Differential susceptibility of fish and rat liver cells to oxidative stress and cytotoxicity upon exposure to prooxidants.
Species differences in the ability to cope with pollutant-mediated oxidative stress can provide insight into the mechanisms behind both the mode of toxicity of a specific chemical as well as the different ways in which an organism may deal with such stressors. In this study, the effects of exposure to model prooxidants on parameters of oxidative stress were investigated in liver cells from both fish (PLHC-1) and rat (H4IIE). The goals of this study were to compare the oxidative stress response of these cell lines and to assess the relative utility of several different measures of oxidative stress as signals preceding cytotoxicity. Cellular response to two model prooxidants, copper and Fenton reagents (ferrous sulfate plus hydrogen peroxide), was assessed by measuring cytotoxicity, lipid peroxidation, total glutathione (GSHT), and percent glutathione disulfide (%GSSG). Additionally, transcriptional activation of an antioxidant response element (ARE) reporter gene was measured using the chloramphenicol acetyltransferase (CAT) assay in response to these chemicals. In general, the fish cells were more sensitive than rat cells to prooxidants, and the assays for lipid peroxidation and ARE reporter gene activation were more sensitive for measuring oxidative stress than GSH or %GSSG. Fish cells were significantly (P < 0.0001) more sensitive to copper sulfate and Fenton reagent induced oxidative stress, as measured through lipid peroxidation and ARE reporter gene transcriptional activation. Copper sulfate and Fenton reagents caused a two-fold increase in %GSSG in both cell lines. Basal levels of GSHT were higher in the HII4E cells than the PLHC-1 cells, and Fenton reagents significantly reduced GSHT in fish cells but showed no effect on the rat cells. Significant differences were also observed in the cytotoxicity of the test chemicals to both cell lines, with the fish cells demonstrating a higher level of cell death. Lipid peroxidation and ARE transcriptional activation appeared to better reflect subsequent cytotoxicity than a change in GSHT or %GSSG. These results suggest that HII4E (rat) cells are more protected from oxidative stress than PLHC-1 (fish) cells. Additional studies are addressing oxidative stress-mediated signal transduction pathways that may play a role in the differential responses of these cells lines.


NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats.
Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg(-1)·day(-1)) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl(4)-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.


IMP3 expression in urothelial carcinomas of the urinary bladder.
Superficial tumors including Ta, Tis, and T1 make up 75% of urothelial carcinomas of the bladder. While the behavior of these superficial urothelial cancers is relatively benign, invasive tumors have a significant mortality rate. However, Ta and T1 tumors might display different biological behavior. There is therefore a great need for biomarkers that can accurately distinguish the behavior of urothelial carcinomas in addition to tumor grade and stage. Our aim was to determine the immunohistochemical expression profile of insulin like growth factor II mRNA binding Protein 3 (IMP3) and its correlation with tumor stage and grade in benign urothelium and bladder urothelial carcinomas. The expression of IMP3 in 91 patients with benign urothelium (20 cases), low grade invasive (17 cases) / noninvasive (20 cases) urothelial carcinoma and high grade invasive (20 cases) / non-invasive (14 cases) urothelial carcinoma was evaluated by immunohistochemistry in this study. IMP3 was not expressed in benign urothelium, low-grade non-invasive urothelial carcinoma and high grade non-invasive urothelial carcinoma. Expression of IMP3 was found in 11.76% of low-grade invasive urothelial carcinomas and 55% of high grade invasive urothelial carcinomas. Statistical analysis including chi2 tests showed that IMP3 expression of invasive urothelial carcinomas was statistically significant (p < 0.000). The detection of IMP3 only in invasive carcinomas although some of them were low grade showed that the expression of IMP3 may be related to aggressive behavior of urothelial carcinomas.


Thiamine treatment of chronic hepatitis B infection.
Chronic hepatitis B is an international health concern that causes cirrhosis, hepatocellular carcinoma, liver failure, and death. Current treatment options are expensive and associated with side effects; however, indirect evidence suggests a relationship between relative thiamine deficiency and chronic hepatitis B infection. The authors present three case studies wherein multiple crossovers of daily thiamine administration were used to evaluate a hypothesized association between thiamine treatment and aminotransferase levels. In each case study, thiamine administration was associated with reduction in aminotransferase levels and the fall of HBV DNA to undetectable levels. Analyses by t test demonstrated a statistically significant reduction in aminotransferase levels in all three cases. The relationship between thiamine administration and chronic hepatitis B infection warrants further study. If proven effective in reducing liver damage or inducing remission of the hepatitis B virus in larger trials, thiamine will offer obvious advantages over the current treatments for chronic viral hepatitis B infection.


Natives with a need for cognitive closure can approve of immigrants' economic effect when they trust pro-immigrant epistemic authorities.
Previous research on the need for cognitive closure (NFC), or the desire for epistemic certainty, has consistently found that it is associated with negative attitudes toward immigrants, among other outgroups, potentially because they represent agents of change and/or due to a general preference for perceived stability and certainty associated with right-wing politics. However, as individuals with this need theoretically prefer stable and certain knowledge, independent of the specific content, it is also possible that these individuals could have positive attitudes toward immigrants when they are provided with a positive source of information to which they can metaphorically "close" upon. In two studies (n = 397), controlling for participants' political orientation, we found that individuals with an NFC were more likely to accept immigrants when their positive effect was endorsed by an epistemic authority (Study 1), but only when they trusted this source (Study 2).


Human papillomavirus genotypes associated with cervical neoplasia in India.
The aim of this study was to determine the prevalence of human papillomavirus (HPV) genotypes in tissue with cervical neoplasias in patients from south and east India. Cross-sectional cervical tissue was obtained from 100 patients from south India and 30 patients from east India who had a biopsy for clinically invasive cervical cancer or cervical intraepithelial neoplasia (CIN) in a tertiary care hospital in India. DNA amplification was done with biotinylated PGMY 09/11 primers, and the line blot assay was used to determine the HPV genotype. HPV DNA was detected in 95% of invasive cancers (113/119) and 91% of CINs (10/11). A single HPV type was found in 100 women (77%), and mixed infections were found in 23 women (18%). HPV 16 (60%) and HPV 18 (14%) were the most frequent types, but 16 other types (26, 31, 33, 35, 42, 45, 51, 52, 53, 56, 58, 61, 62, 64, 81, and 82) were also identified. HPV 16 was present in 63% of patients from south India and in 50% of patients from east India, while HPV 18 was present in 12% and 20%, respectively. There are several high-risk HPV types associated with cervical neoplasias of which types 16 and 18 are the most common.


5-Lipoxygenase expression in Langerhans cells of normal human epidermis.
We studied expression of the 5-lipoxygenase (5-LO) pathway in normal human skin. In situ hybridization revealed a 5-LO mRNA-containing epidermal cell (EC) population that was predominantly located in the midportion of the spinous layer, in outer hair root sheaths, and in the epithelial compartment of sebaceous glands. Examination of skin specimens by immunohistochemistry and of primary ECs by flow cytometry mapped the 5-LO protein exclusively to Langerhans cells (LCs). The LC 5-LO protein was largely found in the nuclear matrix, in nuclear envelopes, and perinuclear regions as indicated by in situ confocal laser scan microscopy. Reverse transcription-PCR and immunoblot analyses of purified primary EC populations further indicated that LCs are major 5-LO expressing cells. Enriched primary LCs were also found to contain 5-LO activating protein (FLAP), leukotriene (LT) C4 synthase, and LTA4 hydrolase. By contrast, 5-LO, FLAP, and LTC4 synthase were undetectable or largely reduced, but LTA4 hydrolase transcripts and protein were identified in ECs depleted of LCs. These data show that naive LCs are major, and possibly the sole, 5-LO pathway expressing cells in the normal human epidermis.


Restructured membrane contacts rewire organelles for human cytomegalovirus infection.
Membrane contact sites (MCSs) link organelles to coordinate cellular functions across space and time. Although viruses remodel organelles for their replication cycles, MCSs remain largely unexplored during infections. Here, we design a targeted proteomics platform for measuring MCS proteins at all organelles simultaneously and define functional virus-driven MCS alterations by the ancient beta-herpesvirus human cytomegalovirus (HCMV). Integration with super-resolution microscopy and comparisons to herpes simplex virus (HSV-1), Influenza A, and beta-coronavirus HCoV-OC43 infections reveals time-sensitive contact regulation that allows switching anti- to pro-viral organelle functions. We uncover a stabilized mitochondria-ER encapsulation structure (MENC). As HCMV infection progresses, MENCs become the predominant mitochondria-ER contact phenotype and sequentially recruit the tethering partners VAP-B and PTPIP51, supporting virus production. However, premature ER-mitochondria tethering activates STING and interferon response, priming cells against infection. At peroxisomes, ACBD5-mediated ER contacts balance peroxisome proliferation versus membrane expansion, with ACBD5 impacting the titers of each virus tested.


"(Not) all (dead) things share the same breath": identification of cell death mechanisms in anticancer therapy.
During the last decades, the knowledge of cell death mechanisms involved in anticancer therapy has grown exponentially. However, in many studies, cell death is still described in an incomplete manner. The frequent use of indirect proliferation assays, unspecific probes, or bulk analyses leads too often to misunderstandings regarding cell death events. There is a trend to focus on molecular or genetic regulations of cell demise without a proper characterization of the phenotype that is the object of this study. Sometimes, cancer researchers can feel overwhelmed or confused when faced with such a corpus of detailed insights, nomenclature rules, and debates about the accuracy of a particular probe or assay. On the basis of the information available, we propose a simple guide to distinguish forms of cell death in experimental settings using cancer cell lines.


Metastatic Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and Treatment.
The treatment landscape for metastatic castration-sensitive prostate cancer (mCSPC) has rapidly evolved over the past 5 years. Although androgen-deprivation therapy (ADT) is still the backbone of treatment, the addition of docetaxel or abiraterone acetate has improved outcomes for patients with mCSPC and become standard of care. With multiple treatment options available for patients with mCSPC, treatment selection to optimize patient outcomes has become increasingly difficult. Here, we review the clinical trials involving ADT plus docetaxel or abiraterone and provide clinicians with guidelines for treatment. Although surgery and/or radiation are standard of care for localized, intermediate- and high-risk prostate cancer, these treatments are not routinely used as part of initial treatment plans for patients with de novo mCSPC. Recent clinical data are challenging that dogma, and we review the literature on the addition of surgery and radiation to systemic therapy for mCSPC. Finally, the standard of care for oligometastatic prostate cancer (a subset of mCSPC with limited metastases) has not been established compared with that for some other cancers. We discuss the recent studies on metastasis-directed therapy for treatment of oligometastatic prostate cancer.


Presence of two distinct regions in the coiled-coil structure of the streptococcal Pep M5 protein: relationship to mammalian coiled-coil proteins and implications to its biological properties.
The complete amino acid sequence of Pep M5, a biologically active 197-residue fragment comprising nearly half of the group A streptococcal M5 protein, has structural features characteristic of an alpha-helical coiled-coil protein. Fourier analyses of the nonpolar residues show strong periodicities based on repeats of 7 residues (7/2 and 7/3). Except for the nonhelical NH2-terminal 12-residue segment, the 7-residue periodicity in the distribution of nonpolar residues extends through the remainder of the Pep M5 molecule, with some discontinuities and irregularities. The molecule contains two distinct regions that differ in the pattern of distribution of the nonpolar and charged residues. The 7-residue pattern "a, b, c, d, e, f, g" in region 13-121 is atypical in that position "a" is predominantly occupied by asparagine, rather than nonpolar residues. On the other hand, the periodicity in region 122-196 is more typical of that found in other coiled-coil proteins, such as the myosin rod region, keratin, desmin, and vimentin, rather than tropomyosin. Although the periodicity in nonpolar residues is not highly regular, the predominance of basic and acidic residues in the inner "e" and "g" positions, respectively, suggests that ionic interactions between chains may contribute significantly to the stability of the coiled-coil. The distribution of charged residues in the outer positions within the two regions of the molecule is also distinct. The NH2-terminal region carries a significantly higher net negative charge than the COOH-terminal region, suggesting that the former region may play an important role in some of the biological functions of the Pep M5 molecule.


Uric acid levels are relevant in patients with stroke treated with thrombolysis.
Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=-0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=-2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage post-thrombolysis. Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis.


Ligilactobacillus Salivarius improve body growth and anti-oxidation capacity of broiler chickens via regulation of the microbiota-gut-brain axis.
Certain strains of probiotic bacteria can secret functional substances namely digestive enzymes and functional peptides to regulate physiological conditions such as digestion and anti-oxidation, which are often incorporated in industrial broiler chick production. However, few studies have detailed the action mechanisms and effects of these bacteria on regulating growth and anti-oxidation levels in broiler chickens. Ligilactobacillus salivarius is a strain of probiotic bacteria used as dietary supplement. In the present study, Ligilactobacillus salivarius was evaluated for its secreted digestive enzymes in vitro. To detailed evaluate the action mechanisms and effects of gastrointestinal tract (GIT) microbiota on alleviating anti-oxidation levels of broiler chickens through the gut-brain axis. Ligilactobacillus salivarius was cultured and supplemented in the food of broilers to evaluate the probiotic effect on growth and anti-oxidation by modulation of gut microbial composition and its functional metabolites using metagenomic and metabolomic assays. Biochemical results showed that Ligilactobacillus salivarius secreted digestive enzymes: protease, lipase, and amylase. Broiler chickens with Ligilactobacillus salivarius supplemented for 42 days, showed increased body weights, a reduced oxidative status, decreased malondialdehyde levels, and improved activities rates of total superoxide dismutase, glutathione peroxidase IIand IV improved. The microbial composition of caecum was more abundant than those broiler without probiotics supplementation, owing 400 of total number (489) of bacterial operational taxonomic units (OTU). The genera of Lactobacillus, Megamonas, Ruminoccoccaceae, Ruminococcus, Alistipes and Helicobacter shared the dominant proportion of Candidatus _Arthromitus compared with the control chickens. These functional bacteria genera assisted in the transportation and digestion of amino acids, carbohydrates, and ions, synthesis of cellular membranes, and anti-oxidation. Uncultured_organism_g_ Anaerosporobacter, Lactobacillus salivarius, uncultured_bacterium_g_ Ruminococcaceae_UCG-014, uncultured_bacterium_g_ Peptococcus were strongly and positively correlated with body growth performance and anti-oxidation. A metabonomic assay suggested that the secreted of gamma-aminobutyric acid and monobactam was metabolized according to the Kyoto Encyclopedia of Genes and Genomes analysis. In conclusion, Ligilactobacillus salivarius optimized microbial composition of the caecum and secreted functional peptides through gut-brain axis to improve the body growth and antioxidation of broiler chicken.


Inverse regulation of protein turnover and amino acid transport in skeletal muscle of hypercatabolic patients.
We have investigated the relationships between the rates of muscle protein synthesis and degradation and of transmembrane transport of selected amino acids in leg skeletal muscle of 19 severely burned patients and 18 normal controls in the postabsorptive state. Patients were studied on the 14 +/- 5 postburn day, and their mean burn size was 66% +/- 18% of total body surface area. Methods were based on the leg arteriovenous balance technique in combination with biopsies of the vastus lateralis muscle and infusions of isotopic tracers of amino acids. Net muscle protein breakdown was greater in the patients because of an 83% increase in the rate of muscle protein degradation. The rate of muscle protein synthesis was also increased in the patients but to a lesser extent than protein degradation, i.e. by 50% with the arteriovenous phenylalanine balance technique and by 49% with the direct tracer incorporation method. The absolute values of inward transport of phenylalanine, leucine, and lysine were not significantly different in the two groups. However, the ability of transport systems to take up amino acids from the bloodstream, as assessed by dividing inward transport by amino acid delivery to leg muscle, were 50-63% lower in the patients. In contrast, outward phenylalanine and lysine transport were 40% and 67% greater in the patients than in the controls, respectively. We conclude the primary alteration in muscle protein metabolism is an acceleration of protein breakdown, and the increase in protein synthesis likely is due to increased intracellular amino acid availability as a result of accelerated breakdown. Transmembrane transport in the outward direction is accelerated, presumably to facilitate the export of amino acids from muscle to other tissues. In contrast, transmembrane transport in the inward direction is impaired relatively to the increased delivery of circulating amino acid to skeletal muscle secondary to accelerated blood flow.


Biological approaches to therapy of pancreatic cancer.
Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials.


Evidence that the aberrant alpha 1-->2fucosyltransferase found in colorectal carcinoma may be encoded by Fuc-TIII (Le) gene.
The accumulation of alpha 1-->2fucosylated antigens such as Le(b) and Y and the presence of aberrant alpha 1-->2 fucosyltransferase(s) (alpha 12FT) which showed new substrate specificities and must be involved in the accumulation of alpha 1-->2fucosylated antigens in colorectal carcinoma has been observed in our previous studies. In this study, we examined the substrate specificities of purified alpha 12FT from Colo201 cells and COS-1 cells transfected with the Fuc-TIII (Le) gene from a patient with colorectal carcinoma. It was demonstrated that activities of not only the Le gene related alpha 1-->3/4-fucosyltransferase but also the aberrant alpha 12FT were present in the purified preparation and in the extract of transfected COS-1 cells on which the Le(b) activity was expressed. These results suggested that the aberrant alpha 12FT was associated with the Le enzyme and that both enzymes could be encoded by the Fuc-TIII gene.


Effect of cyclooxygenase inhibitors and protease inhibitors on phorbol-induced stimulation of oxygen consumption and superoxide production by rat pulmonary macrophages.
Oxygen consumption and superoxide anion production by pulmonary macrophages are both increased by phorbol myristate acetate (PMA) but the two processes have been separated using protease inhibitors and cyclooxygenase inhibitors. Pretreatment with the protease inhibitors (L-1-tosylamido-2-phenylethylchloromethyl ketone (TPCK) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), as well as with the cyclooxygenase inhibitors acetylsalicylic acid (ASA) and ibuprofen (IBU), inhibited the stimulation of superoxide production and oxygen consumption by phorbol myristate acetate. However, whereas the order of potency for inhibition of stimulation of superoxide production was TPCK greater than TLCK greater than IBU greater than ASA, the order of potency for inhibition of stimulation of oxygen consumption was ASA greater than IBU greater than TPCK = TLCK. Although all four agents were effective inhibitors of PMA-stimulated superoxide production and oxygen consumption when added before PMA, in contrast to the cyclooxygenase inhibitors. TPCK was unable to inhibit oxygen consumption by more than 70-80% regardless of the concentration used, although superoxide generation could be inhibited completely. When added after PMA, ASA did not suppress either oxygen consumption or superoxide production and ibuprofen was only one-half as effective as an inhibitor. TPCK and TLCK, when added after PMA, accelerated the return to basal rates of both oxygen consumption and superoxide production. None of the four agents had any effect on basal superoxide production or oxygen consumption at the concentrations used. The data support the interpretation that both prostaglandin biosynthesis and protease activity may be associated with the activation of the superoxide-generating system of pulmonary macrophages. The consumption of molecular oxygen following stimulation of the cells with phorbol myristate acetate is not due solely to the generation of superoxide, however, since each process is inhibited with different potency by the same group of inhibitors. There appears to be a component of oxygen consumption which results from the activation of cyclooxygenase and, unlike superoxide production, cannot be completely inhibited by treatment with protease inhibitors.


An Outbreak of Highly Pathogenic Avian Influenza (H7N7) in Australia and the Potential for Novel Influenza A Viruses to Emerge.
In 2020, several geographically isolated farms in Victoria, Australia, experienced an outbreak of highly pathogenic avian influenza (HPAI) virus H7N7 and low pathogenic avian influenza (LPAI) viruses H5N2 and H7N6. Effective containment and control measures ensured the eradication of these viruses but the event culminated in substantial loss of livestock and significant economic impact. The avian HPAI H7N7 virus generally does not infect humans; however, evidence shows the ocular pathway presents a favourable tissue tropism for human infection. Through antigenic drift, mutations in the H7N7 viral genome may increase virulence and pathogenicity in humans. The Victorian outbreak also detected LPAI H7N6 in emus at a commercial farm. Novel influenza A viruses can emerge by mixing different viral strains in a host susceptible to avian and human influenza strains. Studies show that emus are susceptible to infections from a wide range of influenza viral subtypes, including H5N1 and the pandemic H1N1. The emu's internal organs and tissues express abundant cell surface sialic acid receptors that favour the attachment of avian and human influenza viruses, increasing the potential for internal genetic reassortment and the emergence of novel influenza A viruses. This review summarises the historical context of H7N7 in Australia, considers the potential for increased virulence and pathogenesis through mutations and draws attention to the emu as potentially an unrecognised viral mixing vessel.


The effects of ultrasound-guided adductor canal block versus femoral nerve block on quadriceps strength and fall risk: a blinded, randomized trial of volunteers.
Adductor canal block (ACB) has been suggested as an analgesic alternative to femoral nerve block (FNB) for procedures on the knee, but its effect on quadriceps motor function is unclear. We performed a randomized, blinded study to compare quadriceps strength following adductor canal versus FNB in volunteers. Our hypothesis was that quadriceps strength would be preserved following ACB, but not FNB. Secondary outcomes included relative preservation of hip adduction and degree of balance impairment. The ACB was performed in one leg and the FNB in the contralateral leg in 16 volunteers using a randomized block sequence. For all blocks, 15 mL of 3% chloroprocaine was injected under ultrasonographic guidance. Maximal voluntary isometric contraction of knee extension and hip adduction was measured at baseline and at 30 and 60 minutes after block. After 60-minute assessments were complete, the second block was placed. A test of balance (Berg Balance Scale) was performed 30 minutes after the first block only. Quadriceps strength and balance scores were similar to baseline following ACB. Following FNB, there was a significant reduction in quadriceps strength (95.1% ± 17.1% vs 11.1% ± 14.0%; P < 0.0001) and balance scores (56 ± 0 vs 37 ± 17.2; P = 0.02) compared with baseline. There was no difference in hip adductor strength (97.0% ± 10.8% vs 91.8% ± 9.6%; P = 0.17). Compared with FNB, ACB results in significant quadriceps motor sparing and significantly preserved balance.


Complex rectification of Müller cell Kir currents.
Although Kir4.1 channels are the major inwardly rectifying channels in glial cells and are widely accepted to support K+- and glutamate-uptake in the nervous system, the properties of Kir4.1 channels during vital changes of K+ and polyamines remain poorly understood. Therefore, the present study examined the voltage-dependence of K+ conductance with varying physiological and pathophysiological external [K+] and intrapipette spermine ([SP]) concentrations in Müller glial cells and in tsA201 cells expressing recombinant Kir4.1 channels. Two different types of [SP] block were characterized: "fast" and "slow." Fast block was steeply voltage-dependent, with only a low sensitivity to spermine and strong dependence on extracellular potassium concentration, [K+]o. Slow block had a strong voltage sensitivity that begins closer to resting membrane potential and was essentially [K+]o-independent, but with a higher spermine- and [K+]i-sensitivity. Using a modified Woodhull model and fitting i/V curves from whole cell recordings, we have calculated free [SP](in) in Müller glial cells as 0.81 +/- 0.24 mM. This is much higher than has been estimated previously in neurons. Biphasic block properties underlie a significantly varying extent of rectification with [K+] and [SP]. While confirming similar properties of glial Kir and recombinant Kir4.1, the results also suggest mechanisms underlying K+ buffering in glial cells: When [K+]o is rapidly increased, as would occur during neuronal excitation, "fast block" would be relieved, promoting potassium influx to glial cells. Increase in [K+]in would then lead to relief of "slow block," further promoting K+-influx.


Acupuncture stimulation of ST36 (Zusanli) attenuates acute renal but not hepatic injury in lipopolysaccharide-stimulated rats.
We sought to determine the effects of ST36 acupuncture on sepsis-induced kidney and liver injuries. A total of 120 rats were randomized into 10 groups: 1) lipopolysaccharide (LPS), 2) normal saline (N/S), 3) LPS + ST36, 4) ST36, 5) LPS + P-ST36, 6) P-ST36, 7) LPS + Sham, 8) Sham, 9) LPS + P-Sham, and 10) P-Sham groups. Rats in the LPS + ST36, ST36, LPS +Sham, and Sham groups received ST36 (designated as "ST36") or a nonacupoint (designated as "Sham") acupuncture for 30 min followed by LPS or N/S injection. Rats in the LPS + P-ST36, P-ST36, LPS + P-Sham, and P-Sham groups received LPS or N/S injection for 3 h followed by a 30 min of ST36 or a "nonacupoint" acupuncture. Rats were killed at 6 h after LPS injection. LPS caused prominent kidney and liver injuries. The renal and hepatic nitric oxide (NO) concentrations and inducible NO synthase (iNOS) expression were also increased by LPS. ST36 acupuncture pretreatment significantly attenuated the LPS-induced kidney injury and the increases in renal NO concentration and iNOS expression. However, ST36 acupuncture pretreatment did not affect the LPS-induced liver injury and increases in hepatic NO concentration or iNOS expression. Furthermore, ST36 acupuncture performed after LPS did not affect the LPS-induced organ injuries or increases in NO concentration and iNOS expression. ST36 acupuncture pretreatment significantly attenuated sepsis-induced kidney, but not liver, injury in rats, whereas ST36 acupuncture performed after sepsis induction had no protective effects against sepsis-induced organ injuries.


The accumulation of multiple sources of psychosocial disadvantage and their correlation to reported overall health: establishing a threshold.
Psychosocial disadvantage and lower socioeconomic status are associated with increased risk of poor health. The purposes of this study are to identify a threshold at which cumulative psychosocial risk factors become significantly associated with a decrease in health status and to examine whether women are at higher risk than men. Using secondary cross-sectional data, a correlation of self-reported health rating and psychosocial risk factors was conducted. Participant characteristics by number of health-related psychosocial risks were constructed. The accumulation of risk factors had a negative effect on health status at the threshold of two; health status significantly decreased with the addition of each risk factor. Gender significantly moderated the relationship between number of risks and self-reported health status, with women's health decreasing as the number of risks increased. Risk factors in this study are typically part of client assessments and can be used in assisting social workers to identify those most at risk. Those with two or more risk factors are significantly more at risk for poorer health. Moreover, women and ethnic minorities were at more risk for poor health with the addition ofjust one risk factor.


Pseudo-random mating systems for 3-allele loci.
A random mating population attains equilibrium by the Hardy-Weinberg law. By demonstrating some simple examples for 2-allele loci, Li (1988) showed that a nonrandom mating population of certain mating patterns may also attain equilibrium. He called such a type of population a pseudo-random mating population. Tai (1990), then, gave a generalized representation of these pseudo-random mating systems. In this paper the clear patterns of pseudo-random mating behavior for a 3-allele locus are derived. Both autosomal and sex-linked systems are discussed. The study of these mating patterns provides a way to understand the complicated mating system of a population, which usually is only with difficulty realized through sampled individuals from that population.


[Chronic prostatitis and chronic pelvic pain syndrome].
Acute prostatitis is infrequent and is manifested as a severe systemic infection requiring hospitalization. Some of these cases may result in a chronic infection requiring long-term antibiotic courses. However, chronic non-bacterial prostatitis is much more frequent, and as such, it it is frequently underdiagnosed and maltreated. The symptoms are variant and include pain and discomfort in the pelvic area, perineum, scrotum, penis and pelvis, and are named "Chronic pelvic pain syndrome (CPPS)". Antibiotics prescribed are of temporary relief in some of the cases as the disease does not really fit the criteria of an infectious disease. This review deals with these difficulties and describes new and other methods to fight this frustrating syndrome for both patients and urologists.


Opportunities and challenges in antimicrobial resistance behavior change communication.
Antimicrobial Resistance (AMR) is already affecting human and animal health sectors negatively. The UN General Assembly has listed AMR among issues that need urgent address; subsequently FAO/OIE/WHO tripartite took lead and jointly developed Global Action Plan (GAP) to tackle the problem. States and Governments have developed AMR National Action Plans (NAP), Policies and Communication Strategies. In health communication realms AMR is a distinctive and novel phenomenon. Consequently, communication theories and principles on this issue have not been tested adequately; even as literature around AMR is growing. While there are lessons that can be learned from previous and ongoing health communication campaigns targeting various audiences and coined around behavior change strategies; AMR is certainly a unique and maiden case. Kenya developed and is implementing its AMR - NAP. Kenya is among few countries that have developed and implemented an AMR Communication Strategy with the goal to create awareness and subsequently change audience behavior. This paper presents a review of available literature, reports, Kenya experiences and theories that can be applied to AMR communications. It illustrates the gaps, opportunities and challenges and proposes strategies that can be applied at the moment as more literature on AMR communication is collected through research and documentation of country experiences.


Chemotherapy for teratoma with malignant transformation.
Teratoma with malignant transformation (MT) is a well-described entity that refers to the MT of a somatic teratomatous component in a germ cell tumor (GCT) to a histology that is identical to a somatic malignancy (eg, rhabdomyosarcoma [RMS]). Surgical resection has been the mainstay of therapy for localized transformed disease because these tumors are thought to be resistant to standard treatment. We report that chemotherapy has a role in selected patients with MT, determined by cell type. Chemotherapy was administered to 12 patients with MT of GCT limited to a single cell type (two patients with primitive neuroectodermal tumors, five with undifferentiated RMS, one with anaplastic small-cell tumor, two with adenocarcinoma, and two with leukemia); 10 patients had measurable disease. GCT origin was confirmed by molecular cytogenetics in five patients. Each patient received chemotherapy regimens based on the specific malignant cell observed in the transformed histology. Seven patients with measurable disease achieved a partial response, with the duration of response ranging between 1 month and 7 years. Three of those patients are alive. Three patients did not respond to treatment, and all of those patients died as a result of their disease. Chemotherapy for MT limited to a single cell type may result in major responses and long-term survival in selected patients. Local therapy after chemotherapy is an important component of treatment to achieve maximum response.


Word search performance for diagnoses of equine surgical colics in free-text electronic patient records.
The objectives of the current project were to: (1) identify limitations of search sensitivity and positive predictive value (PPV) for free-text surgical diagnoses included in electronic patient records maintained at the University of California, Davis, Veterinary Medical Teaching Hospital (VMTH), (2) develop procedural or programmable recommendations for removing these limitations, and (3) provide guidelines for effective search strategies for users performing aggregate searches using the VMTH clinical information system. Search sensitivity corresponds to detection sensitivity (the capacity of a search term to 'identify' a relevant document) and search PPV indicates the proportion of retrieved documents that are relevant. All horses submitted to the VMTH for a gastrointestinal (GI) disorder requiring surgical intervention in 1995 were identified using procedure codes for billing purposes and stored in the electronic patient record. Patient records and surgical reports were reviewed for causes of GI disorders, and variation in naming of these disorders. Key word searches were performed for four GI disorders, and search performance was evaluated by estimating search sensitivity and PPV. Search sensitivity ranged from 33% to 98%, and PPV ranged from 2% to 74%. The procedural recommendation that would likely have the greatest influence on minimizing these search limitations would be more uniform naming of GI disorders. This would free searchers from having to anticipate all of the exact word combinations that could be used in the relevant documents, and also minimize retrieval of irrelevant documents.


The changing demand for health services: a historical perspective and some thoughts for the future.
Among the many factors contributing to the rise in health care costs, recent attention has concentrated on the supply side. Demand factors have generally been neglected or misunderstood. Developments discussed in this paper include: growing public skepticism toward new therapies and drugs; increasing emphasis on patient autonomy and other indications of willingness by the public to assume greater responsibility for its own health; changing relations between income, education, and health care use; the aging of the population and the concomitant rise in chronic conditions; the recent reversal of the former quest for greater equity in health care; and the shrinking American family. Despite the complexity and contradictions within these developments, I perceive a leveling off of demand, especially for acute hospital care, even apart from external financial constraints, accompanied by a rising demand for preventive services and primary and long-term care. It is time to recognize the policy implications of these developments and begin to reorganize our health care system accordingly. But is it too late? Have we the will to do so?


Underestimation of visual texture slant by human observers: a model.
The perspective image of an obliquely inclined textured surface exhibits shape and density distortions of texture elements which allow a human observer to estimate the inclination angle of the surface. However, it has been known since the work of Gibson (1950) that, in the absence of other cues, humans tend to underestimate the slant angle of the surface, particularly when the texture is perceived as being "irregular." The perspective distortions which affect texture elements also shift the projected spatial frequencies of the texture in systematic ways. Using a suitable local spectral filter to measure these frequency gradients, the inclination angle of the surface may be estimated. A computational model has been developed which performs this task using distributions of outputs from filters found to be a good description of simple-cell receptive fields. However, for "irregular" textures the filter output distributions are more like those of "regular" textures at shallower angles of slant, leading the computational algorithm to underestimate the slant angle. This behavioral similarity between human and algorithm suggests the possibility that a similar visual computation is performed in cortex.


Hereditary proximal spinal and bulbar motor neuron disease of late onset. A report of six cases.
Six cases of a comparatively rare motor neuron disease are described. Essential features of this syndrome include (1) X-linked inheritance; (2) adult onset in the fourth to fifth decades; (3) slow progression; (4) predominant proximal and bulbar muscle involvement; and (5) absence of sensory or pyramidal tract signs. The previously reported finding of gynecomastia was absent, whereas longitudinal midline furrowing of the tongue was present in only one case. Electromyography in five patients revealed neurogenic changes. Muscle biopsies in two patients showed fiber type grouping with type I fiber predominance. The coexistence of this form of motor neuron disease and diabetes mellitus is prominent in family 2. It is important to recognize that these patients have a chronic, slowly progressive illness. The prognosis for longevity is good, although severe disability is inevitable. Management includes reassurance, supportive therapy, genetic counseling, and periodic testing for diabetes.


Nitroglycerin protects the endothelium from ischaemia and reperfusion: human mechanistic insight.
Nitroglycerin (GTN) modulates tissue damage induced by ischaemia and reperfusion (IR) in a mechanism that is similar to ischaemic preconditioning. We set out to study, using a human model of endothelial IR injury, whether GTN-induced endothelial preconditioning is mediated by reactive oxygen species (ROS) formation and/or opening of mitochondrial permeability transition pores (mPTP). In two double-blind, randomized, parallel studies, a total of 66 volunteers underwent measurement of radial artery endothelium-dependent, flow-mediated dilation (FMD) before and after local IR. Subjects were treated, 24 h before IR, with different drugs in order to test the mechanism of GTN-induced endothelial protection. Transdermal GTN (0.6 mg h(-1) for 2 h, administered 24 h before IR) significantly reduced the impairment of FMD caused by IR (placebo group: FMD after IR, 1.3 +/- 0.8%; GTN group: FMD after IR, 5.3 +/- 0.9%, P < 0.01 compared with placebo). This protective effect was lost when vitamin C (2 g i.v. at the time of GTN administration) or ciclosporin (an inhibitor of mPTP, 100 mg 2 h prior to GTN administration) were coadministered (FMD after IR: vit C + GTN group, 2.1 +/- 1.0%; ciclosporin + GTN group, 1.7 +/- 0.8%; both P < 0.05 compared with GTN alone). We demonstrate that GTN protects the endothelium against IR-induced endothelial dysfunction, in an effect similar to delayed ischaemic preconditioning. Using a human model, we provide evidence supporting the concept that this protective effect is mediated by ROS release and mPTP opening upon GTN administration.


Parenting Stress of Parents of Adolescents with Attention-Deficit Hyperactivity Disorder.
This study examined parenting stress among parents of adolescents with Attention-Deficit Hyperactivity Disorder (ADHD). The sample comprised 138 adolescents (84 ADHD, 52 boys, 32 girls; 54 non-ADHD, 24 boys, 30 girls) age 13 to 18 and their parents. Mothers (n = 135) and fathers (n = 98) of participating teens completed the Stress Index for Parents of Adolescents. Mothers and fathers of adolescents with ADHD reported more stress than parents of adolescents without ADHD with regard to their children's challenging behaviors (Adolescent domain stress). Mothers of adolescents with ADHD also reported that they experienced elevated levels of stress in terms of role restrictions, feelings of social alienation, conflict with their partner, feelings of guilt and incompetence (Parent domain stress), and relationship with their children (Adolescent-Parent Relationship domain stress; APR). The extent to which clinical levels of adolescent Oppositional Defiant Disorder (ODD) symptoms or externalizing behavior in general were associated with parenting stress depended on the rater of these behaviors. Parenting stress was associated with higher levels of ODD and other externalizing behaviors when these behaviors were rated by parents but not when they were rated by teachers. In addition, over and above adolescent ADHD classification, mothers' self-reported ADHD symptoms were associated with higher parenting stress in the Adolescent and Parent domains, and fathers' self-reported ADHD symptoms were associated with lower APR stress. The results suggest directions that should be considered for addressing parenting stress when designing interventions for families of adolescents with ADHD.


Polymer-induced inverse-temperature crystallization of nanoparticles on a substrate.
Using molecular dynamics simulations, we study the properties of liquid state polymer-nanoparticle composites confined between two parallel substrates, with an attractive polymer-substrate interaction. Polymers are in the semidilute regime at concentrations far above the overlap point, and nanoparticles are in good solvent and without enthalpic attraction to the substrates. An increase of temperature then triggers the crystallization of nanoparticles on one of the two substrate surfaces-a surprising phenomenon, which is explained in terms of scaling theory, such as through competing effects of adsorption-and correlation blobs. Moreover, we show that the first, closely packed layer of nanoparticles on the substrate increases the depletion attraction of additional nanoparticles from the bulk, thereby enhancing and stabilizing the formation of a crystalline phase on the substrate. Within the time frame accessible to our numerical simulations, the crystallization of nanoparticles was irreversible; that is, their crystalline phase, once created, remained undamaged after a decrease of the temperature. Our study leads to a class of thermoreactive nanomaterials, in which the transition between a homogeneous state with dissolved nanoparticles and a surface-crystallized state is triggered by a temperature jump.


Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury.
Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect, however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated silent information regulator 1 (SIRT1) and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.


Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes.
The inhibitory effect of chloramphenicol on human cytochrome P450 (CYP) isoforms was evaluated with human liver microsomes and cDNA-expressed CYPs. Chloramphenicol had a potent inhibitory effect on CYP2C19-catalyzed S-mephytoin 4'-hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation, with apparent 50% inhibitory concentrations (inhibitory constant [K(i)] values are shown in parentheses) of 32.0 (7.7) and 48.1 (10.6) microM, respectively. Chloramphenicol also weakly inhibited CYP2D6, with an apparent 50% inhibitory concentration (K(i)) of 375.9 (75.8) microM. The mechanism of the drug interaction reported between chloramphenicol and phenytoin, which results in the elevation of plasma phenytoin concentrations, is clinically assumed to result from the inhibition of CYP2C9 by chloramphenicol. However, using human liver microsomes and cDNA-expressed CYPs, we showed this interaction arises from the inhibition of CYP2C19- not CYP2C9-catalyzed phenytoin metabolism. In conclusion, inhibition of CYP2C19 and CYP3A4 is the probable mechanism by which chloramphenicol decreases the clearance of coadministered drugs, which manifests as a drug interaction with chloramphenicol.


explAIner: A Visual Analytics Framework for Interactive and Explainable Machine Learning.
We propose a framework for interactive and explainable machine learning that enables users to (1) understand machine learning models; (2) diagnose model limitations using different explainable AI methods; as well as (3) refine and optimize the models. Our framework combines an iterative XAI pipeline with eight global monitoring and steering mechanisms, including quality monitoring, provenance tracking, model comparison, and trust building. To operationalize the framework, we present explAIner, a visual analytics system for interactive and explainable machine learning that instantiates all phases of the suggested pipeline within the commonly used TensorBoard environment. We performed a user-study with nine participants across different expertise levels to examine their perception of our workflow and to collect suggestions to fill the gap between our system and framework. The evaluation confirms that our tightly integrated system leads to an informed machine learning process while disclosing opportunities for further extensions.


Inhibition of the Chromatin Remodeling Factor NURF Rescued Sterility by a Clinic Variant of NuRD.
The nucleosome remodeling and deacetylase (NuRD) complex is essential for gene expression and cell fate determination, and missense mutations of NuRD caused neurodevelopmental diseases. However, the molecular pathogenesis of clinic NuRD variants is unknown. Here, we introduced a clinic CHD3(L915F) variant into C. elegans homolog LET-418, impairing germline and vulva development and ultimately causing animal sterility. Our ATAC-seq and RNA-seq analyses revealed that this variant generated an abnormal open chromatin structure and disrupted the expression of developmental genes. Through genetic suppressor screens, we uncovered that intragenic mutations, likely renovating NuRD activity, restored animal viability. We also found that intergenic mutations in nucleosome remodeling factor NURF that counteracts NuRD rescued abnormal chromatin structure, gene expression, and animal sterility. We propose that two antagonistic chromatin-remodeling factors coordinate to establish the proper chromatin status and transcriptome and that inhibiting NURF may provide insights for treatment of NuRD mutation-related diseases.


Biological basis for the surgical treatment of depression.
An estimated 20% of patients with major depression are refractory to existing therapies. The purpose of this review is to provide a theoretical and neuroscientific framework in which to interpret new work in the field of surgical treatment for depression. This review focuses on existing clinical and imaging data, current disease models, and results of recent case reports and patient series that together may inform the construction of appropriate clinical trials for the surgical treatment of refractory depression.


Materials tactile logic via innervated soft thermochromic elastomers.
Conventional machines rely on rigid, centralized electronic components to make decisions, which limits complexity and scaling. Here, we show that decision making can be realized on the material-level without relying on semiconductor-based logic. Inspired by the distributed decision making that exists in the arms of an octopus, we present a completely soft, stretchable silicone composite doped with thermochromic pigments and innervated with liquid metal. The ability to deform the liquid metal couples geometric changes to Joule heating, thus enabling tunable thermo-mechanochromic sensing of touch and strain. In more complex circuits, deformation of the metal can redistribute electrical energy to distal portions of the network in a way that converts analog tactile 'inputs' into digital colorimetric 'outputs'. Using the material itself as the active player in the decision making process offers possibilities for creating entirely soft devices that respond locally to environmental interactions or act as embedded sensors for feedback loops.


Functional genomic analyses of Enterobacter, Anopheles and Plasmodium reciprocal interactions that impact vector competence.
Malaria exerts a tremendous socioeconomic impact worldwide despite current control efforts, and novel disease transmission-blocking strategies are urgently needed. The Enterobacter bacterium Esp_Z, which is naturally harboured in the mosquito midgut, can inhibit the development of Plasmodium parasites prior to their invasion of the midgut epithelium through a mechanism that involves oxidative stress. Here, a multifaceted approach is used to study the tripartite interactions between the mosquito, Esp_Z and Plasmodium, towards addressing the feasibility of using sugar-baited exposure of mosquitoes to the Esp_Z bacterium for interruption of malaria transmission. The ability of Esp_Z to colonize Anopheles gambiae midguts harbouring microbiota derived from wild mosquitoes was determined by qPCR. Upon introduction of Esp_Z via nectar feeding, the permissiveness of colonized mosquitoes to Plasmodium falciparum infection was determined, as well as the impact of Esp_Z on mosquito fitness parameters, such as longevity, number of eggs laid and number of larvae hatched. The genome of Esp_Z was sequenced, and transcriptome analyses were performed to identify bacterial genes that are important for colonization of the mosquito midgut, as well as for ROS-production. A gene expression analysis of members of the oxidative defence pathway of Plasmodium berghei was also conducted to assess the parasite's oxidative defence response to Esp_Z exposure. Esp_Z persisted for up to 4 days in the An. gambiae midgut after introduction via nectar feeding, and was able to significantly inhibit Plasmodium sporogonic development. Introduction of this bacterium did not adversely affect mosquito fitness. Candidate genes involved in the selection of a better fit Esp_Z to the mosquito midgut environment and in its ability to condition oxidative status of its surroundings were identified, and parasite expression data indicated that Esp_Z is able to induce a partial and temporary shutdown of the ookinetes antioxidant response. Esp_Z is capable of inhibiting sporogonic development of Plasmodium in the presence of the mosquito's native microbiota without affecting mosquito fitness. Several candidate bacterial genes are likely mediating midgut colonization and ROS production, and inhibition of Plasmodium development appears to involve a shutdown of the parasite's oxidative defence system. A better understanding of the complex reciprocal tripartite interactions can facilitate the development and optimization of an Esp_Z-based malaria control strategy.


Advances in EPG for treatment and research: an illustrative case study.
Electropalatography (EPG), a technique which reveals tongue-palate contact patterns over time, is a highly effective tool for speech research. We report here on recent developments by Articulate Instruments Ltd. These include hardware for Windows-based computers, backwardly compatible (with Reading EPG3) software systems for clinical intervention and laboratory-based analysis for EPG and acoustic data, and an enhanced clinical interface with client and file management tools. We focus here on a single case study of a child aged 10+/-years who had been diagnosed with an intractable speech disorder possibly resulting ultimately from a complete cleft of hard and soft palate. We illustrate how assessment, diagnosis and treatment of the intractable speech disorder are undertaken using this new generation of instrumental phonetic support. We also look forward to future developments in articulatory phonetics that will link EPG with ultrasound for research and clinical communities.


Astrocytes of the brain synthesize interleukin 3-like factors.
Interleukin 3 (IL 3) is produced by T lymphocytes and T cell lines, as well as by a myelomonocytic cell line (WEHI-3), and it activates lymphocytes and mast cells, as well as macrophages. Recently we have demonstrated that astrocytes act as immune accessory cells through the secretion of interleukin 1 and the presentation of antigens to T lymphocytes. Here we show that cultured astrocytes from newborn mice release a 30,000 m.w. factor that induces the expression of 20-alpha-hydroxysteroid dehydrogenase in nu/nu spleen cells and the proliferation of the IL 3-dependent cell line 32DCL. An analogous biological activity was detected in supernatant of cultured rat C6 glioma cells. Production of IL 3-like factors by astrocytes of the central nervous system may be essential for development and maintenance of hemo and lymphopoietic cells within inflammatory brain lesions.


Current Reports on Perinatal Intimate Partner Violence.
The purpose of this study was to review the literature on perinatal intimate partner violence, focusing on recent knowledge to guide mental health professionals on the best approaches to identify and treat women exposed to perinatal intimate partner violence. Risk factors have been broadened from individual victim and perpetrator factors to include relationship, community, and societal factors which interact together. Better information is now available on how to identify, document, and treat women exposed to violence around the time of conception, pregnancy, and the postpartum period. Recent information helps psychiatrists and other mental health professionals assist women exposed to violence related to the perinatal period; however, further research is needed to provide improved evidence for optimal interventions for better patient outcomes.


Effect of stage, comorbidities and treatment on survival among cancer patients with or without mental illness.
BackgroundEarlier research suggests poorer outcome of cancer care among people with severe mental illness (SMI).AimsTo assess the effect of stage at presentation, comorbidities and treatment on differences in survival among cancer patients with and without a history of SMI in Finland.MethodThe total population with a first cancer diagnosis in 1990-2013 was drawn from the Finnish Cancer Registry. Hospital admissions because of SMI and deaths were obtained from administrative registers. We calculated Kaplan-Meier estimates and Cox regression models to examine survival differences.ResultsWe found excess mortality in people with a history of psychotic and substance use disorders. Cancer stage and comorbidity did not explain mortality differences. Controlling for cancer treatment decreased the differences. The mortality gap between patients with psychosis and cancer patients without SMI increased over time.ConclusionsIntegrated medical and psychiatric care is needed to improve outcomes of cancer care among patients with SMI.


Primary and secondary drug screening assays for Friedreich ataxia.
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix for the assembly of iron-sulfur clusters (ISCs), which are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain (ETC). Decreased expression of frataxin or the yeast frataxin orthologue, Yfh1p, is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. Using yeast depleted of Yfh1p, a high-throughput screening (HTS) assay was developed in which mitochondrial function was monitored by reduction of the tetrazolium dye WST-1 in a growth medium with a respiration-only carbon source. Of 101 200 compounds screened, 302 were identified that effectively rescue mitochondrial function. To confirm activities in mammalian cells and begin understanding mechanisms of action, secondary screening assays were developed using murine C2C12 cells and yeast mutants lacking specific complexes of the ETC, respectively. The compounds identified in this study have potential relevance for other neurodegenerative disorders associated with mitochondrial dysfunction, such as Parkinson disease.


An urologic face of chronic lymphocytic leukemia: sequential prostatic and penis localization.
We report a patient with chronic lymphocytic leukemia (CLL) in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed the neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is uncommon in CLL patients. However, it should be considered in CLL patients with urologic symptoms and a long history of the disease.


Infants recruit logic to learn about the social world.
When perceptually available information is scant, we can leverage logical connections among hypotheses to draw reliable conclusions that guide our reasoning and learning. We investigate whether this function of logical reasoning is present in infancy and aid understanding and learning about the social environment. In our task, infants watch reaching actions directed toward a hidden object whose identity is ambiguous between two alternatives and has to be inferred by elimination. Here we show that infants apply a disjunctive inference to identify the hidden object and use this logical conclusion to assess the consistency of the actions with a preference previously demonstrated by the agent and, importantly, also to acquire new knowledge regarding the preferences of the observed actor. These findings suggest that, early in life, preverbal logical reasoning functions as a reliable source of evidence that can support learning by offering a logical route for knowledge acquisition.


Plant sterols the better cholesterol in Alzheimer's disease? A mechanistical study.
Amyloid-β (Aβ), major constituent of senile plaques in Alzheimer's disease (AD), is generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretase. Several lipids, especially cholesterol, are associated with AD. Phytosterols are naturally occurring cholesterol plant equivalents, recently been shown to cross the blood-brain-barrier accumulating in brain. Here, we investigated the effect of the most nutritional prevalent phytosterols and cholesterol on APP processing. In general, phytosterols are less amyloidogenic than cholesterol. However, only one phytosterol, stigmasterol, reduced Aβ generation by (1) directly decreasing β-secretase activity, (2) reducing expression of all γ-secretase components, (3) reducing cholesterol and presenilin distribution in lipid rafts implicated in amyloidogenic APP cleavage, and by (4) decreasing BACE1 internalization to endosomal compartments, involved in APP β-secretase cleavage. Mice fed with stigmasterol-enriched diets confirmed protective effects in vivo, suggesting that dietary intake of phytosterol blends mainly containing stigmasterol might be beneficial in preventing AD.


Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers.
Oral tyrosine kinase inhibitor (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success. In this report, we aim to quantify the symptomatic benefit, progression-free survival (PFS) and overall survival (OS) when erlotinib is given as second-line treatment in Head and neck cancers. This was a post-hoc retrospective analysis of a randomized study comparing metronomic chemotherapy with cisplatin. A patient who progressed on chemotherapy and had a PS0-2 were offered second-line chemotherapy. Patients who had received erlotinib (150 mg PO OD) as second line treatment were selected for this analysis. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCAE version 4.02 (NCI,USA) and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death. Twenty-three patients were identified. The median age of these patients at the start of the second line was 47 years (interquartile range 40.5-51.75 years). The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%).The best radiological response documented were a partial response in 04 patients (19.2%). The median estimated PFS and OS were 110 days (95% confidence interval [CI]: 61-175 days) and 156 days (95% CI: 126-185 days) respectively. Erlotinib single agent has promising activity in the second line and needs to be explored in future studies.


Modeling SHANK3-associated autism spectrum disorder in Beagle dogs via CRISPR/Cas9 gene editing.
Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.


T helper 17 cells and related cytokines after allergen inhalation challenge in allergic asthmatics.
T helper (Th)17 cells may play a role in allergic asthma. This study assessed the effect of allergen inhalation challenge on circulating Th17 cells and related cytokines in allergic asthmatics. Peripheral blood mononuclear cells were collected from 16 atopic asthmatics before and 24 h after allergen challenge, as well as from 10 atopic nonasthmatics and 10 normal controls. Cells were stained for Th17 cytokines and their receptors (IL-17A, IL-17F, IL-21, IL-22, IL-17R, and IL-23R) using flow cytometry. Cytokine concentrations from cell culture supernatants were quantified using a multiplex assay for IL-17A, IL-17F, IL-21, IL-22, and IL-23. At baseline, asthmatics had a higher percentage of circulating Th17 cells (1.2 ± 0.5%) compared to normal controls (0.9 ± 0.66%, p < 0.001) but not compared to atopic nonasthmatics (1.13 ± 0.5%). There was a significant increase in Th17 cells in asthmatics after allergen challenge to 1.55 ± 0.4% (p < 0.05) and a trend toward significance in IL-17R expression from 3.4 ± 4.3 to 6.86 ± 6.84% after allergen challenge (p = 0.06). There was also a significant reduction in IL-21-positive cells following allergen challenge from 3.46 ± 1.85 to 2.33 ± 1.37% (p < 0.001). There were no significant differences in IL-17F, IL-22 and IL-23R expression. The concentration of IL-17A in culture supernatant was significantly higher in asthmatics compared to normal controls and IL-17A significantly increased 24 h after allergen challenge. The increase of Th17 cells and IL-17A in atopic asthma after allergen inhalation challenge suggests a possible role for Th17 in allergen-induced airway responses.


[Endometrial survey during phytoestrogens therapy in postmenopausal women].
The aim of this study was to verify the effects on endometrium of short-term phytoestrogens therapy in postmenopausal women. This randomized study compared two groups of 50 patients undergone respectively to phytoestrogens therapy or placebo. An endometrial survey was performed on the study groups by ultrasound and hysteroscopy at baseline and at 6 and 12 months. The ultrasonographic findings and the hysteroscopic biopsies in the 47 women submitted to phytoestrogens therapy that completed the follow-up showed an atrophic and/or inactive endometrial mucosa less than in one patients (2.1%) with endometrial thickness and proliferative endometrium bioptical sample after 12 months of treatment; no cases of endometrial hyperplasia were found. In the authors' 12 month experience, phytoestrogens therapy in postmenopausal women was safe for endometrial stimulation because did not cause any significant alteration of the mucosa in a short-term administration.


Betaine and L-carnitine transport by Listeria monocytogenes Scott A in response to osmotic signals.
The naturally occurring compatible solutes betaine and L-carnitine allow the food-borne pathogen Listeria monocytogenes to adjust to environments of high osmotic strength. Previously, it was demonstrated that L. monocytogenes possesses an ATP-dependent L-carnitine transporter (A. Verheul, F. M. Rombouts, R. R. Beumer, and T. Abee, J. Bacteriol. 177:3205-3212, 1995). The present study reveals that betaine and L-carnitine are taken up by separate highly specific transport systems and support a secondary transport mechanism for betaine uptake in L. monocytogenes. The initial uptake rates of betaine and L-carnitine are not influenced by an osmotic upshock, but the duration of transport of both osmolytes is directly related to the osmotic strength of the medium. Regulation of uptake of both betaine and L-carnitine is subject to inhibition by preaccumulated solute. Internal betaine inhibits not only transport of external betaine but also that of L-carnitine and, similarly, internal L-carnitine inhibits transport of both betaine and L-carnitine. The inhibition is alleviated upon osmotic upshock, which suggests that alterations in membrane structure are transmitted to the allosteric binding sites for betaine and L-carnitine of both transporters at the inner surface of the membrane. Upon osmotic downshock, betaine and L-carnitine are rapidly released by L. monocytogenes as a consequence of activation of a channel-like activity. The osmolyte-sensing mechanism described is new and is consistent with various unexplained observations of osmoregulation in other bacteria.


Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways.
Altered cardiac gene expression in heart failure (HF) has mostly been identified by single-point analysis of end-stage disease. This may miss earlier changes in gene expression that are transient and/or directionally opposite to those observed later. Myocardial datasets from the largest microarray data repository (Gene Expression Omnibus) yielded six HF studies with time-course data. Differentially expressed transcripts between nonfailing controls, early HF (<3 days after cardiac insult) and late HF (usually >2 wk) were determined, and analysis of KEGG pathways and predicted regulatory control elements performed. We found that gene expression followed varying patterns: Downregulation of metabolic pathways occurred early and was sustained into late-stage HF. In contrast, most signaling pathways undergo a complex biphasic pattern: Calcium signaling, p53, apoptosis, and MAPK pathways displayed a bidirectional response, declining early but rising late. These profiles were compatible with specific microRNA (miRNA) and transcription regulators: Estrogen-related receptor-α and myocyte-enhancer factor-2 binding sites were overrepresented in the promoter regions of downregulated transcripts. Concurrently, there were overrepresented binding sites for E2f and ETS family members (E-Twenty Six, including Gabp, Elf1, and Ets2), serum response and interferon regulated factor in biphasic-bidirectional and late-upregulated transcripts. Binding sites for miRNAs downregulated by HF were more common in upregulated transcripts (e.g., miRNA-22,-133a/b, and -150 in early HF and miRNA-1,-9,-499 in late HF). During the development of HF, gene expression is characterized by dynamic overlapping sets of transcripts controlled by specific interrelated regulatory mechanisms. While metabolic gene classes show early and sustained downregulation in HF, signaling pathways undergo a complex biphasic pattern with early down- and more pronounced late upregulation.


Interobserver and intraobserver reliability and validity of the Vancouver classification system of periprosthetic femoral fractures after hip arthroplasty.
The Vancouver classification system of periprosthetic fractures has been revalidated in this study, using the radiographs of 45 patients. Three consultants and 3 trainees reviewed the radiographs independently, on 2 separate occasions, at least 2 weeks apart. Interobserver and intraobserver agreement and validity were analyzed, using weighted κ statistics. The mean κ value for interobserver agreement was found to be 0.69 (0.63-0.72) for consultants and 0.61 (0.56-0.65) for the trainees, both representing substantial agreement. Intraobserver κ values ranged from 0.74 to 0.90, showing substantial agreement. Validity analysis of 37 type B cases revealed 81% agreement within B1, B2, and B3 subgroups with a κ value of 0.68 (substantial agreement). This study has reconfirmed the reliability and validity of the Vancouver classification while it also emphasizes the intraoperative assessment of implant stability.


The effects of x-axis vertebral translation on projected y-axis vertebral rotation.
Few studies have quantified the projection/distortion errors that occur in anteroposterior (AP) radiographs. To quantify the projection/distortion errors on AP radiographs caused by lateral translation of the vertebrae. To demonstrate the effect of vertebral shape on projection errors. Three models of increasing complexity were constructed to document the distortion. Model 1 consisted of three metal pins embedded in a piece of metal tubing that was X-rayed in three positions. Model 2, a simple model of the X-ray beam mounted on a wooden platform, allowed for translation of a vertebral model in a simulated X-ray beam and the measurement of projected points of contact between the model and rays of the simulated beam. Model 3 is a computer simulation of the X-ray beam in which a vertebral model was translated laterally to varying locations. The projected points of contact between the simulated rays and the vertebral body margins and lamina junction were measured. Model 3 also showed that vertebral body shape has a large effect on the projected axial rotation. Two other simple models were created and discussed in relation to shape-dependent projection errors. X-axis translation results in projected y-axis rotation. Increasing magnitudes of x-axis vertebral translation results in increasing magnitudes of projected y-axis vertebral rotation. The projected rotation is also influenced by vertebral shape. We have shown that three-dimensional lateral translation projects as axial rotation on the AP radiograph. Projection error is largely influenced by the shape of the object and by the increasing obliquity of the rays of the X-ray beam. This would seemingly create confusion and invalidate spinal listings of vertebral position obtained from the AP radiographic image.


Development and Initial Assessment of [18F]OP-801: a Novel Hydroxyl Dendrimer PET Tracer for Preclinical Imaging of Innate Immune Activation in the Whole Body and Brain.
Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [18F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. OP-801 was radiolabeled in two steps: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150-250 μCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n=14) or saline (n=6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. [18F]OP-801 was produced with >95% radiochemical purity, 12-52 μCi/μg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples (n=4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p=0.009), lung (p=0.030), and spleen (p=0.004). Brain PET/CT images (summed 50-60 min) revealed linearly increasing [18F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score (r=0.85, p<0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p<0.05). [18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation.


[Effect of 8-Br-ATP and 8-Oxy-ATP on RNA synthesis by RNA polymerase from Escherichia coli].
The effect of 8-Br-ATP and 8-oxy-ATP on RNA synthesis on calf thymus DNA and on abortive synthesis of di- and trinucleotides on promoter AI of phage T7 delta DIII DNA in the case of an incomplete set of substrates was studied. It was shown that the ATP analogs used inhibit the RNA and di- and trinucleotide synthesis. In all cases, 8-oxy-ATP was a more effective inhibitor than 8-Br-ATP. Both analogs are incapable of being the primer and they do not replace ATP in the course of abortive initiation of pppApU synthesis.


Synthesis, conformation and enzymatic properties of 1-(beta-D-allofuranosyl)uracil and some derivatives.
A new route for the synthesis of 1-(beta-D-allofuranosyl)uracil ("allo-uridine") and the corresponding 6'-deoxy-derivative ("6'-deoxy-allo-uridine") as well as for 1-(beta-D-altrofuranosyl) uracil ("altro-uridine") is described. NMR studies of allo-uridine revealed a preferred conformation with the base in anti-position, C-2'-endo-pucker of the sugar moiety, the 5'-OH-group above the furanose ring and the 5'-CH2OH-group in a gt position with the OH-group in the plane of the furanose ring. The same conformation is found for the 5'- and 6'-phosphate, indicated by the influence of the phosphate group on the H-6 signal. Allo-uridine is phosphorylated by the phosphotransferases from carrot and from malt sprouts only in the 6'-position. The phosphate ester is hydrolysed by unspecific phosphatases but not by 5'-nucleotidase. A (3' leads to 6')-dinucleoside phosphate is formed by pancreatic ribonuclease with 2',3'-cyclic cytidylic acid and allo-uridine. It is split by nuclease S1, but not by snake-venom phosphodiesterase. It has no primer activity for polynucleotide phosphorylase. All-uridine 6'-diphosphate could not be prepared enzymatically by nucleotide kinase or by chemical methods, where 5',6'-cyclic phosphates are formed, which are hydrolysed exclusively to 6'-monophosphates.


Introduction of a rapid response system at a United States veterans affairs hospital reduced cardiac arrests.
We sought to determine the impact of a rapid response system on cardiac arrest rates and mortality in a United States veteran population. We describe a prospective analysis of cardiac arrests in 9 months before and 27 months after institution of a rapid response system, and retrospective analysis of mortality 3.5 years before the intervention and 27 months after the intervention. The study included all inpatients from a university-affiliated United States Veterans Affairs Medical Center, before and after implementation of a rapid response system, including an educational program, patient calling criteria, and a physician-led medical emergency team. Primary end points were hospital-wide cardiac arrests and mortality rates normalized to hospital discharges. Comparisons of event rates between various time points during the implementation process were made by analysis of variance. Three hundred seventy-eight calls were made to the medical emergency team in the time period studied. Compared with preintervention time points, cardiac arrests were reduced by 57%, amounting to a reduction of 5.6 cardiac arrests per 1000 hospital discharges (P < 0.01). Mortality was reduced during the intervention, but this was attributable to a natural decrease occurring over all phases of the study. A significant reduction in the rate of cardiac arrests was realized with this intervention, as well as a trend toward lower mortality. We estimate that 51 arrests were prevented in the timeframe studied. Our results suggest that further reductions in morbidity can be realized by expansion of rapid response systems throughout the Veterans Affairs network.


Interaction of sulfonylureas and exercise on glucose homeostasis in type 2 diabetic patients.
To determine whether the plasma glucose-lowering effects of sulfonylureas and acute submaximal exercise are additive and, accordingly, to determine whether they may increase the risk of hypoglycemia when combined in fasting patients. Eight postabsorptive type 2 diabetic patients were examined at three occasions: after oral sulfonylurea (7 mg glibenclamide), during 60 min of ergometer cycle exercise at 57 +/- 3% of VO2max, and during exercise after glibenclamide. Heart rate, VO2, and lactate responses to exercise were comparable (P > 0.05) on days with and without glibenclamide. Plasma insulin concentrations were always increased by glibenclamide, and they were lowered identically by exercise with and without glibenclamide. However, throughout exercise, absolute concentrations of insulin were lower on days without glibenclamide compared with days with glibenclamide (34.5 +/- 4.7 vs. 47.4 +/- 5.5 pmol/l; P < 0.05). At the start of exercise, glucose concentrations were similar between experiments (P > 0.05). The rate of decrease in glucose during exercise was higher (P < 0.05) on days with both glibenclamide and exercise, compared with days with glibenclamide alone and days with exercise alone (-0.035 +/- 0.009 vs. -0.016 +/- 0.002 and -0.022 +/- 0.005 mmol.l-1.min-1, respectively). Consequently, the glucose nadir was lower on days with glibenclamide and exercise than on days with glibenclamide or exercise alone (6.7 +/- 1.1 vs. 8.1 +/- 0.9 and 7.6 +/- 1.0 mmol/l, respectively; P < 0.05). During exercise, the rate of appearance of plasma glucose determined by 3-[3H]glucose infusion was lower on days with glibenclamide than on days without glibenclamide (2.3 +/- 0.1 vs. 2.9 +/- 0.1 mg.min-1.kg-1; P < 0.05). In contrast, glucose clearance was identical (P > 0.05). In postabsorptive type 2 diabetic patients, the hypoglycemic action of glibenclamide and exercise is enhanced when the treatments are combined. The interaction reflects an increased inhibition by glibenclamide-enhanced insulin levels of hepatic glucose production when hepatic glucose production is accelerated by exercise.


Development of the ETOC: a European test of olfactory capabilities.
A number of smell tests designed to evaluate human olfactory capabilities have been published, but none have been validated cross-culturally. The aim of this study was therefore to develop a reliable and quick olfactory test that could be used to evaluate efficiently the olfactory abilities of a European population. This test, named ETOC and based on a combination of a supra-threshold detection task and an identification task, was designed to be a cross-cultural tool that would measure the decline in olfactory performance with ageing. Two versions of the ETOC, one easy and one less easy, were used to test the olfactory performance of European citizens in three countries (France, Sweden and the Netherlands). The results indicated that neither version of the ETOC is culture-dependent, and that both give scores that well reflect the decrease in olfactory abilities with increasing age. A retest session showed that the less easy (and final) version of the ETOC is also highly reliable.


Intraoperative and Postoperative Outcomes of Modified Bidirectional Intra-Umbilical Incision versus Infra-Umbilical Incision for Direct Trocar Insertion in Gynaecological Laparoscopy: A randomised controlled trial.
This study aimed to describe a modified, curved, deep, bidirectional, intra-umbilical, vertical incision for primary trocar insertion and prospectively compare its intraoperative and postoperative outcomes with an infra-umbilical incision in gynaecologic laparoscopy. Between August 2019 and March 2021, 110 patients subjected to the direct trocar insertion technique for laparoscopic intervention were classified into two groups. Group A comprised 55 cases of infra-umbilical incision, whereas group B comprised 55 cases of a modified, curved, longitudinal, deep, bidirectional, intra-umbilical incision. Afterwards, intraoperative and postoperative assessments were performed. The increase in the numbers of parity, gravidity and previous caesarean sections was found to be statistically significant; a smaller number of infertility complaints were observed in group B. Similarly, group B expressed a statistically significant less peri-trocar CO2 leakage (46 [83.6%] patients versus 28 [50.9%] patients) and more tightness of the primary portal entry (45 [81.8%] patients versus 30 [54.5%] patients) when compared to group A throughout the whole operation. After a one-month follow-up, a statistically significant (P = 0.029) decrease in the Observer Scar Assessment Scale and Patient Scar Assessment Scale scores in group B (10.4 ± 4.2 and 11.8 ± 4.3, respectively), demonstrating better cosmoses when compared to group A (13.3 ± 5.7 and 16.0 ± 6.8, respectively). Performing a modified, curved, deep, bidirectional, intra-umbilical, vertical incision for the insertion of a primary laparoscopic trocar (i.e. Darwish laparoscopic entry) is a simple and fast step that results in the elimination of intraoperative gas leakage and trocar slippage without the need for any additional sutures. Aesthetically, it results in a better scar with satisfactory cosmoses when compared to an infra-umbilical incision.


Dysfunctional family environments and childhood psychopathology: the role of psychiatric comorbidity.
The study of the association between specific characteristics of family environments and different types of psychopathology may contribute to our understanding of these complex disorders and ultimately inform therapeutics. To compare the family characteristics of four groups: typically developing children; children with anxiety disorders only; children with externalizing disorders only; and children with both anxiety and externalizing disorders. This study enrolled 115 individuals from the community. Child psychiatrists made psychiatric diagnoses using a structured clinical interview. The Family Environment scale was used to evaluate six domains of family function. The group with both anxiety and externalizing disorders had higher levels of conflict in family environment and lower levels of organization when compared with typically developing children. In addition, internalizing and externalizing symptoms were positively associated with conflict and negatively with organization. Maternal depressive and anxious symptoms were also associated with higher conflict and lower organization scores. An important between-group difference in comorbid cases of anxiety and behavioral disorders suggests that children with this comorbidity are potential candidates for family interventions to address family conflicts and organizational aspects.


Sexuality of dissocial persons.
The development of personality disorders as well as sexual disorders is defined by the common time spectrum as well as deficits and changes in such areas as biological, environmental and mental area. Dissocial (antisocial) personality disorder is characterised by a pervasive pattern of disregard for, or violation of, the rights of others. The indices of the discussed disorder can be found in specific patterns of social inadequacy occurring during childhood and puberty. At the same time, characteristic indices of social functioning at a young age often indicate subsequent dysfunctions in the area of sexuality. The aim of this paper is to explain sexual functioning of persons with dissocial personality disorder (including the relation with sexual dysfunctions), and to ascertain issues that need further empirical studies. As a result of analysis of available literature (matched with EBSCO database search fulfilling criteria of sample size, accuracy of examination procedure, conclusions and discussion) 5 articles fulfilling criteria cited above has been found. Based on literature overview, it appeared to be impossible to determine one coherent way of sexual functioning of dissocial persons, and to establish causal relationship of sexual dysfunctions and dissocial personality disorder. However, it is possible to indicate group of most characteristic dysfunctional sexual behaviours. Noteworthy, available publication analyse only selected aspects of sexual behaviours in small, homogenous groups. There is a lack of review studies as well as multi-faceted studies.


[Combined pathogenetic therapy of epilepsy in experiment].
Combined pathogenetic therapy (CPT) of experimental convulsive syndrome (maximal electroshock) included combined action of the drugs on the basic mechanisms of epileptogenesis by means of increase of the inhibitory GABA-ergic processes and inhibition of neuronal Ca-2+2 and Na(-)+ uptake. It was established that combined usage of certain preparations permitted to decrease considerably their doses and to receive either sufficiently high therapeutic index of the combinations or relatively low potentiation of the toxic effects. The most effective combinations of the drugs were determined. They may be recommended for clinical examination. The results obtained by the authors justify CPT usage for suppression of epileptic activity.


A bacteriophage cocktail targeting Escherichia coli reduces E. coli in simulated gut conditions, while preserving a non-targeted representative commensal normal microbiota.
Antibiotics offer an efficient means for managing diseases caused by bacterial pathogens. However, antibiotics are typically broad spectrum and they can indiscriminately kill beneficial microbes in body habitats such as the gut, deleteriously affecting the commensal gut microbiota. In addition, many bacteria have developed or are developing resistance to antibiotics, which complicates treatment and creates significant challenges in clinical medicine. Therefore, there is a real and urgent medical need to develop alternative antimicrobial approaches that will kill specific problem-causing bacteria without disturbing a normal, and often beneficial, gut microbiota. One such potential alternative approach is the use of lytic bacteriophages for managing bacterial infections, including those caused by multidrug-resistant pathogens. In the present study, we comparatively analysed the efficacy of a bacteriophage cocktail targeting Escherichia coli with that of a broad-spectrum antibiotic (ciprofloxacin) using an in vitro model of the small intestine. The parameters examined included (i) the impact on a specific, pre-chosen targeted E. coli strain, and (ii) the impact on a selected non-targeted bacterial population, which was chosen to represent a defined microbial consortium typical of a healthy small intestine. During these studies, we also examined stability of bacteriophages against various pH and bile concentrations commonly found in the intestinal tract of humans. The bacteriophage cocktail was slightly more stable in the simulated duodenum conditions compared to the simulated ileum (0.12 vs. 0.58 log decrease in phage titers, respectively). It was equally effective as ciprofloxacin in reducing E. coli in the simulated gut conditions (2-3 log reduction), but had much milder (none) impact on the commensal, non-targeted bacteria compared to the antibiotic.