escherichia coli.
Although Escherichia coli can be an innocuous resident of the gastrointestinal tract, it also has the pathogenic capacity to cause significant diarrheal and extraintestinal diseases. Pathogenic variants of E. coli (pathovars or pathotypes) cause much morbidity and mortality worldwide. Consequently, pathogenic E. coli is widely studied in humans, animals, food, and the environment. While there are many common features that these pathotypes employ to colonize the intestinal mucosa and cause disease, the course, onset, and complications vary significantly. Outbreaks are common in developed and developing countries, and they sometimes have fatal consequences. Many of these pathotypes are a major public health concern as they have low infectious doses and are transmitted through ubiquitous mediums, including food and water. The seriousness of pathogenic E. coli is exemplified by dedicated national and international surveillance programs that monitor and track outbreaks; unfortunately, this surveillance is often lacking in developing countries. While not all pathotypes carry the same public health profile, they all carry an enormous potential to cause disease and continue to present challenges to human health. This comprehensive review highlights recent advances in our understanding of the intestinal pathotypes of E. coli.


Robust and Flexible Aramid Nanofiber/Graphene Layer-by-Layer Electrodes.
Aramid nanofibers (ANFs), or nanoscale Kevlar fibers, are of interest for their high mechanical performance and functional nanostructure. The dispersible nature of ANFs opens up processing opportunities for creating mechanically robust and flexible nanocomposites, particularly for energy and power applications. The challenge is to manipulate ANFs into an electrode structure that balances mechanical and electrochemical performance to yield a robust and flexible electrode. Here, ANFs and graphene oxide (GO) sheets are blended using layer-by-layer (LbL) assembly to achieve mechanically flexible supercapacitor electrodes. After reduction, the resulting electrodes exhibit an ANF-rich structure where ANFs act as a polymer matrix that interfacially interacts with reduced graphene oxide sheets. It is shown that ANF/GO deposition proceeds by hydrogen bonding and π-π interactions, leading to linear growth (1.2 nm/layer pairs) and a composition of 75 wt % ANFs and 25 wt % GO sheets. Chemical reduction leads to a high areal capacitance of 221 μF/cm2, corresponding to 78 F/cm3. Nanomechanical testing shows that the electrodes have a modulus intermediate between those of the two native materials. No cracks or defects are observed upon flexing ANF/GO films 1000 times at a radius of 5 mm, whereas a GO control shows extensive cracking. These results demonstrate that electrodes containing ANFs and reduced GO sheets are promising for flexible, mechanically robust energy and power.


The rationale for probiotics in female urogenital healthcare.
Urogenital infections are a major reason that women visit their family physician and are referred to gastroenterology, gynecology, urology, and infectious disease specialists. The association between abnormal vaginal microbiota and increased risk for sexually transmitted infections, bladder and vaginal infections per se, and a higher rate of preterm labor indicate the need to better understand and manage urogenital health. The concept of probiotics arose from the realization that humans are inhabited with microbes from birth and that these organisms play a role in preventing disease. Defined as "live microorganisms, which when administered in adequate amounts confer a health benefit on the host," probiotic strains have already been shown to effectively prevent diarrhea and to hold potential in preventing and treating tonsillitis, caries, renal calculi, and respiratory infections. This review provides a rationale for the use of probiotics in maintaining female vaginal and bladder health and as a treatment option for recurrent bacterial vaginosis, urinary tract infection, yeast vaginitis, and sexually transmitted infections. We consider only probiotic strains that fulfill the United Nations/World Health Organization Guidelines for Probiotics in being fully characterized and clinically documented through scientific investigations describing known or presumed mechanisms of action. Although medical practitioners as yet are unable to access these probiotic strains, an awareness of recent and ongoing research for probiotics is important, as results are encouraging. The concept of probiotic therapy is familiar to many consumers and although it has historically lacked credibility in the medical community, perceptions are changing.


Prolonged exercise in type 1 diabetes: performance of a customizable algorithm to estimate the carbohydrate supplements to minimize glycemic imbalances.
Physical activity in patients with type 1 diabetes (T1DM) is hindered because of the high risk of glycemic imbalances. A recently proposed algorithm (named Ecres) estimates well enough the supplemental carbohydrates for exercises lasting one hour, but its performance for prolonged exercise requires validation. Nine T1DM patients (5M/4F; 35-65 years; HbA1c 54 ± 13 mmol · mol(-1)) performed, under free-life conditions, a 3-h walk at 30% heart rate reserve while insulin concentrations, whole-body carbohydrate oxidation rates (determined by indirect calorimetry) and supplemental carbohydrates (93% sucrose), together with glycemia, were measured every 30 min. Data were subsequently compared with the corresponding values estimated by the algorithm. No significant difference was found between the estimated insulin concentrations and the laboratory-measured values (p = NS). Carbohydrates oxidation rate decreased significantly with time (from 0.84 ± 0.31 to 0.53 ± 0.24 g · min(-1), respectively; p < 0.001), being estimated well enough by the algorithm (p = NS). Estimated carbohydrates requirements were practically equal to the corresponding measured values (p = NS), the difference between the two quantities amounting to -1.0 ± 6.1 g, independent of the elapsed exercise time (time effect, p = NS). Results confirm that Ecres provides a satisfactory estimate of the carbohydrates required to avoid glycemic imbalances during moderate intensity aerobic physical activity, opening the prospect of an intriguing method that could liberate patients from the fear of exercise-induced hypoglycemia.


Synaptic organization of claustral and geniculate afferents to the visual cortex of the cat.
Claustral and geniculate afferents to area 17 were labeled by anterograde axonal transport of peroxidase-conjugated wheatgerm agglutinin, and examined in the electron microscope. A peroxidase reaction protocol that led to labeling in the form of minute holes in the EM sections was used. Both types of afferents formed type 1 (presumed excitatory) synapses exclusively. In agreement with previous reports the great majority of geniculate afferents to layers 4 and 6 contacted dendritic spines. The claustral afferents to layers 1 and 6 also predominantly contacted spines. In layer 4, however, claustral afferents contacted spines and dendritic shafts about equally. The results suggest a substantial claustral input to smooth-dendrite cells in layer 4, which are thought to be inhibitory in function. This may be the circuit by which the claustrum helps to generate end-stopped cortical receptive fields (Sherk and LeVay, 1983).


Glutamate-stimulated protein phosphorylation in cultured hippocampal pyramidal neurons.
The regulation of second-messenger production and protein phosphorylation by glutamate has been investigated in primary cultures of pure hippocampal pyramidal neurons. Embryonic rat pyramidal neurons were prepared according to the procedures of Bartlett and Banker (1984) and studied 1-21 d after plating. Glutamate caused a transient increase in intracellular free [Ca2+], determined with fura-2, in the presence of 1.26 mM extracellular Ca2+, but not in 50 nM free Ca(2+)-containing solution. Glutamate also transiently increased cellular diacylglycerol content in both normal and low-[Ca2+] media. Neurons were prelabeled with 32P-orthophosphate to label intracellular ATP, then stimulated with glutamate (100 microM). A rapid transient incorporation of 32P into primarily three proteins of 120, 87, and 48 kDa was found by analysis of two-dimensional gels. At 30 sec after glutamate stimulation, 32P incorporation into the 87-kDa and 48-kDa proteins peaked (240% and 170% basal levels, respectively), and by 2 min, phosphorylation of the 87-kDa protein had returned to basal levels, while that of the 48-kDa protein decreased but remained above control levels. The phosphorylation of these proteins appeared to be mediated by protein kinase C (PKC) because all three showed an increase in phosphorylation after phorbol ester treatment of cultures. Phosphate incorporation was accompanied by an acidic shift in the isoelectric point of both 87- and 48-kDa proteins. Glutamate stimulation resulted in phosphorylation in the presence and absence of Ca2+ influx. Antibody recognition and biochemical characteristics indicated that the 87-kDa phosphoprotein is the PKC substrate MARCKS (myristoylated, alanine-rich C-kinase substrate). The 48-kDa protein, though very similar to GAP-43, was not recognized by specific antibodies raised against GAP-43. These results suggest that glutamate stimulates the transient generation of second messengers that activate PKC in hippocampal neurons, resulting in a significant increase in the phosphorylation of three specific proteins.


Surgical treatment of persistent fetal vasculature and visual rehabilitation: one-year followup.
We present the management and postoperative course of a persistent fetal vasculature (PFV) case. A four-year-old girl visited the Eye Department of Hippokration, General Hospital of Thessaloniki due to reduced visual acuity of her left eye. She was diagnosed with PFV and underwent surgery (lensectomy, capsulorhexis of the posterior capsule, insertion of an intraocular lens in the posterior chamber, and posterior vitrectomy) in order to dissect the PFV. Along with the postoperative medical care, she underwent intensive treatment for amblyopia. The postoperative course was uncomplicated, and the visual acuity of her left eye improved from hand movement to 20/25 with proper correction. Patients with unilateral PFV and gradually deteriorating visual acuity could be good candidates for a combined surgical procedure, as the one described above, with a good prognosis.


Basic fibroblast growth factor released from a platinum coil with a polyvinyl alcohol core enhances cellular proliferation and vascular wall thickness: an in vitro and in vivo study.
We developed a new type of platinum coil that has a polyvinyl alcohol (PVA) core to absorb and release various biologically active materials for the endovascular treatment of intracranial aneurysms. We evaluated its efficacy as an embolic material with basic fibroblast growth factor (bFGF) in an in vitro and in vivo study. A small PVA thread was inserted into the central space of the primary coil. This coil was named the PVA-core coil. Ten-millimeter segments of the PVA-core coil were used in this study. PVA-core coils were immersed in a bFGF solution for 1 hour. The PVA-core coil, which absorbed bFGF in the PVA-core, was named the FGF-core coil. Initially, the dose of bFGF released from the PVA core into saline was measured by performing an enzyme-linked immunosorbent assay. In the in vitro study, FGF-core coils, PVA-core coils, and unmodified coils were cultured with fibroblasts (NIH3T3), and then their surfaces were observed with electron microscopy. In the in vivo study, each coil was implanted into a rat common carotid artery. The rats were killed, and the arterial lumen was histologically examined at 14 and 28 days after coil implantation. BFGF was released from the PVA core into saline within 24 hours by performing an enzyme-linked immunosorbent assay. Electron microscopic findings demonstrated remarkable cellular adhesion to the surfaces of the FGF-core coils, but no adhesion to the surfaces of the PVA-core coils and the unmodified coils was found. Histologically, remarkable cell proliferation in the vascular lumen was demonstrated in the common carotid arteries of the FGF-core coil implantation group at the 14th and 28th days. Cellular components proliferated around the implanted coil, and these components mainly stained blue with Masson trichrome. These changes did not occur in the PVA-core coil group and the unmodified coil group. We suggest that FGF-core coils may be effective in inducing fibrotic changes inside aneurysms. These coils may be used as an embolic material to cure cerebral aneurysms.


The Self-Invalidation Due to Emotion Scale: Development and psychometric properties.
Self-stigma involves internalized negative evaluation in people with a societally prescribed label (i.e., mental health diagnosis). Thus, measures of self-stigma due to mental illness exclude people without a diagnosis who may negatively evaluate themselves because of their emotions-a process we define as self-invalidation due to emotion. In the current research, we introduced a novel measure of self-invalidation due to emotion distinct from measures of self-stigma due to mental illness and perceived emotion invalidation. After expert review of the item pool (Study 1), and principal component (Study 2) and confirmatory factor analysis (Study 3), a 10-item scale for Self-Invalidation Due to Emotion Scale (SIDES) was developed, with subscales of self-invalidation due to high and low emotional experience. A college student and community sample (Study 4) confirmed test-retest reliability and demonstrated that greater self-invalidation due to high emotional experience predicted greater emotion dysregulation, emotional reactivity and expressivity, and beliefs about emotion uncontrollability. In contrast, greater self-invalidation due to low emotional experience predicted less emotional reactivity and expressivity, and greater beliefs about emotion controllability. Finally, in a community sample of people with a history of mental illness (Study 5), greater self-invalidation due to high but not low emotional experience predicted symptoms of borderline personality pathology and distress regardless of self-stigma due to mental illness or perceived emotion invalidation. The current research supports the SIDES as a psychometrically sound, more inclusive measure of self-stigma, relevant for predicting distress and maladaptive emotional tendencies in people with and without a mental illness. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Single-cell RNA-seq reveals MIF-(CD74 + CXCR4) dependent inhibition of macrophages in metastatic papillary thyroid carcinoma.
The mechanism promoting papillary thyroid carcinoma (PTC) metastasis remains unclear. We aimed to investigate the potential metastatic mechanisms at a single-cell resolution. We performed single-cell RNA-seq (scRNA-seq) profiling of thyroid tumour (TT), adjacent normal thyroid (NT) and lymph node metastasized tumour (LN) from a young female with PTC. Validation of our results was conducted in 31 tumours with metastasis and 30 without metastasis. ScRNA-seq analysis generated data on 38,215 genes and 0.14 billion transcripts from 28,839 cells, classified into 18 clusters, each annotated to represent 10 cell types. PTC cells were found to originate from epithelial cells. Epithelial cells and macrophages emerged as the strongest signal emitters and receivers, respectively. After reclustering epithelial cells and macrophages, our analysis, incorporating gene set variation analysis (GSVA), SCENIC analysis, and pseudotime trajectory analysis, indicated that subcluster 0 of epithelial cells (EP_0) showed a more malignant phenotype, and subclusters 3 and 4 of macrophages (M_3 and M_4) demonstrated heightened activity. Further analysis suggested that EP_0 may suppress the activity of M_3 and M_4 via MIF - (CD74 + CXCR4) in the MIF pathway. After analysing the expression of the 4 genes in the MIF pathway in both the TCGA cohort and our cohort (n = 61), CD74 was identified as significantly overexpressed in PTC tumours particularly those with lymph node metastasis. Our study revealed that PTC may facilitate lymph node metastasis by inhibiting macrophages via MIF signalling. It is suggested that malignant PTC cells may suppress the immune activity of macrophages by consistently releasing signals to them via MIF-(CD74 + CXCR4).


Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone.
Nuclear receptor subfamily 1, group I, member 3 (NR1I3) is reported to be a possible novel therapeutic target for some cancers, including lung, brain and hematopoietic tumors. Here, we characterized expression of NR1I3 in a mouse model of lung carcinogenesis induced by 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone (NNK), the most potent tobacco carcinogen. Lung tumors were collected from mice treated with NNK (400 mg/kg) and euthanized after 52 weeks. Benign and malignant lesions were formalin-fixed and paraffin-embedded for histology and immunohistochemistry, with samples snap-frozen for mRNA analysis. Immunohistochemically, we found that most macrophages and type I and II pneumocytes expressed NR1I3, whereas fibroblasts and endothelial cells were NR1I3-. Compared with benign lesions, malignant lesions had less NR1I3+ tumor cells. Gene expression analysis also showed an inverse correlation between NR1I3 mRNA expression and tumor size (P=0.0061), suggesting that bigger tumors expressed less NR1I3 transcripts, in accordance with our immunohistochemical NR1I3 tests. Our results indicate that NR1I3 expression decreased during progression of malignant lung tumors induced by NNK in mice.


Antiplatelet Therapy Monitoring in Neonates and Children.
Antiplatelet agents are used for the prevention and treatment of thromboembolic disease in an increasingly complex population of pediatric patients. Despite their importance for clinical outcome, there is no consensus on the most effective monitoring strategies. This review describes the current state of knowledge focusing on antiplatelet therapy monitoring in children. The authors searched five databases (PubMed-NCBI, MEDLINE-OVID, SCOPUS-Elsevier, ScienceDirect, and Cochrane) from January 2000 to October 2017 using keywords selected a priori. Identified articles were sorted according to the antiplatelet agents administered, methods of antiplatelet monitoring, and outcome measures. Twenty studies were included, with 14 cohort studies, 3 randomized controlled trials, and 3 cross-sectional studies. Eleven different antiplatelet monitoring tools were used, with the most common being Light Transmission Aggregometry, Urinary Thromboxane, Thromboelastography with Platelet Mapping, and VerifyNow. In the majority of studies, antiplatelet therapy monitoring was used to describe adequacy or responsiveness to treatment based on laboratory cut-off values, which were not uniform and sourced from adult studies or extrapolated from test manuals. Several studies evaluated monitoring related to clinical outcome or adjusted therapy to reach predefined therapeutic targets. There was no single laboratory method found to be distinctly better for monitoring antiplatelet treatment. Associations between laboratory assays and clinical outcomes or assays and gold standard measurements were highly inconsistent. The current literature lacks consensus on clinical benefits and measurable effects of monitoring antiplatelet therapy in pediatric patients. This review highlights important areas for research required to determine the value of antiplatelet therapy monitoring in children.


Oxidative Dissolution of Sulfide Minerals Tends to Accumulate More Dissolved Heavy Metals in Deep Seawater Environments than in Shallow Seawater Environments.
Deep-sea mining magnifies the release of heavy metals into seawater through oxidative dissolution of seafloor massive sulfide (SMS). At present, there is little information about how the metals released into seawater might be affected by the mineral assemblages, seawater conditions, and solid percentages. Here, leaching experiments were carried out to examine the behavior of three sulfides from the Southwest Indian Ridge, under conditions that replicated deep and shallow seawater environments at three solid-liquid ratios. The results demonstrated that sphalerite dissolved rapidly, and the metals released in both experimental conditions were comparable, potentially reflecting galvanic interactions between the sulfide minerals. Large quantities of the released metals were removed from the solutions when hydrous ferric oxides formed, especially for shallow seawater conditions. A comparison of metal concentrations in the leachates with the baseline metal concentrations in natural seawater indicated that most of the released metals, when diluted with seawater, would not have widespread impacts on ecosystems. Based on the obtained unique oxidative dissolution properties of each SMS at variable solid-liquid ratios, targeted wastewater discharge treatments are proposed to minimize impacts from the dissolved metals. This study will support the development of robust guidelines for deep-sea mining activities.


Unilateral paranasal sinus diseases: analysis of the clinical characteristics, diagnosis, pathology, and computed tomography findings.
This study observed a much higher percentage of unilateral sinus pathology than reported in the literature. Comprehensive evaluations of patient age, presenting symptoms, nasoendoscopy examination, and computed tomography (CT) findings help in the diagnosis of unilateral sinus disease. Nevertheless, histological confirmation remains obligatory for diagnosis. To evaluate the clinical features, diagnosis, pathology, and CT findings in patients who had undergone sinus surgery for unilateral sinus diseases. Among 524 patients who had undergone sinus surgery, patients with unilateral sinus opacification on the preoperative CT scans were selected. Data were collected from the medical records and CT findings were evaluated. Unilateral sinus opacification was identified in 121 (23.1%) patients. Male gender was predominant and the greatest number of patients had chronic rhinosinusitis. The mean age was oldest for fungus ball and youngest for antrochoanal polyp. Purulent discharge and foul odor were the common presenting symptoms under inflammatory conditions, while frequent epistaxis and cheek swelling were the main symptoms in neoplastic diseases. Calcifications were observed only in patients with fungus ball, while bony destruction was detected in both benign and malignant tumors. Punch biopsy performed in the office offered accurate histopathologic diagnosis in 94.3% of the patients.


Modeling the variability of single-cell lag times for Listeria innocua populations after sublethal and lethal heat treatments.
Optical density measurements were used to estimate the effect of heat treatments on the single-cell lag times of Listeria innocua fitted to a shifted gamma distribution. The single-cell lag time was subdivided into repair time (the shift of the distribution assumed to be uniform for all cells) and adjustment time (varying randomly from cell to cell). After heat treatments in which all of the cells recovered (sublethal), the repair time and the mean and the variance of the single-cell adjustment time increased with the severity of the treatment. When the heat treatments resulted in a loss of viability (lethal), the repair time of the survivors increased with the decimal reduction of the cell numbers independently of the temperature, while the mean and variance of the single-cell adjustment times remained the same irrespective of the heat treatment. Based on these observations and modeling of the effect of time and temperature of the heat treatment, we propose that the severity of a heat treatment can be characterized by the repair time of the cells whether the heat treatment is lethal or not, an extension of the F value concept for sublethal heat treatments. In addition, the repair time could be interpreted as the extent or degree of injury with a multiple-hit lethality model. Another implication of these results is that the distribution of the time for cells to reach unacceptable numbers in food is not affected by the time-temperature combination resulting in a given decimal reduction.


Effect of Sodium Dodecyl Sulfate Adsorption on the Behavior of Water inside Single Walled Carbon Nanotubes with Dissipative Particle Dynamics Simulation.
Dissipative particle dynamics (DPD) simulations were utilized to investigate the ability of sodium dodecyl sulfate (SDS) to adsorb inside a single-walled, arm-chair carbon nanotube (SWCNT), as well as the effect of surfactant on the properties of water inside the SWCNT. The diameter of the SWCNT varied from 1 to 5 nm. The radial and axial density profiles of water inside the SWCNTs were computed and compared with published molecular dynamics results. The average residence time and diffusivity were also calculated to show the size effect on mobility of water inside the SWCNT. It was found that nanotubes with diameter smaller than 3 nm do not allow SDS molecules to enter the SWCNT space. For larger SWCNT diameter, SDS adsorbed inside and outside the nanotube. When SDS was adsorbed in the hollow part of the SWCNT, the behavior of water inside the nanotube was found to be significantly changed. Both radial and axial density profiles of water inside the SWCNT fluctuated strongly and were different from those in bulk phase. In addition, SDS molecules increased the retention of water beads inside SWCNT (d ≥ 3nm) while water diffusivity was decreased.


pH-dependent fusion between the flavivirus West Nile and liposomal model membranes.
Fusion between purified [3H]uridine-labelled West Nile virus (WNV) particles and liposomes containing RNase, was assayed by degradation of the viral RNA to trichloroacetic acid-soluble material. Fusion of virus with liposomes containing phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and cholesterol (at a molar ratio of 1:1:1:1.5) was found to be dependent on pH with maximum fusion occurring at pH 6.7 and below. At pH 6.6 fusion was rapid and was essentially complete within 2 min at 37 degrees C. At this time, approximately 50% of the viral RNA had been degraded and increasing the concentration of liposomes or time allowed for fusion increased this percentage only slightly. Fusion was dependent on temperature, was almost totally non-leaky and was not dependent on the presence of divalent cations. The lipid composition of liposomes was found to influence both the pH optimum for fusion and the maximum degree of fusion observed. Electron microscopy was used to visualize the fusion reaction between liposomes and virus particles.


Investigation of the ecology of Francisella tularensis during an inter-epizootic period.
A 1-year study of the ecological cycle of Francisella tularensis was performed in an enzootic area during an inter-epizootic period. The study was based on multiple sampling of all major constituents of the disease cycle. Seroprevalence of tularemia in the European brown hare (Lepus europaeus) population was 5.1% (10/197) with low antibody titers (1/10 and 1/20), and F. tularensis ssp. holarctica was isolated from four hares. F. tularensis was not detected in the 38 common voles (Microtus arvalis), 110 yellow-necked mice (Apodemus flavicollis), or 15 stripped field mice (Apodemus agrarius) trapped during the study, or the by-catch of 8 Eurasian pygmy shrews (Sorex minutus) or 6 common shrews (Sorex araneus). A total of 1106 Ixodes ricinus and 476 Haemaphysalis concinna ticks were collected from vegetation, and 404 I. ricinus, 28 H. concinna ticks, and 15 Ctenophtalmus assimilis and 10 Nosopsyllus fasciatus fleas were combed off small mammals. One H. concinna female and one nymph collected from the vegetation was found infected with F. tularensis ssp. holarctica by TaqMan polymerase chain reaction, thus resulting a 0.42% (2/476) prevalence. F. tularensis-specific DNA was not detected in environmental water samples, and the examined 100 sheep, 50 cows, and 50 buffalos grazed at the study area were all seronegative. During inter-epizootic periods, F. tularensis ssp. holarctica seems to persist only in the European brown hare--H. concinna cycle at the studied habitat. H. concinna may not serve exclusively as an arthropod vector, but it may also harbor bacteria for 3-4 years through multiple life stages and act as an important reservoir of F. tularensis. Rodent species probably do not serve as true reservoir hosts of tularemia.


Contrast media of high and low molecular weights in the detection of recurrent herniated disks.
Our goal was to compare contrast enhancement of recurrent herniated disk fragments and scar after intravenous injection of a new high-molecular-weight contrast medium, Gadomer 17 (gadomer), with that after injection of a low-molecular-weight contrast medium, (gadopentetate dimeglumine). Recurrent herniated disks were modeled in dogs by placing a fragment of intervertebral disk cartilage in the epidural space at laminectomy. MR imaging was performed with one of the contrast media at 20 and 50 days and with the other medium at 22 and 52 days. The changes in signal intensity from baseline in the disk fragment and in the adjacent scar tissue was measured at 2, 22, and 45 minutes. Differences were tested for significance with a student t-test. At 50 days after surgery, signal intensity in the intervertebral disk fragment increased by an average of 0.52 at 2 minutes after injection of gadomer and by an average of 0.90 after injection of gadopentetate. For scar, the increases in signal intensity were 1.41 (gadomer) and 1.62 (gadopentetate). At 22 and 45 minutes after injection, the signal intensity change in the disk fragment continued to be significantly greater after gadopentetate than after gadomer injection. In comparison with the changes at 50 days, both scar and disk fragment tended to show greater signal intensity changes at 20 days. Signal intensity changes in the disk fragments were significantly less after gadomer than after gadopentetate. Signal intensity changes in scar were slightly less with gadomer than with gadopentetate. Greater contrast is achieved between scar and recurrent herniated disk with a higher-molecular-weight contrast medium than with one of lower molecular weight. The difference between the high- and low-molecular-weight contrast media increases with maturation of the scar tissue.


Wasf3 Deficiency Reveals Involvement in Metastasis in a Mouse Model of Breast Cancer.
The WASF3 gene has been implicated in cancer cell movement, invasion, and metastasis by regulating genetic pathways important in these processes. Invasion and metastasis assays, however, are largely centered on xenograft models in immune-compromised mice. To facilitate analysis of the role of WASF3 in the spontaneous development of cancer cell metastasis, we generated a Wasf3 null strain by deleting exons 4 and 5, which encode essential motifs for Wasf3 function. On exposure to cre-recombinase a stop codon is generated immediately downstream in exon 6. Using a cytomegalovirus (CMV)-cre strain, Wasf3 constitutively was inactivated, which led to viable mice with no visible morphologic or behavioral abnormalities. There was no abnormal development or function of the mouse mammary gland in the Wasf3 null mice and brain development was normal. In the mouse mammary tumor virus (MMTV)-driven polyoma middle-T oncogene strain, which shows early onset breast cancer development and metastasis, Wiskott-Aldrich syndrome protein family member 3 (Wasf3) is up-regulated in metastatic lesions. When this oncogene was introduced onto the Wasf3-null background, although metastasis was observed in these mice, there was a reduction in the number and size of metastatic lesions in the lungs. These data provide evidence for a role in WASF3 in the development of metastasis in a spontaneous model of breast cancer.


[Landscape ecology of hantavirosis in Rio Grande do Sul state].
The aim of this work was to study the landscape ecology of hantavirosis in Rio Grande do Sul state, Brazil. This was achieved through geocoding the occurrence of cases and overlaying onto vegetation and relief maps. The majority of cases occurred during Spring, in highland areas dominated by secondary vegetation and agricultural activity.


'Omics' approaches to understanding interstitial cystitis/painful bladder syndrome/bladder pain syndrome.
Recent efforts in the generation of large genomics, transcriptomics, proteomics, metabolomics and other types of 'omics' data sets have provided an unprecedentedly detailed view of certain diseases, however to date most of this literature has been focused on malignancy and other lethal pathological conditions. Very little intensive work on global profiles has been performed to understand the molecular mechanism of interstitial cystitis/painful bladder syndrome/bladder pain syndrome (IC/PBS/BPS), a chronic lower urinary tract disorder characterized by pelvic pain, urinary urgency and frequency, which can lead to long lasting adverse effects on quality of life. A lack of understanding of molecular mechanism has been a challenge and dilemma for diagnosis and treatment, and has also led to a delay in basic and translational research focused on biomarker and drug discovery, clinical therapy, and preventive strategies against IC/PBS/BPS. This review describes the current state of 'omics' studies and available data sets relevant to IC/PBS/BPS, and presents opportunities for new research directed at understanding the pathogenesis of this complex condition.


Psychosocial Characteristics and Gestational Weight Change among Overweight, African American Pregnant Women.
Objectives. To describe psychosocial factors identified as contributors of weight gain in the general population and to examine the relationship between these factors and gestational weight gain among low socioeconomic status, African American, overweight pregnant women. Methods. African American women (n = 120) with a pregravid body mass index ≥25 kg/m(2) completed measures of eating, sleep, and depressed mood between 14 and 24 weeks of gestation. Weight was tracked. Descriptive statistics, correlations, and linear regression modeling were used to characterize the sample and examine predictors of gestational weight gain. Results. Four percent screened positive for night eating syndrome, with 32% consuming at least 25% of their daily caloric intake after dinner (evening hyperphagia). None met criteria for binge eating disorder; 4% reported occasional binge episodes. Cognitive restraint over eating was low. Participants slept 7.1 (SD = 1.9) h per night and reported 4.3 (SD = 3.6) awakenings per week; 18% reported some level of depressed mood. Night and binge eating were related to each other, sleep quality, and depressed mood. Eating due to cravings was the only psychosocial variable to predict gestational weight gain. Conclusions. Depressed mood, night eating, and nighttime awakenings were common in this cohort, while cognitive restraint over eating was low. Most psychosocial variables were not predictive of excess gestational weight gain.


Detomidine reduces isoflurane anesthetic requirement (MAC) in horses.
To quantitate the dose- and time-related magnitude of the anesthetic sparing effect of, and selected physiological responses to detomidine during isoflurane anesthesia in horses. Randomized cross-over study. Three, healthy, young adult horses weighing 485 ± 14 kg. Horses were anesthetized on two occasions to determine the minimum alveolar concentration (MAC) of isoflurane in O2 and then to measure the anesthetic sparing effect (time-related MAC reduction) following IV detomidine (0.03 and 0.06 mg kg-1). Selected common measures of cardiopulmonary function, blood glucose and urinary output were also recorded. Isoflurane MAC was 1.44 ± 0.07% (mean ± SEM). This was reduced by 42.8 ± 5.4% and 44.8 ± 3.0% at 83 ± 23 and 125 ± 36 minutes, respectively, following 0.03 and 0.06 mg kg-1, detomidine. The MAC reduction was detomidine dose- and time-dependent. There was a tendency for mild cardiovascular and respiratory depression, especially following the higher detomidine dose. Detomidine increased both blood glucose and urine flow; the magnitude of these changes was time- and dose-dependent CONCLUSIONS: Detomidine reduces anesthetic requirement for isoflurane and increases blood glucose concentration and urine flow in horses. These changes were dose- and time-related. The results imply potent anesthetic sparing actions by detomidine. The detomidine-related increased urine flow should be considered in designing anesthetic protocols for individual horses.


Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.
Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.


Change in osmolarity of disodium cromoglycate solution and protection against exercise-induced bronchospasm in children with asthma.
It has been suggested that osmolarity and/or nebulizer output may affect the protective effects of disodium cromoglycate (DSCG) in asthma. The aim of this study was to evaluate the influence of osmolarity of the DSCG solution on exercise-induced bronchospasm (EIB) in children with bronchial asthma. A jet nebulizer was used for DSCG inhalation in Study 1 and an ultrasonic nebulizer in Study 2. Thirteen asthmatic children (7 males and 6 females, aged 6-14 yrs) were enrolled in Study 1, and nine asthmatic children (5 males and 4 females, aged 9-13 yrs) in Study 2. After pretreatment with saline (control), hypotonic DSCG or isotonic DSCG, children underwent exercise challenge with a cycle ergometer. The percentage fall in forced expiratory volume in one second (FEV1) was measured at 5 and 15 min postexercise. The data were compared by analysis of variance (ANOVA). Both in Study 1 and Study 2, there were no significant differences in minute ventilation volume or maximum heart rate during exercise between the different treatment groups. Both hypotonic and isotonic DSCG significantly reduced the maximum percentage fall in FEV1. There were no significant differences in protective effects between hypotonic and isotonic DSCG in either study. We conclude that the efficacy of hypotonic and isotonic disodium cromoglycate solutions is similar for protection against exercise-induced bronchospasm. Hypotonic disodium cromoglycate seems to be clinically effective for prevention of exercise-induced bronchospasm and treatment of asthmatic children.


Surface treated titanium dioxide nanoparticles as inorganic UV filters in sunscreen products.
TiO(2) nanoparticles were used in this research as an inorganic UV absorber for preparation of a sunscreen that ensures optically transparent films with adequate SPF. TiO(2) nanoparticles in rutile crystal form, produced in Cinkarna Celje, were used in this research. The elementary principle of the nanograde TiO(2) production is the sulphate synthesis process, which is upgraded for the synthesis of final nano product. TiO(2) nanoparticles were subsequently surface modified by coating with sodium silicate as the source of silica. The resulting silica coated TiO(2) nanoparticles were examined by scanning (SEM) and transmission electron microscopy (TEM). Uniform particles distribution and homogeneous amorphous coatings, formed in heterogeneous nucleation of silica molecules on the surface of TiO(2) nanoparticles, were observed. Sun-protection factor (SPF) of 28 was determined for sunscreen with incorporated 9.0 wt. % TiO(2) nanoparticles, surface treated with 5.0 wt. % silica according to the "Method for the In Vitro Determination of UVA Protection Provided by Sunscreen Products".


Blood Thiamine Level and Cognitive Function in Older Hospitalized Patients.
We sought to identify any association between whole blood thiamine level and functional status in older hospitalized patients. This cross-sectional study retrospectively analyzed the results of routine measurements of whole blood thiamine levels of 233 older patients who were consecutively hospitalized to a geriatric acute care ward. Nutritional status, depression, and the participants' cognitive impairment were evaluated using the Mini Nutritional Assessment-Short Form, Depression in Old Age Scale, and Montreal Cognitive Assessment, respectively. Activities of daily living were determined using Barthel Index (BI) on admission and at the time of discharge. Diagnoses of dementia and delirium were derived from the patients' medical records. Of 233 participants (mean age 82.1 [7.1]), 47.0% and 39.0% were at risk of malnutrition and malnourished, respectively. There was no thiamine deficiency (<20 ng/mL) in total population. Nearly all patients (95%) were screened with impaired cognitive function, in which 36% and 9% had the diagnosis of dementia and delirium, respectively. Patients with dementia (P = .040) and delirium (P = .002) demonstrated lower mean thiamine blood levels compared to patients without. Mean blood vitamin B1 was higher in patients with functional recovery (change in BI ≥5 points during hospitalization; P = .018). In a binary logistic regression analysis, blood vitamin B1, weight loss, and female gender were the major independent risk factors for delirium but not for dementia. Despite the absence of thiamine deficiency, whole blood thiamine was lower in patients with dementia and delirium compared to those without. Higher thiamine levels were significantly associated with functional recovery during hospitalization.


Different myrosinases activate sequestered glucosinolates in larvae and adults of the horseradish flea beetle.
β-Glucosidases play an important role in the chemical defense of many insects by hydrolyzing and thereby activating glucosylated pro-toxins that are either synthesized de novo or sequestered from the insect's diet. The horseradish flea beetle, Phyllotreta armoraciae, sequesters pro-toxic glucosinolates from its brassicaceous host plants and possesses endogenous β-thioglucosidase enzymes, known as myrosinases, for glucosinolate activation. Here, we identify three myrosinase genes in P. armoraciae (PaMyr) with distinct expression patterns during beetle ontogeny. By using RNA interference, we demonstrate that PaMyr1 is responsible for myrosinase activity in adults, whereas PaMyr2 is responsible for myrosinase activity in larvae. Compared to PaMyr1 and PaMyr2, PaMyr3 was only weakly expressed in our laboratory population, but may contribute to myrosinase activity in larvae. Silencing of PaMyr2 resulted in lower larval survival in a predation experiment and also reduced the breakdown of sequestered glucosinolates in uninjured larvae. This suggests that PaMyr2 is involved in both activated defense and the endogenous turnover of sequestered glucosinolates in P. armoraciae larvae. In activity assays with recombinant enzymes, PaMyr1 and PaMyr2 preferred different glucosinolates as substrates, which was consistent with the enzyme activities in crude protein extracts from adults and larvae, respectively. These differences were unexpected because larvae and adults sequester the same glucosinolates. Possible reasons for different myrosinase activities in Phyllotreta larvae and adults are discussed.


Incidence of ventricular arrhythmias during silent myocardial ischaemia in coronary artery disease.
This study investigated the relationship between silent myocardial ischaemia during daily life and ventricular ectopic activity in patients with angiographically confirmed coronary artery disease and preserved left ventricular function. We studied 45 patients (37 men, 8 women, aged 42-70 years) who satisfied the above criteria. All underwent 72-h continuous electrocardiographic monitoring for the detection of silent ischaemic episodes and ventricular arrhythmias. A total of 225 ischaemic episodes were recorded, of which 198 (88%) were silent. Fourteen of the silent episodes (7.1%) were associated with ventricular arrhythmias. There was no statistically significant relationship between the association of silent ischaemia with arrhythmias and the patients' exercise test or angiography findings. However, the ventricular arrhythmias tended to be associated with ischaemic episodes of longer duration and with greater maximum ST-segment depression. Silent myocardial ischaemia during everyday activity is accompanied by ventricular ectopic activity in only a small percentage of cases. The association between ischaemia and ventricular arrhythmias seems to have more to do with the duration of the ischaemic episode and the degree of ST segment depression than with the severity of the underlying coronary artery disease.


Multidetector computed tomographic angiography of the cardiovascular system.
The introduction of multidetector computed tomography (MDCT) is considered a dramatic development in CT imaging that has direct implication in the imaging of various systems, in particular the cardiovascular system. The advantages of MDCT are an enormous increase in imaging acquisition speed, more coverage of the patient, and high spatial resolution. This article reviews the recent developments in CT angiography and discusses the clinical application relevant to diagnosis and endovascular treatment of cardiovascular diseases.


Factors associated with the length of fit note-certified sickness episodes in the UK.
To identify diagnostic, patient/employee, general practitioner (GP) and practice factors associated with length of certified sickness episodes. Twelve-month collection of fit note data at 68 general practices in eight regions of England, Wales and Scotland between 2011 and 2013. Secondary analysis of sick note data collected at seven general practices in 2001/2002. All employed patients receiving at least one fit note at practices within the collection period were included in the study. Main study outcomes were certified sickness episodes lasting longer than 3, 6 and 12 weeks. The data from seven practices contributing in 2013, and a decade previously, suggest that periods of long-term sickness absence may be falling overall (risk >12 weeks absence, OR=0.65) but the proportion of mild-moderate mental disorder-related (M-MMD) episodes is rising (26% to 38%). Over 32% (8064/25 078) of fit notes issued to working patients in the 68 practices were for a M-MMD. A total of 13 994 patient sickness 'episodes' were identified. Diagnostic category of episode, male patients, older patient age and higher social deprivation were significantly associated with the >3 week, >6 week and long-term (>12 week) outcomes, and GP partner status with the long-term outcome only. In the context of a rapidly changing legislative environment, the study used the largest sickness certification database constructed in the UK to enhance the evidence base relating to factors contributing to long-term work incapacity.


Physical illness, pain, and suicidal behavior.
The relevant literature on the relationship between physical illness and suicide is briefly reviewed. Some important studies on the relationship between pain from physical illnesses like duodenal ulcer, uterine diseases (dysmenorrhea, dysfunctional uterine bleeding) and suicide are referred to. The Madurai studies reveal that high scores on hopelessness and suicide intent in patients with pain from duodenal ulcer, dysmenorrhea, and other uterine problems are associated with suicidal behavior. The need for assessing the suicide risk in such patients under the care of nonpsychiatric medical personnel is discussed. A simple, easy-to-administer questionnaire is presented.


Prevention of experimental allergic encephalomyelitis (EAE) in the SJL/J mouse by whole body ultraviolet irradiation.
The cellular requirements for the in vivo induction of experimental allergic encephalomyelitis (EAE) were investigated in the SJL/J mouse. Exposure of mice to whole body ultraviolet (UV) irradiation, a treatment that has been shown in other systems to interfere selectively with antigen-presenting cell function, prevented the development of clinical and pathologic signs of acute EAE. Splenic T cells from UV-treated animals did not adoptively transfer resistance to EAE, making it unlikely that UV irradiation resulted in the generation of a specific suppressor cell population responsible for protection from EAE. UV irradiation was effective in preventing EAE when administered before initial immunization; UV irradiation was ineffective in modifying ongoing EAE or in preventing relapses of EAE induced by reimmunization. In additional experiments, adult thymectomized, lethally x-irradiated mice reconstituted with syngeneic marrow cells depleted of mature T lymphocytes were found to be resistant to the induction of EAE. Susceptibility was restored by the addition of splenic T cells, demonstrating that EAE induction is T cell-dependent in the mouse. The prevention of an experimental autoimmune demyelinating disease by whole body UV irradiation suggests that interference with the function of Ia-bearing accessory cells may represent an approach for immunotherapy in autoimmune disorders.


Speech spoken by familiar people is more resistant to interference by linguistically similar speech.
Understanding speech in adverse conditions is affected by experience-a familiar voice is substantially more intelligible than an unfamiliar voice when competing speech is present, even if the content of the speech (the words) are controlled. This familiar-voice benefit is observed consistently, but its underpinnings are unclear: Do familiar voices simply attract more attention, are they inherently more intelligible because they have predictable acoustic characteristics, or are they more intelligible in a mixture because they are more resistant to interference from other sounds? We recruited pairs of native English-speaking participants who were friends or romantic couples. Participants reported words from closed-set English sentences (i.e., Oldenburg Matrix Test; Zokoll et al., 2013) spoken by a familiar talker (the participant's partner) or an unfamiliar talker. We compared 3 masker conditions that are acoustically similar but differ in their demands: (1) English Oldenburg sentences; (2) Oldenburg sentences in a language incomprehensible to the listener (Russian or Spanish); and (3) unintelligible signal-correlated noise. We adaptively varied the target-to-masker ratio to obtain 50% speech reception thresholds. We observed a large (∼5 dB) familiar-voice benefit when the target and masker were both English sentences. This benefit was attenuated (to ∼2 dB) when the masker was in an incomprehensible language and disappeared when it was signal-correlated noise. These results suggest that familiar voices did not benefit intelligibility because they were more predictable or because they attracted greater attention, rather familiarity with a target voice reduced interference from maskers that are linguistically similar to the target. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Formation and mitigation of PAHs in barbecued meat - a review.
Polycyclic Aromatic Hydrocarbons (PAHs) are chemicals, which can occur in barbecued or grilled foods, and particularly in meats. They originate from incomplete combustion of the heat source, pyrolysis of organic compounds, or fat-induced flame formation. This review therefore summarizes relevant parameters for mitigation of especially carcinogenic PAHs in barbecued meat. Consumption of PAHs increases the risk of cancer, and thus the relevance for the mitigation of PAHs formation is very high for barbecued meat products. Parameters such as heat source, barbecue geometry, and meat type as well as marinating, adding spices, and other antioxidants reduce the final benzo[a]pyrene and PAHs concentrations and minimize the exposure. Overall, mitigation of carcinogenic PAHs from barbecuing includes removal of visual charring, reducing fat pyrolysis by minimizing dripping from the meat onto the heat source, the use of acidic marinades or choosing leaner cuts of meat. Estimation of human exposure to barbecued meat, includes several challenges such as substantial differences in barbecuing frequencies and practices, heat sources and meat types used for grilling.


Re-expression of 117 antigen, a cell surface glycoprotein of aggregating cells, during terminal differentiation of Dictyostelium discoideum prespore cells.
117 antigen is a glycoprotein expressed on the surface of D. discoideum cells at aggregation. It then disappears and is later re-expressed on the surface of a subpopulation of cells at culmination, the terminal differentiation stage (Sadeghi et al. 1987). A cDNA clone was used to show that the appearance of cell surface 117 antigen accurately reflects the expression of the 117 gene as measured by mRNA levels. It was also shown that during multicellular development there is a reciprocal relationship between the levels of 117 mRNA and the mRNA which codes for prespore surface glycoprotein, PsA. Dual parameter flow cytometry was used to demonstrate that the 117 antigen is found on the surface of maturing prespore cells after the PsA glycoprotein disappears, but that it is not found on mature spores. Using three monoclonal antibodies which identify respectively 117 antigen, PsA, and MUD3 antigen (a spore coat glycoprotein--probably Sp96), two new stages of final spore maturation were defined. These results indicate that there is a recapitulation of at least one aggregative cell surface glycoprotein in the prespore subpopulation of cells as they rise up the stalk during final spore development. This raises the possibility that culmination, which involves complex three dimensional morphogenetic movements not unlike those observed during animal embryogenesis, involves components of the two-dimensional pattern seen during aggregation.


Use of first- and second-generation antipsychotic medications in older patients with schizophrenia in Asia (2001-2009).
This study examined the prescribing patterns of several first- (FGAs) and second-generation antipsychotic (SGAs) medications administered to older Asian patients with schizophrenia during the period between 2001 and 2009. Information on hospitalized patients with schizophrenia aged 65 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001-2009). There were no older patients in Thailand, therefore data on 467 patients in eight Asian countries and territories including China, Hong Kong SAR, India, Japan, Korea, Malaysia, Singapore, and Taiwan were analysed. Cross-sectional socio-demographic data, clinical characteristics and antipsychotic prescriptions were assessed using a standardized protocol and data collection procedure. Of the 467 patients, 192 patients (41.1%) received FGAs only, 166 (35.5%) received SGAs only and 109 (23.3%) received a combination of FGAs and SGAs. Of the FGAs, haloperidol was the most commonly used (31.3%; mean 9.4 ± 6.7 mg/day), followed by chlorpromazine (15.4%; mean 126.4 ± 156.4 mg/day) and sulpiride (6.6%; mean 375.0 ± 287.0 mg/day). Of the SGAs, risperidone was the most commonly used (31.5%; mean 4.5 ± 2.7 mg/day), followed by olanzapine (13.1%; mean 13.6 ± 6.5 mg/day), quetiapine (7.3%; mean 325.0 ± 237.3 mg/day) and aripiprazole (1.9%; mean 17.6 ± 7.7 mg/day). FGAs and higher doses of certain SGAs (risperidone, olanzapine and quetiapine) were still commonly dispensed to older Asian patients with schizophrenia. Considering older patients' reduced tolerability of potentially severe side effects associated with FGAs and higher doses of certain SGAs, continuing education and training addressing the rational use of antipsychotics in this population is clearly needed.


Low indoleamine 2, 3 dioxygenase (IDO) activity is associated with psycho-obstetric risk.
Preeclampsia and depression in pregnancy are among the most prevalent obstetric disorders with no known cures. While depression and preeclampsia each increase risk for the other, shared mechansisms are unclear. One possibility is low levels of Indoleamine 2,3 dioxygenase (IDO), which links immune dysregulation and oxidative arterial damage resulting in poor vascular function in both preeclampsia and depression. We hypothesized low circulating IDO activity levels in pregnancy would correspond to poor vascular function and depression symptoms. In this nested case-control study, clinical, demographic, and biologic data from a cohort of pregnant women recruited to longitudinal studies measuring noninvasive vascular function and circulating factors were analyzed. IDO activity across all three trimesters of pregnancy was measured using a colorimetric assay. Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, was also assessed throughout gestation by non-invasive applanation tonometry. Depression symptoms were assessed in pregnancy via the validated patient health questionnaire 9 (PHQ9). Participants with low second and third trimester IDO activity had significantly decreased cfPWV. This association remained statistically significant when controlled for confounders such as BMI and chronic hypertension in the third but not second trimester. While PHQ9 scores were not associated with cfPWV differences, IDO activity was lower in moderate and severely depressed relative to non-depressed pregnant individuals. These results implicate IDO in arterial stiffness and depression symptoms, suggesting that decreased IDO may be a central target for improved psycho-obstetric health.


The myelin protein MAL affects peripheral nerve myelination: a new player influencing p75 neurotrophin receptor expression.
The myelin and lymphocyte protein (MAL) is a raft-associated membrane protein predominantly expressed by oligodendrocytes and Schwann cells. Here we show that MAL regulates myelination in the peripheral nervous system. In mice overexpressing MAL, myelination was retarded and fibers were hypomyelinated, whereas myelination in MAL knockout mice was accelerated. This was not due to impaired Schwann cell proliferation, differentiation or axonal sorting. We found that the expression level of p75 neurotrophin receptor mRNA and protein was strongly reduced in developing sciatic nerves in MAL-overexpressing mice. This reduction is well correlated with the observed alterations in myelination initiation, speed of myelination and alterations in Remak bundle development. Our results suggest a functional role for MAL in peripheral myelination by influencing the expression of membrane components that mediate axon-glia interaction during ensheathment and myelin wrapping.


Using health policy and systems research to influence national health policies: lessons from Mexico, Cambodia and Ghana.
Health system reforms across Africa, Asia and Latin America in recent decades demonstrate the value of health policy and systems research (HPSR) in moving towards the goals of universal health coverage in different circumstances and by various means. The role of evidence in policy making is widely accepted; less well understood is the influence of the concrete conditions under which HPSR is carried out within the national context and which often determine policy outcomes. We investigated the varied experiences of HPSR in Mexico, Cambodia and Ghana (each selected purposively as a strong example reflecting important lessons under varying conditions) to illustrate the ways in which HPSR is used to influence health policy. We reviewed the academic and grey literature and policy documents, constructed three country case studies and interviewed two leading experts from each of Mexico and Cambodia and three from Ghana (using semi-structured interviews, anonymized to ensure objectivity). For the design of the study, design of the semi-structured topic guide and the analysis of results, we used a modified version of the context-based analytical framework developed by Dobrow et al. (Evidence-based health policy: context and utilisation. Social Science & Medicine 2004;58:207-17). The results demonstrate that HPSR plays a varied but essential role in effective health policy making and that the use, implementation and outcomes of research and research-based evidence occurs inevitably within a national context that is characterized by political circumstances, the infrastructure and capacity for research and the longer-term experience with HPSR processes. This analysis of national experiences demonstrates that embedding HPSR in the policy process is both possible and productive under varying economic and political circumstances. Supporting research structures with social development legislation, establishing relationships based on trust between researchers and policy makers and building a strong domestic capacity for health systems research all demonstrate means by which the value of HPSR can be materialized in strengthening health systems.


Factors Associated with Extraction following Root Canal Filling in Adults.
Essentially, root fillings are performed to preserve natural teeth. Over time, however, some root-filled teeth will inevitably be extracted. The aim of this historical prospective cohort study in the adult Swedish population was to identify factors associated with extractions within 5 y of registration of a root filling. The cohort consisted of all those whose root fillings had been reported to the tax-funded Swedish Social Insurance Agency (SSIA) in 2009. Demographic data on the individuals registered with a root filling (sex, age, country of birth, disposable income, educational level, and marital status) were received from Statistics Sweden or the SSIA. Dental care setting, tooth type, and any registration of subsequent restorations within 6 mo were received from the SSIA. Multivariable regression analysis was used, and P < 0.05 was considered statistically significant. In total, 216,764 individuals had been registered with at least 1 root filling. Individuals (n = 824) without complete data were excluded from the analyses. After 5 y, 9.3% of the root-filled teeth had been registered as extracted. Logistic regression analysis found significant associations for all variables except country of birth, disposable income, and educational level. The highest odds ratios for extractions were associated with the type of restoration: teeth with no registration of any restoration and teeth with a direct restoration combined with a post were 3 times more likely to undergo extraction than teeth restored with an indirect restoration combined with a post and core. Overall, high odds ratios for extractions were associated with any type of composite restoration, including composite fillings and crowns combined with or without any post. In summary, after root filling in the Swedish adult population, several individual- and tooth-specific variables were associated with extraction. The reasons for the extractions remain to be studied further.


Changes of muscular load with aging in the motion of pulling up disposable diapers.
To elucidate how aging affects the muscular load required for pulling up pants-style disposable diapers, and why some elderly people cannot pull up the rear of their disposable diapers well, we evaluated the electromyogram (EMG) of 8 young subjects (21.5+/-1.5 years) and 7 elderly subjects (71.6+/-6.1 years). EMG was measured for four muscles--biceps brachii, deltoid, brachioradialis, and flexor carpi ulnaris. We evaluated the muscular load during a series of motions for pulling a disposable diaper up at the front and the rear of the body using an EMG-Video Synchronous Split Method. The analysis revealed that the front and the rear integral EMG of elderly subjects were both significantly larger than those of young subjects for all four muscles. For the deltoid and flexor carpi ulnaris muscles, the maximum amplitude of EMG when pulling up the rear of the disposable diapers was significantly larger in the elderly subjects than the young ones. These results suggest that the muscular load involved in pulling up the rear of disposable diapers may increase due to changes in body habitus caused by aging. Since muscular strength decreases with age, it seems likely that the elderly individuals will eventually be unable to pull up the rear of their diapers.


IL-17A is involved in the hyperplasia of blood vessels in local lesions of psoriasis by inhibiting autophagy.
Increased angiogenesis is a pathological feature of psoriasis, but the pathomechanisms of angiogenesis in psoriasis are not clear. Interleukin-17A (IL-17A) is the major effect factor in the pathogenesis of psoriasis. Our results showed that IL-17A can promote angiogenesis and cause endothelial cell inflammation. Autophagy plays an important role not only in regulating inflammation, but also in regulating angiogenesis. Whether angiogenesis in psoriasis is related to autophagy remains unclear. In this study, we treated human umbilical vein endothelial cells (HUVECs) with IL-17A to simulate increased angiogenesis to study whether increased angiogenesis in psoriasis is related to autophagy. Our results showed that treatment of HUVECs with IL-17A significantly increased angiogenesis and expression levels of mRNA for multiple proinflammatory cytokines (CCL20, IL-8, CCL2, IL-6, and IL-1β) and, while decreasing intracellular levels of nitric oxide (NO) and NO synthase (NOS) activity. Moreover, IL-17A inhibited autophagy as shown that IL-17A significantly increased expression levels of LC3II and p62 proteins. Induction of autophagy ameliorated IL-17A-mediated inflammatory response and inhibited angiogenesis, accompanied by increased p-AMPKα(Thr172) and p-ULK1(Ser555) expression, and decreased p-mTOR(Ser2448) and p-ULK1(Ser757) expression. Furthermore, inhibition of either AMPK or lysosomal acidification completely overrode autophagy-induced changes in angiogenesis and NOS activity. Finally, induction of autophagy decreased apoptosis and caspase-3 activity in IL-17A-treated HUVECs. These results showed that IL-17A is involved in angiogenesis and inflammatory response by inhibiting autophagy through AMPK signaling pathway, suggesting that autophagy may be a new therapeutic target for psoriasis.


Evaluating the growth of Listeria monocytogenes in refrigerated ready-to-eat frankfurters: influence of strain, temperature, packaging, lactate and diacetate, and background microflora.
This research was conducted to study the growth of Listeria monocytogenes inoculated on frankfurters stored at different conditions as a basis for a safety-based consume by shelf life date label. Three L. monocytogenes strains were separately inoculated at 10 to 20 CFU/cm2 onto frankfurters that were previously formulated with or without high pressure and with or without added 2% potassium lactate (PL) and 0.2% sodium diacetate (SD). Inoculated frankfurters were air or vacuum packaged; stored at 4, 8, or 12 degrees C; and L. monocytogenes and psychrotrophic plate counts were determined for 90, 60, and 45 days, respectively, or until the stationary phase was reached. The data (log CFU per square centimeter versus time) were fitted using the Baranyi-Roberts model to determine maximum growth rates and lag-phase time. The maximum growth rates and the lag time under each growth condition were used to calculate the time to reach 100-fold the initial Listeria population. In frankfurters lacking PL and SD, the count of all strains increased by 2 log after 18 to 50 days at 4 degrees C and 4 to 13 days at 8 degrees C. The growth was inhibited at 4 and 8 degrees C in frankfurters containing PL and SD, but one ribotype was capable of growing, with the time to reach 100-fold the initial Listeria population ranging from 19 to 35 days at 12 degrees C. In most cases, the time to reach 100-fold the initial Listeria population of L. monocytogenes was significantly longer in vacuum-packaged frankfurters as compared with air-packaged samples. Inclusion of PL and SD also inhibited the growth of psychrotrophs, but at all temperatures the psychrotrophic plate counts were greater than 4 log CFU/cm2 at the end of the experiments. These results indicated that despite the use of antimicrobials, certain L. monocytogenes strains could be capable of growing under storage-abuse conditions. Growth kinetics data could be useful for establishing a shelf life date label protocol under different handling scenarios.


Sugar-free synapses run on mitochondrial Sirtuin 3.
Metabolic plasticity of neurons ensures their activity continues when glucose is limited. Walsh and Simon discuss new work by Ashrafi and colleagues (https://doi.org/10.1083/jcb.202305048) that finds Sirtuin 3 directs local metabolic adaptation at synapses during sustained glucose deprivation.


Controlling solid state gain media by deposition of silver nanoparticles: from thermally- quenched to plasmon-enhanced Nd(3+) luminescence.
We show the possibility of controlling the optical properties of Nd(3+) laser ions by using different configurations of metallic nanoparticles (NPs) deposited on a solid state gain medium. In particular, we analyze the effect of two different silver NP arrangements on the optical properties of Nd(3+) ions in LiNbO(3): a two-dimensional (2D) high density and disordered Ag NP distribution and a one-dimensional (1D) long single chain of Ag NPs. We demonstrate that while the 2D disordered distribution produces a thermal quenching of the Nd(3+) luminescence, the 1D single chain leads to the enhancement of the fluorescence from the (4)F(3/2) metastable state. The experimental data are theoretically interpreted by taking into account the different character, radiative or non-radiative, of the localized surface plasmonic modes supported by the Ag nanoparticle distributions at the excitation wavelength. The results point out the capabilities of rare earth ions as optical tools to probe the local plasmonic fields and are relevant to determine the optimal configuration of metallic arrays to improve the performance of potential rare earth ion based sub-micrometer lasers.


Identification and characterization of Hoxa9 binding sites in hematopoietic cells.
The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation, and transcriptional activation of a network of proto-oncogenes, including Erg, Flt3, Lmo2, Myb, and Sox4. Collectively, this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia.


Mineralocorticoid Receptor Antagonism by Eplerenone and Arterial Inflammation in HIV: The MIRABELLA HIV Study.
The risk for atherosclerotic disease is increased 1.5- to 2.0-fold among persons with HIV (PWH). Increased activation of the renin-angiotensin-aldosterone system may contribute to increased arterial inflammation in this population. To determine the effects of eplerenone on arterial inflammation among well-treated PWH without known cardiovascular disease (CVD). Well-treated PWH who participated in the double-blinded, placebo-controlled, Mineralocorticoid Receptor Antagonism for Cardiovascular Health in HIV (MIRACLE HIV) study between February 2017 and March 2022 assessing the effects of eplerenone on myocardial perfusion were invited to participate in the Mineralocorticoid Receptor Antagonism By Eplerenone to Lower Arterial Inflammation in HIV (MIRABELLA) substudy if there was no current statin use. Participants were enrolled in the MIRABELLA study and underwent additional 18F-fludeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) imaging of the aorta and carotid arteries to assess arterial inflammation over 12 months of treatment with eplerenone vs placebo. Eplerenone, 50 mg, twice a day vs identical placebo. The primary outcome was change in target to background ratio (TBR), a measure of arterial wall inflammation, in the index vessel after 12 months of treatment. The index vessel was defined as the vessel (aorta, left carotid artery, or right carotid artery) with the highest TBR at baseline in each participant. A total of 26 participants (mean [SD] age, 54 [7] years; 18 male [69%]) were enrolled in the study. Treatment groups (eplerenone, 13 vs placebo, 13) were of similar age, sex, and body mass index. Eplerenone was associated with a reduction in TBR of the primary end point, the index vessel (eplerenone vs placebo: model treatment effect, -0.31; 95% CI, -0.50 to -0.11; P = .006; percentage change, -12.4% [IQR, -21.9% to -2.6%] vs 5.1% [IQR, -1.6% to 11.0%]; P = .003). We further observed a significant reduction of the TBR of the most diseased segment (MDS) of the index vessel (eplerenone vs placebo: -19.1% [IQR, -27.0% to -11.9%] vs 6.8% [IQR, -9.1% to 12.1%]; P = .007). A similar result was seen assessing the index vessel of the carotids (eplerenone vs placebo: -10.0% [IQR, -21.8% to 3.6%] vs 9.7% [IQR, -9.8% to 15.9%]; P = .046). Reduction in the TBR of MDS of the index vessel on 18F-FDG PET/CT correlated with improvement in the stress myocardial blood flow on cardiac magnetic resonance imaging (Spearman ρ = -0.67; P = .01). In this small randomized clinical trial, eplerenone was associated with reduction in arterial inflammation among well-treated PWH without known CVD. In addition, reductions in arterial inflammation as measured by 18F-FDG PET/CT were related to improvements in stress myocardial perfusion. Further larger studies should explore whether eplerenone is a potential treatment strategy for inflammatory-mediated CVD in PWH. ClinicalTrials.gov Identifier: NCT02740179.


[Evaluation of antiviral activity of new medicinal forms of foscarnet in genital herpes in guinea pigs].
Antiviral activity of a Russian drug foscarnet (tablets and coated pills) was assessed in guinea pigs with experimental genital herpes. New dosage forms were well tolerated by the animals, causing no manifest symptoms of intoxication irrespective of the doses or protocols of the drug use, Foscarnet in any dosage form in the total daily dose of at least 120 mg/kg had a pronounced antiviral effect towards herpes simplex type II virus, comparable with that of the commercial reference drug virolex: the intensity of clinical symptoms was alleviated and the disease duration shortened.


Digit somatotopy in the human cerebellum: a 7T fMRI study.
The representation of the human body in the human cerebellum is still relatively unknown, compared to the well-studied homunculus in the primary somatosensory cortex. The investigation of the body representation in the cerebellum and its somatotopic organisation is complicated because of the relatively small dimensions of the cerebellum, compared to the cerebrum. Somatotopically organised whole-body homunculi have previously been reported in both humans and rats. However, whether individual digits are represented in the cerebellum in a somatotopically organised way is much less clear. In this study, the high spatial resolution and high sensitivity to the blood oxygenation level dependent (BOLD) signal of 7T fMRI were employed to study the BOLD responses in the human cerebellum to the stroking of the skin of individual digits, the hand and forearm. For the first time, a coarse somatotopic organisation of the digits, ordered from D1-D5, could be visualised in individual human subjects in both the anterior (lobule V) and the posterior (lobule VIII) lobes of the cerebellum using a somatosensory stimulus. The somatotopic gradient in lobule V was found consistently in the posterior to anterior direction, with the thumb most posterior, while the direction of the somatotopic gradient in lobule VIII differed between subjects. No somatotopic organisation was found in Crus I. A comparison of the digit patches with the hand patch revealed that the digit regions are completely covered by the hand region in both the anterior and posterior lobes of the cerebellum, in a non-somatotopic manner. These results demonstrate the promise of ultra-high field, high-resolution fMRI for studies of the cerebellum.


Oral 5-aminolevulinic acid combined with sodium ferrous citrate prevents blood-aqueous barrier breakdown after anterior chamber paracentesis in healthy beagle dogs.
This study investigated the preventive effect of 5-aminolevulinic acid combined with sodium ferrous citrate (5-ALA/SFC) on blood-aqueous barrier (BAB) breakdown induced after anterior chamber paracentesis (ACP) in beagles. 5-ALA/SFC (1/0.64 mg/kg or 3/1.92 mg/kg) or carprofen (4.0 mg/kg) was orally administered daily for 7 days prior to ACP. Then, a sample of the aqueous humor (AH) was collected from one eye via ACP (first sample) and again 60 min later (second sample). The protein and prostaglandin E2 (PGE2) concentrations in both samples were measured. Compared with the control group, high-dose 5-ALA/SFC and carprofen significantly reduced the AH protein and PGE2 concentrations in the second sample. Our findings suggest that 5-ALA/SFC suppresses BAB breakdown in dogs.


Fluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation.
The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.


Stimulation of luteinizing hormone-releasing hormone (LHRH) gene expression in GT1-7 cells by its metabolite, LHRH-(1-5).
Given the central role of the decapeptide LHRH in reproduction and reproductive behavior, it is important to focus on delineating the possible effects of this gene and its products in the regulation of hormone-dependent reproductive processes. In the female, ovulation is preceded by a marked increase in LHRH release; the increase in LHRH release culminates in a preovulatory LH surge, which coincides with a period of sexual receptivity. In contrast to the belief that the proteolytic metabolism of LHRH serves only as a degradative process that removes excess LHRH and attenuates signal transduction through the LHRH receptor, we hypothesized that a metabolite of the decapeptide, LHRH-(1-5), can directly regulate LHRH neuronal function. This study demonstrates the ability of LHRH-(1-5) peptide to regulate LHRH gene expression in the LHRH neuronal cell line, the GT(1-7) cell. The results show that LHRH-(1-5) stimulated LHRH gene expression at the posttranscriptional level. In contrast to the LHRH suppression of its own gene expression, the coadministration of LHRH with the metalloendopeptidase, EC 188.8.131.52, an endopeptidase known to cleave LHRH to form LHRH(1-5), shows a reversal of effect, a stimulation of LHRH gene expression. Finally, the effect of LHRH-(1-5) on LHRH gene expression appears to be mediated by the calcium/calmodulin-dependent protein kinase. The present study supports the hypothesis that the physiological metabolite of LHRH, LHRH-(1-5), is functionally capable of regulating the reproductive neuroendocrine system.


Schisandrin B stereoisomers protect against hypoxia/reoxygenation-induced apoptosis and inhibit associated changes in Ca2+-induced mitochondrial permeability transition and mitochondrial membrane potential in H9c2 cardiomyocytes.
The effects of schisandrin B stereoisomers, (+/-)gamma-schisandrin [(+/-)gamma-Sch] and (-)schisandrin B [(-)Sch B], on hypoxia/reoxygenation-induced apoptosis were investigated in H9c2 cardiomyocytes. Changes in cellular reduced glutathione (GSH) levels, Ca(2+)-induced mitochondrial permeability transition (MPT), and mitochondrial membrane potential (Deltapsi(m)) values, were examined in (+/-)gamma-Sch-pretreated and (-)Sch B-pretreated cells, without or with hypoxia/reoxygenation challenge. The (+/-)gamma-Sch and (-)Sch B (2.5-5.0 microM) pretreatments protected against hypoxia/reoxygenation-induced apoptosis of H9c2 cells in a concentration-dependent manner, with (-)Sch B being more potent. The degrees of protection decreased, however, at the higher drug concentrations of 7.5 microM in both (+/-)gamma-Sch-pretreated and (-)Sch B-pretreated cells. The anti-apoptotic effects of the drugs were further evidenced by the suppression of hypoxia/reoxygenation-induced mitochondrial cytochrome c release and the subsequent cleavage of caspase 3 and poly-ADP-ribose polymerase after (-)Sch B pretreatment. Both (+/-)gamma-Sch and (-)Sch B pretreatments increased GSH levels in H9c2 cells, with (-)Sch B being more potent. Hypoxia/reoxygenation challenge caused a depletion in cellular GSH and the cytoprotection afforded by (+/-)gamma-Sch/(-)Sch B was associated with enhancement of cellular GSH in H9c2 cells, as compared to the drug-unpretreated control. Whereas hypoxia/reoxygenation challenge increased the extent of Ca(2+)-induced MPT pore opening and decreased Deltapsi(m) in H9c2 cardiomyocytes, cytoprotection against hypoxia/reoxygenation-induced apoptosis afforded by (+/-)gamma-Sch/(-)Sch B pretreatments was associated with a decreased sensitivity to Ca(2+)-induced MPT and an increased Deltapsi(m) in both unchallenged and challenged cells, as compared to the respective drug-unpretreated controls. The degrees of protection against apoptosis correlated negatively with the extents of Ca(2+)-induced MPT (r=-0.615, P<0.01) and positively with the values of Deltapsi(m) (r=0.703, P<0.01) in (+/-)gamma-Sch/(-)Sch B-pretreated and hypoxia/reoxygenation challenged cells. The results indicate that (+/-)gamma-Sch/(-)Sch B pretreatment protected against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes and that the cytoprotection afforded by (+/-)gamma-Sch/(-)Sch B may at least in part be mediated by a decrease in cellular sensitivity to Ca(2+)-induced MPT, which may in turn result from enhancement of cellular GSH levels by drug pretreatments.


Intense transpositional activity of insertion sequences in an ancient obligate endosymbiont.
The streamlined genomes of ancient obligate endosymbionts generally lack transposable elements, such as insertion sequences (IS). Yet, the genome of Wolbachia, one of the most abundant bacterial endosymbionts on Earth, is littered with IS. Such a paradox raises the question as to why there are so many ISs in the genome of this ancient endosymbiont. To address this question, we investigated IS transpositional activity in the unculturable Wolbachia by tracking the evolutionary dynamics and history of ISWpi1 elements. We show that 1) ISWpi1 is widespread in Wolbachia, being present in at least 55% of the 40 sampled strains, 2) ISWpi1 copies exhibit virtually identical nucleotide sequences both within and among Wolbachia genomes and possess an intact transposase gene, 3) individual ISWpi1 copies are differentially inserted among Wolbachia genomes, and 4) ISWpi1 occurs at variable copy numbers among Wolbachia genomes. Collectively, our results provide compelling evidence for intense ISWpi1 transpositional activity and frequent ISWpi1 horizontal transmission among strains during recent Wolbachia evolution. Thus, the genomes of ancient obligate endosymbionts can carry high loads of functional and transpositionally active transposable elements. Our results also indicate that Wolbachia genomes have experienced multiple and temporally distinct ISWpi1 invasions during their evolutionary history. Such recurrent exposition to new IS invasions may explain, at least partly, the unusually high density of transposable elements found in the genomes of Wolbachia endosymbionts.


The Cryptococcus neoformans alkaline response pathway: identification of a novel rim pathway activator.
The Rim101/PacC transcription factor acts in a fungal-specific signaling pathway responsible for sensing extracellular pH signals. First characterized in ascomycete fungi such as Aspergillus nidulans and Saccharomyces cerevisiae, the Rim/Pal pathway maintains conserved features among very distantly related fungi, where it coordinates cellular adaptation to alkaline pH signals and micronutrient deprivation. However, it also directs species-specific functions in fungal pathogens such as Cryptococcus neoformans, where it controls surface capsule expression. Moreover, disruption of the Rim pathway central transcription factor, Rim101, results in a strain that causes a hyper-inflammatory response in animal infection models. Using targeted gene deletions, we demonstrate that several genes encoding components of the classical Rim/Pal pathway are present in the C. neoformans genome. Many of these genes are in fact required for Rim101 activation, including members of the ESCRT complex (Vps23 and Snf7), ESCRT-interacting proteins (Rim20 and Rim23), and the predicted Rim13 protease. We demonstrate that in neutral/alkaline pH, Rim23 is recruited to punctate regions on the plasma membrane. This change in Rim23 localization requires upstream ESCRT complex components but does not require other Rim101 proteolysis components, such as Rim20 or Rim13. Using a forward genetics screen, we identified the RRA1 gene encoding a novel membrane protein that is also required for Rim101 protein activation and, like the ESCRT complex, is functionally upstream of Rim23-membrane localization. Homologs of RRA1 are present in other Cryptococcus species as well as other basidiomycetes, but closely related genes are not present in ascomycetes. These findings suggest that major branches of the fungal Kingdom developed different mechanisms to sense and respond to very elemental extracellular signals such as changing pH levels.


Pelvic venous congestion induces lower urinary tract dysfunction in rats.
Pelvic venous congestion (PC) is thought to be related to several diseases of the lower urinary tract (LUT). We examined the characteristics of the LUT in rats with PC. To create PC, female rats were anesthetized with isoflurane, and the bilateral common iliac veins and bilateral uterine veins were ligated. At 1-8 weeks after either ligation or sham surgery, we performed cystometry with or without administration of carbazochrome sodium sulfonate hydrate or propiverine hydrochloride, histologic examination of the bladder, blood flow imaging, assessment of locomotor activity, measurement of urinary 8-hydroxydeoxyguanosine (8-OHdG) and nitric oxide metabolites (NOx), and the Evans blue dye extravasation test. PC elevated frequency of urination after 2-6 weeks, and caused a decrease of spontaneous locomotor activity. In addition, there was a decrease of bladder blood flow, an increase of bladder vascular permeability, an increase of urinary 8-OHdG, a decrease of urinary NOx, and mild inflammatory changes of the bladder. In rats with PC, frequency of urination was normalized by administration of propiverine or carbazochrome. Rats with PC may be used as a model of PC associated with high frequency of urination, and this model may be useful when developing treatment for LUT symptoms associated with PC.


Mechanisms of rule acquisition and rule following in inductive reasoning.
Despite the recent interest in the neuroanatomy of inductive reasoning processes, the regional specificity within prefrontal cortex (PFC) for the different mechanisms involved in induction tasks remains to be determined. In this study, we used fMRI to investigate the contribution of PFC regions to rule acquisition (rule search and rule discovery) and rule following. Twenty-six healthy young adult participants were presented with a series of images of cards, each consisting of a set of circles numbered in sequence with one colored blue. Participants had to predict the position of the blue circle on the next card. The rules that had to be acquired pertained to the relationship among succeeding stimuli. Responses given by subjects were categorized in a series of phases either tapping rule acquisition (responses given up to and including rule discovery) or rule following (correct responses after rule acquisition). Mid-dorsolateral PFC (mid-DLPFC) was active during rule search and remained active until successful rule acquisition. By contrast, rule following was associated with activation in temporal, motor, and medial/anterior prefrontal cortex. Moreover, frontopolar cortex (FPC) was active throughout the rule acquisition and rule following phases before a rule became familiar. We attributed activation in mid-DLPFC to hypothesis generation and in FPC to integration of multiple separate inferences. The present study provides evidence that brain activation during inductive reasoning involves a complex network of frontal processes and that different subregions respond during rule acquisition and rule following phases.


Individual choice in the definition of death.
While there are numerous doubts, controversies and lack of consensus on alternative definitions of human death, it is argued that it is more ethical to allow people to choose either cessation of cardio-respiratory function or loss of entire brain function as the definition of death based on their own views. This paper presents the law of organ transplantation in Japan, which allows people to decide whether brain death can be used to determine their death in agreement with their family. Arguably, Japan could become a unique example of individual choice in the definition of death if the law is revised to allow individuals choose definition of death independently of their family. It suggests that such an approach is one of the reasonable policy options a country can adopt for legislation on issues related to the definition of death.


Epigenetic alterations differ in phenotypically distinct human neuroblastoma cell lines.
Epigenetic aberrations and a CpG island methylator phenotype have been shown to be associated with poor outcomes in children with neuroblastoma (NB). Seven cancer related genes (THBS-1, CASP8, HIN-1, TIG-1, BLU, SPARC, and HIC-1) that have been shown to have epigenetic changes in adult cancers and play important roles in the regulation of angiogenesis, tumor growth, and apoptosis were analyzed to investigate the role epigenetic alterations play in determining NB phenotype. Two NB cell lines (tumorigenic LA1-55n and non-tumorigenic LA1-5s) that differ in their ability to form colonies in soft agar and tumors in nude mice were used. Quantitative RNA expression analyses were performed on seven genes in LA1-5s, LA1-55n and 5-Aza-dC treated LA1-55n NB cell lines. The methylation status around THBS-1, HIN-1, TIG-1 and CASP8 promoters was examined using methylation specific PCR. Chromatin immunoprecipitation assay was used to examine histone modifications along the THBS-1 promoter. Luciferase assay was used to determine THBS-1 promoter activity. Cell proliferation assay was used to examine the effect of 5-Aza-dC on NB cell growth. The soft agar assay was used to determine the tumorigenicity. Promoter methylation values for THBS-1, HIN-1, TIG-1, and CASP8 were higher in LA1-55n cells compared to LA1-5s cells. Consistent with the promoter methylation status, lower levels of gene expression were detected in the LA1-55n cells. Histone marks associated with repressive chromatin states (H3K9Me3, H3K27Me3, and H3K4Me3) were identified in the THBS-1 promoter region in the LA1-55n cells, but not the LA1-5s cells. In contrast, the three histone codes associated with an active chromatin state (acetyl H3, acetyl H4, and H3K4Me3) were present in the THBS-1 promoter region in LA1-5s cells, but not the LA1-55n cells, suggesting that an accessible chromatin structure is important for THBS-1 expression. We also show that 5-Aza-dC treatment of LA1-55n cells alters the DNA methylation status and the histone code in the THBS-1 promoter modifies cell morphology, and inhibits their ability to form colonies in soft agar. Our results suggest that epigenetic aberrations contribute to NB phenotype, and that tumorigenic properties can be inhibited by reversing the epigenetic changes with 5-Aza-dC.