Antiproliferative steroidal glycosides from Digitalis ciliata.
Two new compounds, a furostanol glycoside (1) and a pregnane glycoside (4), along with eight known compounds, belonging to the classes of spirostane (2,3), pregnane (5-7) and cardenolide (8-10) glycosides, were isolated from the seeds of Digitalis ciliata. Their structures were elucidated by 1D and 2D-NMR experiments as well as ESI-MS analysis. For the first time pregnane glycosides of the diginigenin series have been isolated from D. ciliata. The cytotoxic effects of compounds 1-10 on cell viability of several cancer cell lines, namely human breast cancer (MCF-7), human glioblastoma (T98G), human lung adenocarcinoma (A549), human colon carcinoma (HT-29), and human prostate cancer (PC-3) cell lines were evaluated. Compounds 1, 4, 7 and 8 showed antiproliferative effects against MCF-7, HT-29 and A549 cancer cells with IC₅₀ values ranging from 8.3 to 20 μM. The effects of compounds 1-10 on cell proliferation were evaluated on these three cancer cell lines by cell cycle analysis of DNA content using flow cytometry. Compounds 7, 8 and 10 induced significant changes in G₂/M cell cycle phase of all analyzed cells. The obtained results indicate that compounds 7, 8 and 10 are cytostatic compounds effective in reducing cell proliferation by inducing accumulation of the cells in the G₂/M phase of the cell cycle.


Chronic heliodermatitis: a morphologic evaluation of chronic actinic dermal damage with emphasis on the role of mast cells.
Descriptions of actinically damaged human dermis have focused on the late stages of elastotic degeneration. This has diverted attention from preceding events, which are important for understanding the sequence of pathologic changes that culminate in the deranged fibrous structures of elastotic dermis. We studied specimens from the back of the necks (exposed) and inner arms (unexposed) of 24 individuals, aged 35-84 yr, by light and transmission electron microscopy. Intense sunlight exposure was common to all. A previously undescribed finding was the presence of a perivenular, histiocytic-lymphocytic infiltrate in which numerous mast cells, often in close apposition to fibroblasts, were observed. We have termed this "chronic heliodermatitis." We postulate that mast cell-derived mediators in conjunction with enzymes released by the infiltrating cells lead to breakdown of elastic and collagen fibers.


Chronic psychosocial stress disturbs long-bone growth in adolescent mice.
Although a strong association between psychiatric and somatic disorders is generally accepted, little is known regarding the interrelationship between mental and skeletal health. Although depressive disorders have been shown to be strongly associated with osteoporosis and increased fracture risk, evidence from post-traumatic stress disorder (PTSD) patients is less consistent. Therefore, the present study investigated the influence of chronic psychosocial stress on bone using a well-established murine model for PTSD. C57BL/6N mice (7 weeks old) were subjected to chronic subordinate colony housing (CSC) for 19 days, whereas control mice were singly housed. Anxiety-related behavior was assessed in the open-field/novel-object test, after which the mice were euthanized to assess endocrine and bone parameters. CSC mice exhibited increased anxiety-related behavior in the open-field/novel-object test, increased adrenal and decreased thymus weights, and unaffected plasma morning corticosterone. Microcomputed tomography and histomorphometrical analyses revealed significantly reduced tibia and femur lengths, increased growth-plate thickness and reduced mineral deposition at the growth plate, suggesting disturbed endochondral ossification during long-bone growth. This was associated with reduced Runx2 expression in hypertrophic chondrocytes in the growth plate. Trabecular thicknesses and bone mineral density were significantly increased in CSC compared to singly housed mice. Tyrosine hydroxylase expression was increased in bone marrow cells located at the growth plates of CSC mice, implying that local adrenergic signaling might be involved in the effects of CSC on the skeletal phenotype. In conclusion, chronic psychosocial stress negatively impacts endochondral ossification in the growth plate, affecting both longitudinal and appositional bone growth in adolescent mice.


Ovarian reserve in reproductive-aged patients with cancer before gonadotoxic treatment: a systematic review and meta-analysis.
Does cancer itself, before any gonadotoxic treatment, affect ovarian function in reproductive-aged patients? Our study revealed that women with cancer may have decreased ovarian reserve markers even before cancer therapy. With the field 'oncofertility' improving rapidly, cancer therapy-mediated ovarian damage is well characterized. However, there is a controversy about whether cancer itself affects ovarian function before gonadotoxic treatment. We conducted a systematic meta-analysis investigating the association between cancer and ovarian function prior to gonadotoxic treatment. Titles or abstracts related to ovarian reserve (e.g. anti-Müllerian hormone (AMH), antral follicle count (AFC), or basal follicle-stimulating hormone (FSH)) combined with titles or abstracts related to the exposure (e.g. cancer*, oncolog*, or malignan*) were searched in PubMed, Embase, and Web of Science databases from inception to 1 February 2022. We included cohort, case-control, and cross-sectional studies in English that examined ovarian reserve in reproductive-aged patients (18-45 years) with cancer compared to age-matched controls before cancer treatment. The quality of the included studies was assessed by ROBINS-I. Fixed or random effects were conducted to estimate standard or weighted mean difference (SMD or WMD, respectively) and CI. Heterogeneity was assessed by the Q test and I2 statistics, and publication bias was evaluated by Egger's and Begg's tests. The review identified 17 eligible studies for inclusion. The results showed that cancer patients had lower serum AMH levels compared to healthy controls (SMD = -0.19, 95% CI = -0.34 to -0.03, P = 0.001), especially women with hematological malignancies (SMD = -0.62, 95% CI = -0.99 to -0.24, P = 0.001). The AFC was also decreased in patients with cancer (WMD = -0.93, 95% CI = -1.79 to -0.07, P = 0.033) compared to controls, while inhibin B and basal FSH levels showed no statistically significant differences. Serum AMH and basal FSH levels in this meta-analysis showed high heterogeneity, and the small number of studies contributing to most subgroup analyses limited the heterogeneity analysis. Moreover, the studies for specific cancer subtypes may be too small to draw conclusions; more studies are needed to investigate the possible impact of cancer type and stage on ovarian function. Our study confirmed the findings that cancer per se, especially hematological malignancies, negatively affects serum AMH level, and AFC values of reproductive-aged women. However, the lower AMH levels and AFC values may also be due to the changes in ovarian physiology under oncological conditions, rather than actual lower ovarian reserves. Based on the meta-analysis, clinicians should raise awareness about the possible need for personalized approaches for young women with cancer who are interested in pursuing fertility preservation strategies before anticancer treatments. This work was financially supported by the National Natural Science Foundation of China (nos 81873824, 82001514, and 81902669) and the Applied Basic Research Program of Wuhan Municipal Bureau of Science and Technology (2019020701011436). The authors declare that they have no conflicts of interest. PROSPERO (CRD42021235954).


ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension.
Non-cirrhotic intrahepatic portal hypertension (NCIPH) is characterized by thrombotic microangiopathy of the portal venous system, low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13), and high vWF (von Willebrand factor) levels. This study aimed to screen for ADAMTS13 mutations, focusing on the CUB domain, in these patients. Prospectively recruited NCIPH patients and healthy volunteers underwent tests for plasma vWF-ADAMTS13 balance. Sanger sequencing of the CUB domain of ADAMTS13 was done in a subset of the NCIPH patients, and the detected mutation was screened for in all the study participants. Next-generation sequencing of clinically relevant exome and liver immunostaining for ADAMTS13 was done in patients with detected ADAMTS13 mutation. Plasma vWF-ADAMTS13 balance was significantly altered in 24 NCIPH patients (Child's class A:23, B:1) as compared to 22 controls. On initial sequencing of the CUB domain (17 cases and 3 controls), one NCIPH patient showed a rare missense variant (SNV) at position c.3829C >T resulting in p.R1277W (rs14045669). Subsequent RFLP analysis targeted to the R1277W variant did not detect this in any other NCIPH patient, nor in any of the 22 controls. The NCIPH patient with the R1277W variant had severe ADAMTS13 deficiency, consistently high vWF, other missense SNVs in ADAMTS13, vWF, and complement genes. Immunostaining of his liver biopsy revealed globules of ADAMTS13 within stellate cells. We report missense variants in ADAMTS13, vWF, and complement genes in a patient with NCIPH who had decreased secretion and activity of ADAMTS13 protein. Further studies are needed in NCIPH patients in this regard.


Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy.
The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials. Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.


Purification and partial characterization of the I variant of placental alkaline phosphatase.
The I variant of placental alkaline phosphatase was purified to homogeneity by means of DEAE-cellulose chromatography, isoelectric focusing, and gel filtration on AcA-34. The specific activity of the I variant was found to be 3.33 micronkat/mg. The enzyme is a dimer with an isoelectric point of 4.6 and a molecular weight of 120,000 as determined by sodium dodecylsulfate electrophoresis. The amino acid composition and other physiocochemical properties of the I variant were compared with those of the more common F and S variants. The low activity associated with the I variant is apparently not due to a low specific activity, but to decreased molecular stability. The behavior in the ultracentrifuge and other observations suggest that the I variant differs from the F and S variants in surface charge distribution.


Sepsis inhibits recycling and glutamate-stimulated export of ascorbate by astrocytes.
Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult.


Genome-Wide Analysis and Expression Profile of Nuclear Factor Y (NF-Y) Gene Family in Z. jujuba.
Nuclear factor-Y (NF-Y) is an important transcription factor in the plant species, which potentially provides a higher level of functional diversity including for abiotic stress tolerance. The genome-wide study and expression analysis of NF-Y gene family in Ziziphus, an elite abiotic stress-tolerant species, assist bioprospecting of genes. Here, a total of 32 NF-Y (8 NF-YA, 15 NF-YB, and 9 NF-YC) genes were identified in genome-wide search of Z. jujuba genome. Physicochemical properties, cellular localization, gene structure, chromosomal location, and protein motifs were analyzed for structural and functional understanding. Identified 12 NF-Ys were responsible for the expansion of NF-Y gene family by tandem duplication in Z. jujuba. Phylogenetic and comparative physical mapping of Z. jujuba NF-Ys with its orthologs illustrated evolutionary and functional insights into NF-Y gene family. A total of 45 perfect microsatellites (20bp to 40bp) were extracted across the ZjNF-Y genes. The promoter and gene ontology study suggested that Z. jujuba NF-Y gene family is functionally diverse and could play a wide-ranging role in plant abiotic stress, development, and cellular processes. An expression study revealed that large numbers of the NF-Ys are differentially expressed in response to drought and salinity. The total 15 and 18 ZjNF-Y genes that are upregulated under drought and salinity stress, respectively, are the potential candidates for further functional analysis for development of climate-resilient crops. The present study established a base for understanding the role of NF-Ys in Z. jujuba under abiotic stress conditions and paved a way for further research.


Impact of hysterectomy on stress urinary incontinence: an identical twin study.
This study uses the unique properties of twin research design to evaluate whether hysterectomy impacts stress urinary incontinence (SUI). As part of the Evanston Twins Sister Study, we performed bivariate and multivariate analyses on 83 identical twin pairs discordant for hysterectomy. In bivariate analysis, SUI was less common in women who had prior hysterectomy (P =0.028). Multivariate analysis suggested that SUI was significantly less common after hysterectomy (odds ratio [OR], 0.55, confidence interval [CI], 0.30 to 1.00). Exclusion of twin pairs with a history of pelvic floor defect surgery eliminated the statistical relationship between hysterectomy and SUI (OR, 0.79, CI, 0.4 to 1.40). Hysterectomy, when analyzed with all cases, was associated with reduced SUI. When concurrent pelvic floor defect surgeries were excluded from the analysis, we found no relationship between hysterectomy and the risk of SUI afterward.


Asymmetries of nature and the origin of biomolecular handedness.
New developments in the problem of the origin of the asymmetry of the living systems are reviewed. The time of the appearance of the asymmetry was very probably during the chemical evolution. The asymmetry of weak interaction is still considered small to be the cause of chiral purity. New sources of asymmetry should also be considered, like the one proposed by Gilat.


Heavy cannabis use among UK teenagers: an exploration.
Findings are presented from a survey of a sample of 2641 UK school students aged 15--16 years. This exercise was part of the 30 country European School Survey Project on Alcohol and other Drugs (ESPAD). The 201 students who reported using cannabis (marihuana) 40 times or more were examined using cluster analysis. They were also compared to other students. Three clusters of heavy cannabis users emerged. The smallest was largely distinguished by antisocial behaviour. Another cluster were clearly unhappy, with little support from parents and friends, high levels of depressed mood and low levels of self-esteem. The largest cluster were 'ordinary' and had little to distinguish them apart from a belief that their environment was stable and predictable and that society's rules should be obeyed. Although clear relationships emerged between heavy cannabis use and heavy use of other substances, the 'ordinary' cluster of heavy cannabis users were less likely than the others to have used other illicit drugs. It is therefore concluded that teenage heavy cannabis users have varied motivations and contexts for their usage. They should not be seen as a homogeneous group and many do not appear to use other illicit drugs.


Domestication of High-Copy Transposons Underlays the Wheat Small RNA Response to an Obligate Pathogen.
Plant genomes have evolved several evolutionary mechanisms to tolerate and make use of transposable elements (TEs). Of these, transposon domestication into cis-regulatory and microRNA (miRNA) sequences is proposed to contribute to abiotic/biotic stress adaptation in plants. The wheat genome is derived at 85% from TEs, and contains thousands of miniature inverted-repeat transposable elements (MITEs), whose sequences are particularly prone for domestication into miRNA precursors. In this study, we investigate the contribution of TEs to the wheat small RNA immune response to the lineage-specific, obligate powdery mildew pathogen. We show that MITEs of the Mariner superfamily contribute the largest diversity of miRNAs to the wheat immune response. In particular, MITE precursors of miRNAs are wide-spread over the wheat genome, and highly conserved copies are found in the Lr34 and QPm.tut-4A mildew resistance loci. Our work suggests that transposon domestication is an important evolutionary force driving miRNA functional innovation in wheat immunity.


Human immune response to allergens of house dust mite, Dermatophagoides pteronyssinus. III. Cross-reactivity of bystander idiotopes on allergen-specific IgE antibodies.
Rabbits were inoculated with affinity-purified human antibodies to the common house dust mite Dermatophagoides pteronyssinus (DPT) to produce anti-idiotypic (Id) antibodies. The Id carried by human IgE antibodies were studied in a radioimmunoassay in which specific anti-DPT IgE were first insolubilized on rabbit F(ab')2 fragments against human Fc epsilon. In a single individual specific anti-DPT IgE antibodies shared bystander idiotopes (i.e. idiotopes located outside the antigen-binding site) with IgG antibodies of the same specificity, since the adsorption on insolubilized anti-DPT IgG almost completely eliminated the binding of anti-Id antibodies to IgE. This differed from our previous observations (J.-M. R. Saint-Remy et al., Eur. J. Immunol. 1986. 16: 575) wherein distinct paratope-associated idiotopes were identified on IgG and IgE anti-DPT antibodies. The frequency of cross-reactions between idiotopes of anti-DPT IgE antibodies observed in ten unrelated individuals was less than 10% for bystander idiotopes. This finding confirmed the private character of the above idiotopes that we found earlier on anti-DPT IgG antibodies. However, one anti-Id antibody preparation was found to react with bystander idiotopes of anti-DPT IgE of most individuals, thereby suggesting the existence of a recurrent idiotope. The low frequency of inter-individual bystander idiotope cross-reactivity contrasted with the public character of paratope-associated idiotopes.


Serum interleukin-2-receptor in rheumatoid arthritis: a prognostic indicator of disease activity?
Interleukin-2 (IL-2) is an important growth factor for T lymphocytes. Its effects are mediated by cell surface receptors (IL-2 R) expressed on activated T cells. Receptor protein can be shed from cell membranes and the soluble form (sIL-2 R) is detectable by enzyme linked immunosorbent assay (ELISA). We have studied serial levels of sIL-2 R in the sera of patients with rheumatoid arthritis (RA). In 13 patients with active disease, the mean serum level of sIL-2 R was raised compared to age-matched healthy controls. In 48 samples taken at different times from 13 patients, serum sIL-2 R correlated significantly with Ritchie joint index, duration of early morning stiffness, patient pain score, physician's assessment, erythrocyte sedimentation rate (ESR) and platelet count. In individual patients, serial sIL-2 R serum levels fell with treatment preceding clinical improvement. In four patients where serum sIL-2 R levels fell and clinical improvement occurred, subsequent spontaneous increases of serum sIL-2 R level preceded increased clinical disease activity by up to 2 weeks. Serum sIL-2 R level in RA probably reflects activation of underlying immunopathogenic mechanisms and appears to be an excellent monitor of clinical disease activity. More importantly, a rising level may also predict exacerbation of disease activity.


Mechanism of wound repair in diabetic rats using nanosilver-free alginate dressing.
Nanosilver-alginate dressing can effectively promote the healing of diabetic wounds in rats. However, due to the potential toxicity of nanosilver, its widespread application in hard-to-heal wound healing is limited. In the present study, the role and potential mechanism of nanosilver-free alginate gel (NSFAG) in the healing process of diabetic wounds were explored. A diabetic rat skin wound model was established, and wounds were treated with saline (NC group), nanosilver gel (NSG group) or nanosilver-free alginate gel (NSFAG group) for seven consecutive days. NSFAG significantly promoted wound healing and increased the content of protein and hydroxyproline in granulation tissues, and was superior to NSG (p<0.05). Immunohistochemical analyses revealed that the skin wound tissue structure of the NSFAG group was intact, and the number of skin appendages in the dermis layer was significantly higher compared with the NC group and the NSG group (p<0.05). Western blot analysis found that the protein expression of the epidermal stem cell marker molecules CK19 and CK14 as well the proliferation marker of keratinocytes Ki67 in the NSFAG group was significantly higher compared with the NC group or NSG group (p<0.05). Additionally, the proliferation marker of keratinocytes Ki67 in the NSFAG group was significantly higher compared with the NC or NSG group (p<0.05). Immunofluorescence staining analyses indicated that the CK19- and CK14-positive cells were mainly distributed around the epidermis and the newly formed appendages in the NSFAG group, and this result was not observed in the NC or NSG groups. The present findings demonstrate that NSFAG can effectively accelerate wound healing in diabetic rats by promoting epidermal stem cell proliferation and differentiation into skin cells, as well as formation of granulation tissue, suggesting that it can be a potential dressing for diabetic wounds.


The effect of ebselen on polymorphonuclear leukocyte migration to joints in rats with adjuvant arthritis.
We have previously reported that ebselen (PZ 51,2-Phenyl-1,2- Benzoisoselenazol-3-(2H)-one), a selinyl organic compound with anti-inflammatory properties, inhibited human polymorphonuclear leukocyte (PMNL) adhesion to and migration through cytokine-activated human umbilical vein endothelium in vitro. Here we investigated the in vivo effect of ebselen on PMNL migration into arthritic joints and dermal inflammation in rats with adjuvant arthritis. The rats were immunized with adjuvant (Mycobacteriaum butyricum in mineral oil) and 13 days later, when arthritis was fully developed, treatment (p.o.) with ebselen, indomethacin or vehicle was initiated. The migration of 51Cr-labelled blood PMNL purified from arthritic donors and extravasation of 125I-labelled HSA in arthritic joints and dermal inflammatory reactions was quantitatively measured. Treatment of rats with 100 mg/kg/day ebselen for 3 days, inhibited by 72-79% the PMNL migration into arthritic joints and tail (spondylitis) and by 50-60% into dermal inflammatory reactions induced with zymosan-activated rat serum (ZAS; C5adesArg), endotoxin (LPS) or IL-1 alpha. The inhibitory effect of ebselen was dose-dependent, because treatment of rats with 100 mg/kg/day ebselen caused significantly more inhibition of PMNL migration than did 30 mg/kg/day, although this dose was still effective. Ebselen inhibited PMNL migration into arthritic joints and dermal inflammation within 3 h of initial oral administration (100 mg/kg). However, ebselen did not suppress plasma albumin extravasation into arthritic joints and dermal inflammatory reactions. Compared to ebselen, treatment with indomethacin (2 mg/kg/day) was significantly less effective in inhibiting PMNL accumulation in joints, but in contrast to ebselen, indomethacin did inhibit plasma albumin extravasation into carpal and talar joints. The results suggest that ebselen effectively and rapidly inhibits PMNL migration in vivo, as also observed in vitro, and that it has anti-inflammatory actions distinct from classic nonsteroidal anti-inflammatory drugs such as indomethacin.


Hepatocellular carcinoma in primary biliary cirrhosis: detection by alpha-fetoprotein estimation.
Serial estimations of serum alpha-fetoprotein in 130 white patients from the United Kingdom with primary biliary cirrhosis who were followed for periods of 1-52 mo revealed 5 cases of hepatocellular carcinoma; all were subsequently confirmed histologically. At the time alpha-fetoprotein was first noted to be elevated, none had signs or symptoms of tumor development. Of the 52 patients who died during the follow-up period, hepatocellular carcinoma was the cause of death in 3 (33%) of the 9 men, and 2 (5%) of the 43 women. Allowing for the marked predominance of women among patients with primary biliary cirrhosis, hepatocellular carcinoma may be no less frequent in primary biliary cirrhosis than in other types of cirrhosis.


Real-world data with afatinib in Spanish patients with treatment-naïve non-small-cell lung cancer harboring exon 19 deletions in epidermal growth factor receptor (Del19 EGFR): Clinical experience of the Galician Lung Cancer Group.
In clinical studies, first-line afatinib demonstrated efficacy in Del19-EGFR NSCLC. This prospective, non-interventional study assessed efficacy and safety of first-line afatinib in patients with advanced/metastatic NSCLC with Del19-EGFR from Galicia (Spain), with a preplanned analysis by age (<70 vs ≥70 years). Median age of 46 patients enrolled was 69.5 years (range 37-87). The objective response rate (ORR) was 78.2%, with median progression-free survival (PFS) of 20.5 months (95% CI 12.7, 28.3) and median overall survival (OS) of 37.5 months (95% CI 19.2-55.8). Outcomes by age (<70 vs ≥70 years) were ORR of 82.6% vs 73.9%, median PFS of 20.2 months (95% CI 14.8-25.6) vs 24.1 (9.8-38.3), and median OS of 45.1 months (95% CI, 17.0-73.1) vs 33.9 (28.7-39.1), respectively. Median treatment duration was 17.2 months (range 0.4-64.1) with 11 patients still on treatment; 14 patients received osimertinib at discontinuation due to T790M. Grade 3 adverse events included mucositis (n = 7, 15.2%), skin toxicity (n = 9, 19.6%), and diarrhea (n = 6, 13.0%) that were manageable with dose reductions. The afatinib dose was reduced in 31 patients (67.4%) and treatment was discontinued in 8 patients (17.4%) due to adverse events. By age (<70 vs ≥70 years), afatinib was dose-reduced in 13 (56.5%) vs 18 patients (78.3%) and discontinued in 3 (13.0%) vs 5 patients (21.7%), respectively. PFS in our patients was longer than reported in clinical studies with similar response rates and toxicity, even in older patients, reflecting a good risk-benefit from afatinib in patients with Del19-EGFR NSCLC. This real-world study of first-line afatinib in Caucasian patients with Del19 EGFR NSCLC reported durable efficacy and showed that older patients (> 70 years) benefitted from afatinib as much as younger patients. The safety profile of afatinib was as expected, albeit more dose reductions in older patients. Afatinib may be an option for patients with Del19 EGFR NSCLC, even in those who are older.


MiR-138 induces cell cycle arrest by targeting cyclin D3 in hepatocellular carcinoma.
The deregulation of microRNA (miRNA) is frequently associated with a variety of cancers, including hepatocellular carcinoma (HCC). In this study, we identified 10 upregulated miRNAs (miR-217, miR-518b, miR-517c, miR-520g, miR-519a, miR-522, miR-518e, miR-525-3p, miR-512-3p and miR-518a-3p) and 10 downregulated miRNAs (miR-138, miR-214, miR-214#, miR-27a#, miR-199a-5p, miR-433, miR-511, miR-592, miR-483-5p and miR-483-3p) by Taqman miRNAs array and quantitative real-time PCR (qRT-PCR) confirmation. Additionally, we investigated the expression and possible role of miR-138 in HCC. qRT-PCR results showed that miR-138 was downregulated in 77.8%(14/18) of HCC tissues compared with adjacent non-tumor tissues. Overexpression of miR-138 reduced cell viability and colony formation by induction of cell arrest in HCC cell lines and inhibited tumor cell growth in xenograft nude mice. The use of miR-138 inhibitor increased cell viability and colony formation in HCC cell lines and tumor cell growth in xenograft nude mice. Using TargetScan predictions, CCND3 was defined as a potential direct target of miR-138. Furthermore, CCND3 protein expression was observed to be negatively correlated with miR-138 expression in HCC tissues. The dual-luciferase reporter gene assay results showed that CCND3 was a direct target of miR-138. The use of miR-138 mimic or inhibitor could decrease or increase CCND3 protein levels in HCC cell lines. We conclude that the frequently downregulated miR-138 can regulate CCND3 and function as a tumor suppressor in HCC. Therefore, miR-138 may serve as a useful therapeutic agent for miRNA-based HCC therapy.


T-cell function in aging: mechanisms of decline.
The above sections have provided numerous facts, many of which are conflicting, regarding the changes that occur with increasing age in T lymphocytes. Although it is impossible to state with absolute certainty the alterations that are responsible for decreased proliferation of lymphocytes from elderly subjects, the following summarizes the current status of the data: 1. The interaction of T lymphocytes with foreign stimuli appears to be generally intact. 2. Changes in numbers of CD3+, CD4+, or CD8+ cells before interaction with foreign stimuli or in the density of these markers or of mitogen receptors on the surface of aged T cells have not been consistently observed. When reported to occur, the changes are not sufficient to account for the significant decrease in T-cell proliferation that occurs with increasing age. 3. A defect in the ability of the membrane interaction with foreign stimulus to signal subsequent internal events may occur, because stimulation with phorbol esters and calcium ionophore can result in increased proliferation in some elderly subjects. 4. Decreased accumulation of cytosolic calcium after stimulation of elderly T cells occurs in mice and may be a major component of the defective activation system. This defect appears to be most apparent in the "memory" T cells (T cells expressing high levels of Pgp-1), which increase in number with increasing age. Decreases in Ca++ accumulation have not been observed in humans, but this may be due to different stimuli used. Further, investigation of an increase in "memory" T cells and of their inability to mobilize Ca++ has not been done in humans and rats. 5. Decreases in mRNA for c-myc, IL-2 receptor, and IL-2 have been reported in some, but not all, species. Whether these decreases are the result of decreases in Ca++ mobilization or are independent events in unknown. 6. Decreases in membrane expression of the activation marker RL388 and of TfR have been reported. 7. Lymphokines: a. Decreases in IL-2 production occur in mice and humans, but not in rats. In individuals with decreased IL-2 production, addition of exogenous IL-2 totally restores proliferative ability in only some individuals. Changes in IL-2R expression (number or affinity) may be an additional defect. b. Decreases in IFN-gamma occur in humans, but not in mice or rats. c. No change in IL-1 occurs in any species. Genotypic effects must be considered when evaluating the preceding observations. The heterogeneity among individuals, even within an inbred strain, cannot be discounted.(ABSTRACT TRUNCATED AT 400 WORDS)


The effect of route of administration of a Babesia divergens inactivated vaccine on protection against homologous challenge.
Two groups of 5 adult cows were immunized with a concentrated lysate of blood from a splenectomized calf infected with Babesia divergens with a parasitaemia of 20 per cent. The lysate was administered in 2 doses with a 14-day interval between them; it was injected subcutaneously to one group and intravenously to the other. Nineteen days after the second inoculation, both groups plus a third group of similar cows which acted as controls were infected subcutaneously with blood containing 10(9) B. divergens of the same strain, and clinical and haematological variables were monitored closely for 3 weeks. Both pretreated groups were much less seriously affected than the controls, with the group inoculated subcutaneously showing the least effects due to the challenge infection. It was concluded that protection could be induced against infections of B. divergens by injection of inactivated parasites of the same strain, and that subcutaneous inoculation was preferable to intravenous.


Evaluation of the metabolism of PEP06, an endostatin-RGDRGD 30-amino-acid polypeptide and a promising novel drug for targeting tumor cells.
PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp (RGDRGD) 30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus. The active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral effect. However, little is known about the kinetics and degradation products of PEP06 in vitro or in vivo. In this study, we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species; we further identified the degradation characteristics of its cleavage products. PEP06 underwent rapid enzymatic degradation in multiple types of living cells, and the liver, kidney, and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06. We identified metabolites of PEP06 using full-scan mass spectrometry (MS) and tandem MS (MS2), wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide, formed by successive losses of amino acids. The metabolites were C and N terminal truncated products of PEP06. The structures of 11 metabolites (M6, M7, M16, M17, M21, M25, M33, M34, M39, M40, and M42) were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites. We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06, which can support further drug research.


A novel DCM-based NIR fluorescent probe for detecting ozone and its bioimaging in live cells.
Nowadays, ozone has been widely applied in industry and medical therapies. However, excessive exposure to ozone can lead to lung dysfunction and many respiratory symptoms. As a member of reactive oxygen species (ROS), ozone was also involved in various physiology and pathology process. Given the fact of this, the effective detection of ozone in the atmosphere and biological system is of vital significance. Herein, we reported a novel dicyanomethylene-4H-pyran (DCM)-based fluorescent probe DCM-O3 with butenyl being the recognition moiety for monitoring ozone. The probe displayed high selectivity towards ozone, and its response towards ozone could be completed within 5 min under the optimal condition. Besides, a good linear correlation was obtained between the ozone concentrations (0-50 μM) and the corresponding fluorescent intensity at 560 nm, and the limit of detection (LOD) was calculated to be 6.2 × 10-7 M. Moreover, the probe DCM-O3 showed low cytotoxicity and was successfully applied to detect ozone in live cells. Given all the merits, the probe DCM-O3 could function as a robust tool for researchers to investigate ozone-related diseases in the complex biological environment.


Directed evolution identifies high-affinity cystine-knot peptide agonists and antagonists of Wnt/β-catenin signaling.
Developing peptide-based tools to fine-tune growth signaling pathways, in particular molecules with exquisite selectivity and high affinities, opens up opportunities for cellular reprogramming in tissue regeneration. Here, we present a library based on cystine-knot peptides (CKPs) that incorporate multiple loops for randomization and selection via directed evolution. Resulting binders could be assembled into multimeric structures to fine-tune cellular signaling. An example is presented for the Wnt pathway, which plays a key role in the homeostasis and regeneration of tissues such as lung, skin, and intestine. We discovered picomolar affinity CKP agonists of the human LPR6 receptor by exploring the limits of the topological manipulation of LRP6 dimerization. Structural analyses revealed that the agonists bind at the first β-propeller domain of LRP6, mimicking the natural Wnt inhibitors DKK1 and SOST. However, the CKP agonists exhibit a different mode of action as they amplify the signaling of natural Wnt ligands but do not activate the pathway by themselves. In an alveolosphere organoid model, the CKP agonists induced alveolar stem cell activity. They also stimulated growth in primary human intestinal organoids. The approach described here advances the important frontier of next-generation agonist design and could be applied to other signaling pathways to discover tunable agonist ligands.


Single-electron counting spectroscopy: simulation study of porphyrin in a molecular junction.
Electron counting of a single porphyrin molecule between two electrodes shows a crossover from sub- to super-Poissonian statistics as the bias voltage is scanned. This is attributed to the simultaneous activation of states with electron transfer rates spanning several orders of magnitude. Time-series analysis of consecutive single-electron transfer events reveals fast and slow transport channels, which are not resolved by the average current alone.


Influence of preoperative 7.5% hypertonic saline on neutrophil activation after reamed intramedullary nailing of femur shaft fractures: a prospective randomized pilot study.
Femoral reaming and intramedullary nailing (IMN) primes polymorphonuclear leukocytes (PMNL) and thereby increases the posttraumatic systemic inflammatory response. Resuscitation with hypertonic saline (HTS) attenuates PMNL activation after trauma-hemorrhage. We hypothesized that preoperative administration of 7.5% HTS attenuates PMNL priming after IMN of unilateral femur shaft fractures compared with 0.9% normal saline. Prospective, randomized, double-blind study. Level I trauma center. Twenty patients between 18 and 80 years of age with an Injury Severity Score less than 25 and a unilateral femur shaft fracture amenable to IMN fixation within 24 hours after injury. Patients were allocated to equally sized HTS or normal saline treatment groups (n = 10) before surgery. Solutions were administered in a blinded bag as a single bolus of 4 mL/kg body weight immediately before surgery. Whole blood samples were collected directly before saline application (t0) and at 6, 12, and 24 hours after surgery. PMNL surface expression of CD11b and CD62L, as determined by flow cytometry analysis. Demographic characteristics of both treatment groups were comparable. Baseline expression of CD11b and CD62L cell markers was in a similar range in the two cohorts. The expression levels of CD11b were comparable between the two groups throughout the observation time, whereas CD62L levels were significantly higher in the HTS group at 6 and 24 hours after surgery. Preoperative infusion of HTS appears to exert an anti-inflammatory effect by attenuating the extent of postoperative PMNL activation after reamed IMN for femoral shaft fractures.


Comparison of magnetic resonance imaging and transvaginal ultrasonography in diagnosing bladder endometriosis.
To take recent progress in magnetic resonance imaging (MRI) into account to determine its accuracy compared with that of transvaginal ultrasonography (TVUS) in diagnosing bladder endometriosis. Retrospective analysis (Canadian Task Force classification II-2). University-affiliated hospital. Twelve women with histologically proved bladder endometriosis. Magnetic resonance imaging with body and endocavitary coils and TVUS. Although TVUS was normal in four patients, MRI enabled endometriotic lesions to be detected in all patients. Magnetic resonance imaging with endocavitary coil established the existence of deep infiltration in three patients when muscularis involvement was not visible with the body coil. In seven women MRI determined how far deep posterior endometriotic lesions extended, whereas with TVUS this was impossible to see. Conclusion. MRI had advantages over TVUS in diagnosing small lesions of associated posterior deep endometriotic lesions. The endocavitary coil gave better results than the phased-array coil for diagnosing deep infiltration. These results are important in that they help guide surgical management.


The effect of an inpatient geriatric stewardship on drug-related problems reported by patients after discharge.
Background Drug-related problems after discharge are common among older adults with polypharmacy. Medication review during hospitalization has been proposed as one solution. Inpatient medication review is often based on clinical records only. An obstacle is the lack of insight into the outpatient history. Therefore, a geriatric stewardship was designed and involved an inpatient medication review by a hospital pharmacist and geriatrician based on (I) clinical records to draft initial recommendations, (II) consultations with primary care providers (general practitioner and community pharmacist) to discuss the hospital-based recommendations, (III) patient interviews to assess their needs, and (IV) a multidisciplinary evaluation of all previous steps to draft final recommendations. Objective To assess the effect of the geriatric stewardship on drug-related problems reported by patients after discharge. Setting General teaching hospital. Methods An implementation study (pre-post design) was performed. Orthopaedic and surgical patients (≥ 65 years) with polypharmacy and a frailty risk factor were included. The pre-group received usual care, the post-group received the geriatric stewardship intervention. Two weeks post-discharge, patient-reported drug-related problems were assessed using a validated questionnaire. Drug-related problems were classified into drug-related complaints, practical problems, and questions about medication. Outcomes The outcomes were the number and type of drug-related problems per patient (primary) and the number of initial recommendations that were altered due to primary care provider and patient input (secondary). Results In total, 127 patients were analysed (usual care n = 74, intervention n = 53). Intervention patients reported fewer drug-related problems compared to usual care: 2.8 versus 3.3 per patient (Adjusted relative risk 0.83, 95% confidence interval 0.66-1.05). This difference resulted from a halving in drug-related complaints (p < 0.05), for example pain, drowsiness, nausea or constipation. Nearly 30% of the initial recommendations based on the clinical records were discarded or modified after primary care provider consultations and patient interviews. Conclusion The geriatric stewardship did not significantly reduce drug-related problems, but it significantly halved drug-related complaints. One-in-three initial recommendations were altered due to primary care provider and patient input. Inpatient medication reviews should not be based on clinical records only; they require transmural collaboration and patient participation to ensure continuity of patient care.


Principles of radiation therapy.
Although resection remains the mainstay in the treatment of gliomas, microscopically complete resection of most central nervous system tumors remains challenging, and is, in fact, rarely accomplished. Considering their invasive nature, gross total resections to clearly negative margins often do or would require removal or transection of functional brain, with likely serious neurologic deficits. Consequently, radiotherapy has emerged as an indispensable component of therapy. It is delivered primarily by external-beam radiotherapy or brachytherapy techniques. Herein, we present the biologic principles, techniques, and applications of radiotherapy in glioma treatment today.


CRISPR-Cas9 to induce fetal hemoglobin for the treatment of sickle cell disease.
Genome editing is potentially a curative technique available to all individuals with β-hemoglobinopathies, including sickle cell disease (SCD). Fetal hemoglobin (HbF) inhibits sickle hemoglobin (HbS) polymerization, and it is well described that naturally occurring hereditary persistence of HbF (HPFH) alleviates disease symptoms; therefore, reawakening of developmentally silenced HbF in adult red blood cells (RBCs) has long been of interest as a therapeutic strategy. Recent advances in genome editing platforms, particularly with the use of CRISPR-Cas9, have paved the way for efficient HbF induction through the creation of artificial HPFH mutations, editing of transcriptional HbF silencers, and modulating epigenetic intermediates that govern HbF expression. Clinical trials investigating BCL11A enhancer editing in patients with β-hemoglobinopathies have demonstrated promising results, although follow-up is short and the number of patients treated to date is low. While practical, economic, and clinical challenges of genome editing are well recognized by the scientific community, potential solutions to overcome these hurdles are in development. Here, we review the recent progress and obstacles yet to be overcome for the most effective and feasible HbF reactivation practice using CRISPR-Cas9 genome editing as a curative strategy for patients with SCD.


Demographic characteristics and risk behaviors associated with HIV positive injecting drug users in Xinjiang, China.
To determine the demographic characteristics and risk behaviors associated with HIV positive and negative injection drug users (IDUs) who were screened for inclusion in a prospective cohort study to estimate HIV incidence in Xinjiang, China. Data analyses were performed on the demographic and risk assessment data collected at screening from high-risk IDUs, defined as anyone who reported injecting drugs at least three times per week in the last month or injected drugs after sharing equipment on at least three occasions in the last three months. HIV antibody prevalence among 781 IDUs at baseline survey was 29%. The following factors were significantly associated with an increase in risk for HIV infection: age > or =26years (OR=3.16, 95% CI [2.02;4.94]), lack of college education (OR=2.32, 95% CI [1.02;5.25]), frequency of heroin use (OR=1.23, 95% CI [1.02;1.47]) and sharing of rinse water (OR=1.47, 95% CI [1.18;1.84]). Female gender (OR=0.44, 95% CI [0.22;0.86]), being Han vs Uighur ethnicity (OR=0.18, 95% CI [0.11;0.27]), and other race vs Uighur ethnicity (OR=0.23, 95% CI [0.12;0.44]) were significantly associated with a lower risk of HIV infection. HIV infection among high risk IDUs in Xinjiang, China is high and is associated with older male Uighur IDUs who lack college education, frequently inject heroin, and/or share rinse water. There is a great potential for HIV transmission from IDUs to the general population. Therefore, related risk behaviors in IDUs, especially their sexual behavior, should be closely monitored.


[Eight cases of intracranial arteriovenous malformations treated by conventional radiation therapy].
We conducted radiotherapy in 8 cases of intracranial arteriovenous malformation that had difficult embolectomy and other surgery from 1983 to October, 1988. The results in 6 cases of dural arteriovenous malformation at the cavernous sinus were "marked effect" in 4 cases, "relapse" in 1 case, and "no effect" in 1 case. One case of dural arteriovenous malformation at the sigmoid venous sinus demonstrated only slight irradiation effect. No irradiation effect was observed in 1 case of cerebral arteriovenous malformation.


Dalbavancin vs standard of care for Staphylococcus aureus bacteraemia in patients unable to receive outpatient parenteral antimicrobial therapy.
This study compared dalbavancin with standard of care (SOC) for patients with Staphylococcus aureus bacteraemia (SAB) who were unable to receive outpatient parenteral antimicrobial therapy (OPAT). This retrospective cohort compared re-admission rates related to the index infection between patients treated with dalbavancin or SOC for SAB. Patients aged ≥18 years seen by the infectious diseases consult service who had received at least one dose of dalbavancin or at least 1 week of SOC parenteral antibacterials as directed therapy for SAB at the time of discharge were included. The SOC group consisted of patients transferred from the main hospital to one of the post-acute care facilities to complete parenteral antibacterials. The primary outcome was re-admission rate within 30 days of completion of therapy. Secondary outcomes included re-admission rate within 90 days of completion of therapy and adherence to the antibacterial regimen. Twenty-seven patients received dalbavancin and 27 patients received SOC. Baseline demographics were comparable between groups, although more patients in the SOC group had indwelling prostheses or hardware (4% vs 22%). The majority of SAB was caused by methicillin-susceptible S. aureus (56% vs 59%). Re-admission rates for the dalbavancin group were similar to those for the SOC group within 30 days (15% vs 22%; P=0.484) and 90 days (19% vs 22%; P=0.735) of completion of therapy. Adherence to the antibacterial regimen was significantly higher among patients treated with dalbavancin compared with SOC (85% vs 44%; P<0.001). Dalbavancin offers similar clinical outcomes to SOC for patients with SAB who are unable to receive OPAT.


Studies of the surface charge of amorphous aluminosilicates using surface complexation models.
Synthetic noncrystalline aluminosilicates with variable charge, similar to allophanes present naturally in volcanic soils, were studied. The surface charge behavior was determined by zero point charge (ZPC) measured by electrophoretic mobility (isoelectric points, IEP) and determined by potentiometric titration (point of zero salt effect, PZSE). The ZPC calculated by Parks model (ZPC(c)), compared with IEP values, showed that the aluminosilicate (AlSi) surface was slightly enriched by AlOH (34% Al(2)O(3) and 66% SiO(2)) compared with the bulk composition (29% Al(2)O(3) and 71% SiO(2)). For aluminosilicate coated with iron oxide (AlSiFe) the ZPC(c) (4.4) was lower than the IEP (8.46), showing that the surface composition is formed mainly from iron oxide. The PZSE values for AlSi and AlSiFe were 6.2 and 4.8, respectively. The differences between the IEP and PZSE are attributed to the formation of Si-O-Fe or Si-O-Al bonds; therefore, the reactivity of Fe and Al atoms was modified on the surface. Two mechanistic models, the constant capacitance model (CCM) and the triple layer model (TLM), using the program FITEQL 3.2 were able to describe the surface behavior of both synthetic aluminosilicates. The acidity constants determined using both models for the aluminosilicates showed differences with respect to pure oxide, mainly attributed to the presence of SiOH sites on the internal surfaces. The ionic strength showed a good relation with the parameters obtained using the CCM (pK(int)(a1), pK(int)(a2) and capacitance values) and the TLM (pK(int)(a1), pK(int)(a2), pK(int)(Cl-), pK(int)(K+), and inner capacitance) for both aluminosilicates. However, the TLM was able to describe the acidity and complexation constants better since it considered the formation of the outer sphere complex between the background electrolyte and the surface. Then, the TLM makes it possible to describe real systems.


Aliphatic ketones are acetylcholinesterase inhibitors but not transition state analogs.
A number of C4--C9 aliphatic ketones are acetylcholinesterase (acetylcholine hydrolase, EC 18.104.22.168) inhibitors, with Ki values in the 0.7--5 mM range. Comparison to analogous substrates would suggest that these ketones are transition state analogs; e.g. 2-pentanone binds to the enzyme approx. 550 times more tightly than ethylacetate. However, a number of other criteria contradict this conclusions: (1) the binding is insensitive to ketone structure: isomeric ketones, cycloalkanones, and sterically hindered ketones have similar inhibitory potencies. (2) Analogous alcohols are also good inhibitors even though they cannot form hemiketals with the enzyme. (3) Representative ketones are relatively ineffective at blocking inactivation of the enzyme by methylsulfonyl fluoride, indicating that ketones do not bind principally at the hydrolytic site. (4) A competition experiment shows that binding of tetramethylammonium chloride excludes binding of 2-pentanone, suggesting that ketones bind to the anionic rather than the hydrolytic site. Thus, observation of tight binding relative to a substrate is not a sufficient criterion to establish that an inhibitor is a transition state analog.


Role of MAP kinases and PI3K-Akt on the cytokine inflammatory profile of peritoneal macrophages from the ascites of cirrhotic patients.
Several new approaches targeting inflammation associated with different diseases are in clinical development. To explore the role played by MAPK and PI3K-Akt pathways on the release of cytokines in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients to identify novel targets for pharmaceutical intervention to prevent hepatic damage. M-DM were isolated from the ascites of cirrhotic patients and stimulated in vitro with LPS and heat-killed Candida albicans in the presence or absence of the inhibitors for MEK1, p38 MAPK, JNK and PI3K. The MAPK phosphorylation levels were determined by Western Blot. Cell culture supernatants were assayed by ELISA for TNF-α, IL-6 and IL-10. The release of the pro-inflammatory cytokines IL-6 and TNF-α at baseline was more effectively reduced by the MAPK inhibitors, while the basal IL-10 anti-inflammatory cytokine secretion was only and strongly (90.3%) affected by the PI3K inhibitor. The incubation of peritoneal M-DM in the presence of LPS and C. albicans increased the release of IL-6, TNF-α and IL-10. LPS-induced pro-inflammatory cytokines secretion was more sensitive to MAPK inhibitors, whereas that induced by C. albicans was more susceptible to inhibition of PI3K. Finally, inhibition of PI3K almost completely suppressed the secretion of IL-10 in stimulated M-DM. These results demonstrate that pro-inflammatory cytokines release in M-DM from this clinical setting strongly depends on the MAPK signalling pathways, differs depending on the microbial stimulus added and confirms the prominent role of the PI3K-Akt pathway in the modulation of IL-10-mediated anti-inflammatory function.


Helicobacter Pylori and Gastric Cancer Progression.
Gastric cancer (GC) remains the fifth most common malignant tumor and the third leading cause of cancer death, despite the decline in incidence and mortality worldwide over the past five decades. Currently, the roles of Helicobacter pylori (H. pylori) in the development of GC have been established. The effects of H. pylori are mediated through interactions of H. pylori pathogen-associated molecular patterns (PAMPs) with pattern-recognition receptors (PRRs) located on immune and epithelial cells. It is known that this interaction leads to the generation of reactive oxygen species (ROS), activation of the mechanisms of angiogenesis, epithelial-mesenchymal transformation (EMT), and immunological tolerance. Not all this excludes the possibility that H. pylori may have an effect not only on the induction, but also on the mechanisms of GC progression. In this review, we will consider the main structural elements of the innate immune system and the mechanisms of their interaction with H. pylori; the possible role of H. pylori in GC progression; relationship of H. pylori with clinical and pathological characteristics and prognosis of GC, as well as data on the effect of eradication therapy on long-term results of GC patient treatment.


Rhynchophylline ameliorates cerebral ischemia by improving the synaptic plasticity in a middle cerebral artery occlusion induced stroke model.
Previous studies have documented that rhynchophylline exerts antioxidative and anti-inflammatory effects on ischemic neuronal damage in vitro or in vivo. There is a considerable lack of direct evidence for its role in neural function and neuroplasticity after ischemic stroke. This study aims to explore the role of rhynchophylline in middle cerebral artery occlusion (MCAO) induced ischemic stroke model and the potential mechanisms. Mice were randomly divided into the following three groups: Sham, MCAO + ddH2O, and MCAO + Rhy(40 mg/kg by oral gavage) groups. Cerebral ischemia was induced by MCAO. Cerebral blood flow was monitored to indicate the success of the ischemic model. The neurological severity score and a series of related behavior tests were performed(after MCAO 3d,7d,14d,21d,28d). Golgi staining and Sholl analysis were used to evaluate the complexity of dendrites and the density of dendritic spines. Immunohistochemistry was used to detect the expression of synapsin I and NeuN. Administration of rhynchophylline for 7 consecutive days after the onset of cerebral ischemia alleviated the sensory-motor functional defects and ameliorated hippocampus-dependent spatial memory injury as well as reduced the infarct volume induced by MCAO. However, golgi staining and sholl analysis showed that rhynchophylline improved dendritic complexity and spine density as well as the synaptic plasticity. Furthermore,the expression of synapsin I and Neun was significantly reduced after cerebral ischemia and rhynchophylline administration ameliorated the loss of synapsin I. Rhynchophylline is a promising treatment for ischemic stroke via improving synaptic plasticity and ameliorating the sensory-motor function.


An enteric-coated dry emulsion formulation for oral insulin delivery.
A novel oral dosage formulation of insulin consisting of a surfactant, a vegetable oil, and a pH-responsive polymer has been developed. First, a solid-in-oil (S/O) suspension containing a surfactant-insulin complex was prepared. Solid-in-oil-in-water (S/O/W) emulsions were obtained by homogenizing the S/O suspension and the aqueous solution of hydroxypropylmethylcellulose phthalate (HPMCP). A microparticulate solid emulsion formulation was successfully prepared from the S/O/W emulsions by extruding them to an acidic aqueous solution, followed by lyophilization. The insulin release from the resultant dry emulsion responded to the change in external environment simulated by gastrointestinal conditions, suggesting that the new enteric-coated dry emulsion formulation is potentially applicable for the oral delivery of peptide and protein drugs.


Survival and recovery modeling of acute kidney injury in critically ill adults.
Acute kidney injury is common among the critically ill. However, the incidence, medication use, and outcomes of acute kidney injury have been variably described. We conducted a single-center, retrospective cohort study to examine the risk factors and correlates associated with acute kidney injury in critically ill adults with a particular focus on medication class usage. We reviewed the electronic medical records of all adult patients admitted to an intensive care unit between 1 February and 30 August 2020. Acute kidney injury was defined by the 2012 Kidney Disease: Improving Global Outcomes guidelines. Data included were demographics, comorbidities, symptoms, laboratory parameters, interventions, and outcomes. The primary outcome was acute kidney injury incidence. A Least Absolute Shrinkage and Selection Operator regression model was used to determine risk factors associated with acute kidney injury. Secondary outcomes including acute kidney injury recovery and intensive care unit mortality were analyzed using a Cox regression model. Among 226 admitted patients, 108 (47.8%) experienced acute kidney injury. 37 (34.3%), 39 (36.1%), and 32 patients (29.6%) were classified as acute kidney injury stages I-III, respectively. Among the recovery and mortality cohorts, analgesics/sedatives, anti-infectives, and intravenous fluids were significant (p-value < 0.05). The medication classes IV-fluid electrolytes nutrition (96.7%), gastrointestinal (90.2%), and anti-infectives (81.5%) were associated with an increased odds of developing acute kidney injury, odd ratios: 1.27, 1.71, and 1.70, respectively. Cox regression analyses revealed a significantly increased time-varying mortality risk for acute kidney injury-stage III, hazard ratio: 4.72 (95% confidence interval: 1-22.33). In the recovery cohort, time to acute kidney injury recovery was significantly faster in stage I, hazard ratio: 9.14 (95% confidence interval: 2.14-39.06) cohort when compared to the stage III cohort. Evaluation of vital signs, laboratory, and medication use data may be useful to determine acute kidney injury risk stratification. The influence of particular medication classes further impacts the risk of developing acute kidney injury, necessitating the importance of examining pharmacotherapeutic regimens for early recognition of renal impairment and prevention.


Growth Kinetics of Listeria monocytogenes on Cut Red Cabbage.
Listeria monocytogenes is a foodborne pathogen associated with fresh produce vectors such as leafy greens. Recent outbreaks and recalls associated with red cabbage-containing salads have brought attention to this food commodity. Although data on the proliferation of L. monocytogenes are available for different varieties of whole and cut white cabbage, no information is available on the fate of this pathogen on red cabbage. The aim of this study was therefore to explore the survival of L. monocytogenes on cut red cabbage (Brassica oleracea L. var. capitata f. rubra) during storage at different temperatures. Red cabbage was cut into pieces (5 by 4 cm) and spot inoculated with a six-strain cocktail of rifampin-resistant L. monocytogenes, resulting in an initial inoculation level of 4 log CFU/g. Samples were stored at 5 or 10°C for 14 days or at 25°C for 7 days. At intervals during storage, L. monocytogenes was enumerated by homogenization of cabbage with Butterfield's phosphate buffer, and serial dilutions were plated onto brain heart infusion agar supplemented with rifampin. No growth of L. monocytogenes was observed on cut red cabbage during storage at 5°C, and only minimal proliferation was observed at the higher temperatures. Significant population increases of 0.58 and 1.07 log CFU/g were determined after 3 days of storage at 10 and 25°C, respectively; however, a significant decrease of 0.77 log CFU/g from 3 to 14 days was also observed at 10°C. The modeled growth rates for L. monocytogenes on cut red cabbage stored at 5 and 10°C were 0.11 ± 0.03 and 0.27 ± 0.07 log CFU/g/day, with calculated times to a 1-log CFU/g increase of 9.51 and 3.70 days, respectively; however, L. monocytogenes did not achieve a 1-log increase at either temperature in this study. At 25°C, the modeled growth rate of L. monocytogenes on cut red cabbage was 1.15 ± 0.36 log CFU/g, leading to a calculated and an observed 1-log increase in 0.87 and 3.00 days, respectively. Results from this study aid in understanding the fate of L. monocytogenes on cut red cabbage during storage at different temperatures.


Assessment of physical activity by questionnaire and personal interview with particular reference to fitness and coronary mortality.
Physical work capacity was measured by means of a symptom limited, near maximal cycle ergometer exercise test in two populations: a random sample of 95 military officers, and 2014 apparently healthy working males, 40-59 years old. Physical activity during leisure hours was assessed by means of a standardized questionnaire and by a personal interview with the officers and with 1769 of the other men. A 3 year total incidence of coronary heart disease (CHD) was recorded in the case of the officers and a 7 year CHD incidence and of CHD deaths was obtained for the 2014 working men. The data show that: A marked underestimation of the habitual levels of physical activity of the officers was obtained from the standardized questionnaire, as compared with that shown by the interview data. A far better agreement between the questionnaire and interview data on leisure time activity was observed among the mainly sedentary men. Physical work capacity was fairly well predicted from the questionnaire data in the sedentary men, but poorly predicted in the officers. CHD mortality in the sedentary men was highly correlated with working capacity in all age groups. Of 58 who died from CHD, 28 belonged to the lowest physical fitness quartile. This study indicates that questionnaires should be used with caution when assessing levels of habitual physical activity. It also suggests that a low physical work capacity is an important risk factor in CHD mortality.


Rice cultivars significantly mitigate cadmium accumulation in grains and its bioaccessibility and toxicity in human HL-7702 cells.
Excessive Cd accumulation in cereals, especially in high-consumption staple crops, such as rice, is of major concern. Therefore, elucidation of cultivar-specific variation in rice grain Cd bioaccessibility and toxicity in humans would help the development of remedial strategies for Cd accumulation and toxicity. The present study combined an in vitro gastrointestinal digestion model with a human HL-7702 cell and assessed Cd bioaccessibility and toxicity to humans from the grains of 30 rice cultivars of different types harvested from Cd-contaminated paddy soil. The mean grain Cd content of cultivars within the type exceeded acceptable national standards. Cadmium bioaccessibility was high in all grains (9.08-23.6%) except the low accumulator (LA) rice cultivar (7.93%). The mean estimated daily intake of Cd via the cultivars (except LA) exceeded the FAO/WHO permissible limit based not only on the total grain Cd concentration but also on bioaccessible Cd concentration. A dose-proportional correlation between the in vitro bioaccessible and total grain Cd concentrations was observed, suggesting that Cd bioaccessibility accurately reflects the transfer of Cd from rice grain to humans. Toxicity assay results demonstrated that Cd from rice grains could commence oxidative stress and injury in HL-7702 cells, except the LA rice, which did not exhibit significant alteration in HL-7702 cells owing to its low Cd concentration. These results provide primary evidence to suggest that the cultivation of the LA rice cultivar is an effective agronomic approach to avert Cd entry into the food chain and alleviate Cd toxicity in humans.


Effects on rabbit spermatogenesis following orthostatic collapse. Light microscope qualitative and quantitative studies.
Forty rabbits were submitted to orthostatic collapse, divided into 9 groups and sacrificed 6, 12, 24, and 48 hours, 4, 7, 15, 30 and 45 days following collapse. Ten animals were used as controls. The testis and epididymis were submitted to microscopic examination. The most striking change was necrosis of seminiferous cells which was most severe in the 24-hour group. The most susceptible cell to necrosis was the primary spermatocyte whilst spermatogonia, Sertoli cells and Leydig cells were not damaged. Other frequent changes included hypertrophic spermatocytes, hypertrophic early spermatids, nonelongated late spermatids, nonelongated multinucleated late spermatids, multinucleated and binucleated early spermatids. A quantitative study done by counting tubular cross-sections with presence of the changes described showed a significant increase of frequency in the rabbits submitted to orthostatic collapse. The histological changes can be related primarily to the circulatory disturbance leading to oligaemia and consequently to anoxia and are strikingly similar to those following experimental ischemia of testis.


"Imagine if I'm not here, what they're going to do?"-Health-care access and culturally and linguistically diverse women in prison.
Women in prison have complex medical needs and poorer health status than the general population. Culturally and linguistically diverse (CALD) women in prison, particularly those with limited English proficiency (LEP), have distinct needs and risk additional isolation, discrimination and marginalization when they are in prison. We sought to examine how cultural and linguistic diversity, particularly LEP, affects the health-care experiences of women in prison. We conducted focus groups and semi-structured qualitative interviews with CALD women and frontline nursing staff in the three female Correctional Centres in New South Wales, Australia. Participants comprised 30 women in prison and nine nurses. Both women and staff reported communication difficulties as a significant and additional barrier to accessing and receiving health care. For some women with LEP, barriers to care were perceived as discrimination. Fellow prisoners were often utilized as support persons and informal interpreters ("peer interpreters") in place of formally trained interpreters. While peer interpreters were perceived as useful, potential challenges to their use were vulnerability to coercion, loss of confidentiality, untrained health advice and errors of interpretation. The persistent use of peer interpreters in prison is complicated by the lack of clearly defined roles, which can include informal peer support roles and lay health advice. These are highly complex roles for which they are unlikely to be adequately trained or supported, despite perceived benefits to their use. Improved understanding and facilitation of health-related communication could enhance equity of access for CALD women in prison.


Prognostic value of the endothelial activation and stress index in patients with upper tract urothelial cancer undergoing radical nephroureterectomy.
The relationship with endothelial activation and stress index (EASIX), which represents the degree of endothelial dysfunction, is unwell known in upper tract urothelial carcinoma (UTUC). The present study aims to assess the prognostic value of the EASIX for recurrence-free survival (RFS) and overall survival (OS) in patients with UTUC who underwent radical nephroureterectomy (RNU). We retrospectively reviewed the clinical data of 627 patients with UTUC who underwent RNU without neoadjuvant chemotherapy at three hospitals between 2002 and 2019. EASIX scores were calculated using the formula "serum lactate dehydrogenase (U/L)×creatinine (mg/dL)/platelet count (109/L)" and evaluated based on log2-transformed values. We divided the patients according to the EASIX score (>1.27 vs. ≤1.27). Among 627 patients, 380 were finally analyzed. Using maximally selected log-rank statistics, the optimal EASIX cutoff value was 1.27 on the log2 scale. The baseline characteristics were similar between the two groups except for age. The high EASIX score group had worse RFS and OS than the low EASIX score group (log-rank p=0.001 and p=0.006, respectively). At 5 years, the mean RFS and OS difference between the low and high EASIX score groups was 11.1 and 7.35 months, respectively. High EASIX score remained a key prognosticator of RFS and OS after RNU in multivariable analysis. EASIX score may represent endothelial dysfunction in patients with UTUC and may serve as a readily available prognostic factor for oncologic outcomes.


[Interferon inhibits transformation of mouse tk- cells by a recombinant plasmid carrying the thymidine kinase gene].
Thymidine kinase deficient L cells treated by interferon become resistant to transformation by a recombinant plasmid carrying the herpes virus tk gene. The number of colonies appearing after transformation is inversely proportional to the interferon concentration.


Using static MLC fields to replace partial transmission cerrobend blocks in treatment planning of rectal carcinoma cases.
A treatment planning technique has been developed for using static multileaf collimators to replace partial transmission blocks for treating rectal or cervix carcinoma. The static MLC fields were used to replace the partial transmission block of the anterior-posterior pelvis field for the so-called "thunderbird" technique. Treatment plans were developed and evaluated on a commercial three-dimensional treatment planning system (FOCUS, Computerized, Medical Systems, St. Louis, MO). The result of the treatment plan comparison indicates that the static MLC fields are capable of achieving the same target, inguinal and pelvic dose distribution as the partial transmission cerrobend blocked fields. The MLC fields are easy to modify particularly for the match line adjustments. In conclusion, it is efficient and effective to use static MLC fields to replace partial transmission blocks in the "thunderbird" technique for treating rectal or cervix carcinoma.


Monocystis julkae sp.nov., (Protista: Apicomplexa: Monocystidae) a new aseptate gregarine species of the genus Monocystis Stein, 1848 obtain from an Indian Earthworm, Eutyphoeus kherai, Julka, 1978.
During the course of a biodiversity survey of the endoparasitic aseptate gregarines in the Malda district of West Bengal, India, seminal vesicles of the earthworm, Eutyphoeus kherai, Julka 1978 were found to be infested with a new species, Monocystis julkae sp.nov., of the genus, Monocystis Stein (Arch Anat Phys Med 181-223, 1848). The trophozoite is elongated but slightly constricted posteriorly. A tail like protrusion appears in the posterior end. Anterior end is rather wider than the posterior one. The whole body size of the trophozoite measures 102.2-184.0 (126.7 ± 19.9) µm × 40.9-81.8 (58.2 ± 10.0) µm. Size of the nucleus ranges from 10.2 to 16.3 (11.9 ± 1.9) µm × 8.1-12.2 (8.8 ± 1.2) µm. The gametocysts are ovoidal containing two unequal gametocytes. Diameter of it measures 61.3-98.1 (75.8 ± 8.6) µm. Oocysts are navicular and measures 6.9-10.0 (8.7 ± 0.9) µm × 3.0-4.6 (4.3 ± 0.4) µm.


Prior exposure to major flooding increases individual preparedness in high-risk populations.
July 2007 brought unprecedented levels of flooding to the United Kingdom. Health and financial implications were vast and still are emerging. Hydrological disasters will increase in frequency. Therefore, individual preparedness is paramount, as it may mitigate some of the devastating impacts of flooding. Literature on individual preparedness for flooding is scarce, so it is key that current levels of awareness, information gathering, and protective behaviors are investigated. It also is not clear whether being in a high-risk area or having recent exposure to flooding are motivational factors for preparedness. The objectives of this study were to: (1) ascertain whether prior experience with flooding is a strong motivational factor for preparedness for future flooding episodes; and (2) assess preparedness in populations at high risk for flooding. A prospective questionnaire survey was sent to individuals living in two towns in the United Kingdom, Monmouth and Tewkesbury. Both towns are deemed to be at significant risk for flooding, and Tewkesbury was severely affected by the July 2007 flooding disaster. Data were obtained from these two populations and analyzed. A total of 125 responses (of 200) were returned, and demographic data indicated no major differences between the two populations. The number of protective behaviors was higher from participants from Tewksbury (flood risk and exposure; p=0.004). Participants from Tewkesbury were more likely to be aware of living in a flood-risk area and of the emergency systems present in the area, and feel prepared for future episodes of major flooding (p=0.03, p=0.005). Awareness of living in a flood risk-area increased the likelihood of being knowledgeable about emergency systems and adopting protective behaviors (p=0.0053, p=0.043). However, feeling prepared for future episodes of flooding was not associated with a strong increase in knowledge gained to prepare for flooding or having an increased number of protective behaviors. Awareness of being at-risk for flooding is vital for self-protective behavior. Both awareness of risk and recent exposure are motivational for flood preparedness. Recent exposure to flooding increases awareness, but it is unknown how long this effect will last. Recent exposure increases the preparedness of individuals for major flooding 18 months after major flooding and, if it continues, will help mitigate the devastating health, financial, and social effects of major flooding.


Phase I study of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours.
This phase I study was conducted to determine the recommended phase II doses, safety profile, and antitumour activity of a combination regimen of cisplatin, irinotecan, and epirubicin administered every 3 weeks in patients with advanced solid tumours. Cisplatin and epirubicin were given at fixed doses of 50 and 60 mg m(-2), respectively. The irinotecan dose was escalated at 10 mg m(-2) increments from a starting dose level of 70 mg m(-2). Epirubicin, irinotecan, and their metabolites were measured with HPLC methods. In all, 35 patients received 141 courses of treatment. Irinotecan dose was escalated in seven cohorts up to 130 mg m(-2), and then finally de-escalated to 110 mg m(-2). The dose-limiting toxicity was neutropenic fever. Nonhaematologic toxicities included mild to moderate nausea/vomiting, diarrhoea and fatigue. Of 34 patients with evaluable disease, one patient had a complete response and nine patients had partial response, yielding an overall response rate of 29.4%. Pharmacokinetic parameters of epirubicin were not affected by the sequence of drug administration. However, the AUCs of irinotecan and its metabolites were increased significantly when irinotecan and epirubicin were administered concurrently. This combination regimen has promising broad antitumour activity, and will be further evaluated in phase II studies in multiple tumour types.


Surgical Outcomes of Percutaneous Pinning and Open Locking Plating in Patients With Intra-articular Fractures of the Base of the Fifth Metacarpal.
The purpose of the study was to demonstrate the results of surgical treatment, including percutaneous K-wire fixation after closed reduction (CRKF) or locking plate fixation after open reduction (ORPF), in patients with intra-articular fractures of the base of the fifth metacarpal. We retrospectively reviewed data of 29 patients who received surgical treatment for closed, intra-articular fractures of the base of the fifth metacarpal and were followed up for at least 1 year after surgery. Sixteen of the 29 patients underwent CRKF, whereas 13 patients underwent ORPF. Attempts were made to address intra-articular step-off with closed reduction in all the patients; however, if inadequate, ORPF was performed. Clinical outcomes were evaluated using Disabilities of the Arm, Shoulder, and Hand scores, visual analog scale pain scores, the total active motion (TAM) of the little finger, and grip strength. Osseous union and posttraumatic arthritis of the fifth carpometacarpal joint were also evaluated. K-wire fixation after closed reduction was performed for 13 simple fractures and 3 comminuted fractures; ORPF was performed for 6 simple fractures and 7 comminuted fractures. All the patients had satisfactory subjective outcomes with over 90% grip strength compared with that on the contralateral side and nearly full TAM. All the patients in both the groups achieved osseous union. There were five cases of grade 1 posttraumatic arthritis after CRKF and seven cases of grade 1 posttraumatic arthritis after ORPF. Surgical treatment provided satisfactory results in patients with intra-articular fractures of the base of the fifth metacarpal treated with either CRKF or ORPF. Our data showed that the patients who underwent CPKF had good results, and those who underwent ORPF after attempt failure of close reduction also had good results. Our experience suggests that ORPF can be a backup plan when CRKF cannot be accomplished in a satisfactory way. Therapeutic IV.


Social anhedonia, social networks, and psychotic-like experiences: A test of social deafferentation.
Social connection is robustly associated with physical and mental health. So important is social connection that it features prominently in several etiological theories of serious psychopathology. Most notably, the social deafferentation hypothesis of schizophrenia posits that social anhedonia (SA) and isolation cause neural changes that produce psychosis. Here, we test several tenants of this theory by examining the relation between SA, psychotic-like experiences (PLE), and social networks. We find that SA and PLE are related to social networks, and that the relation between SA and PLE can be explained, in part, by the impact of SA on social networks.


Avocado roots treated with salicylic acid produce phenol-2,4-bis (1,1-dimethylethyl), a compound with antifungal activity.
We demonstrated the ability of salicylic acid (SA) to induce a compound in avocado roots that strengthens their defense against Phytophthora cinnamomi. The SA content of avocado roots, before and after the application of exogenous SA, was determined by High-Performance Liquid Chromatography (HPLC). After 4h of SA feeding, the endogenous level in the roots increased to 223 μg g(-1) FW, which was 15 times the amount found in control roots. The methanolic extract obtained from SA-treated avocado roots inhibited the radial growth of P. cinnamomi. A thin layer chromatographic bioassay with the methanolic extract and spores of Aspergillus showed a distinct inhibition zone. The compound responsible for the inhibition was identified as phenol-2,4-bis (1,1-dimethylethyl) by gas chromatography and mass spectrometry. At a concentration of 100 μg/mL, the substance reduced germinative tube length in Aspergillus and radial growth of P. cinnamomi. A commercial preparation of phenol-2,4-bis (1,1-dimethylethyl) caused the same effects on mycelium morphology and radial growth as our isolate, confirming the presence of this compound in the root extracts. This is the first report of the induction of this compound in plants by SA, and the results suggest that it plays an important role in the defense response of avocado.


The direction of spread of alpha activity over the scalp.
The direction of spread of alpha activity over the scalp was studied using the modified 'entropy analysis' method which distinguishes the direction of time differences between two correlated signals in the alpha band. The resting EEG was recorded from F3, F4, C3, C4, P3, P4, O1 and O2, each referenced to linked ears in 10 subjects. The directed measure of correlation of alpha activity in two directions (e.g., from O1 and O2 and from O2 to O1) was obtained from all possible pairs of electrodes. The dominant longitudinal direction of alpha activity was found to be anterior to posterior within as well as across hemispheres. No dominant transverse direction was found. This suggests that the spread of alpha activity over the scalp is in the dominant anterior-posterior direction.


An exploration of factors influencing physiotherapists' involvement in student clinical education.
The demand for physiotherapy student clinical placements is increasing in many countries, including Australia, and there is continued reliance on physiotherapists to assume the student clinical educator role. Exploring factors influencing physiotherapists' decision to be involved in clinical education is essential to maintaining and building clinical education capacity for the future. To explore factors influencing Australian physiotherapists' decision to be involved in student clinical education. A qualitative study using data collected from a valid and reliable online survey tool. Respondents were physiotherapists representing public and private workplaces across varied geographical settings in Australia. Data were thematically analyzed. Surveys were completed by 170 physiotherapists. Most respondents were employed in hospital (81/170, 48%) and private (53/170, 31%) settings in metropolitan locations (105/170, 62%). Six themes representing factors influencing physiotherapists' involvement in student clinical education were identified, including perceptions of: professional duty, personal benefits or gains, suitability of workplace, support requirements, role related challenges, and readiness to be a clinical educator. Many factors influence physiotherapists' decisions to assume the clinical educator role. This study could assist clinical education stakeholders to provide practical and targeted strategies to overcome challenges, and optimize support, for physiotherapists in the clinical educator role.


Prevalence of 'Mother/Infant Friendly Worksite Designations' and state laws regulating workplace breastfeeding support in the United States.
Human milk is the normative infant feeding standard. Yet breastfeeding rates in the United States are suboptimal as many women discontinue breastfeeding upon return to work. As a result, the Unites States Congress included the Break time for Nursing Mothers law in the Patient Protection and Affordable Care Act of 2010 (ACA). The law mandates that employers provide break time and a private space for employees to express breastmilk. This federal legislation does not cover all employees. The purpose of this project was to identify state legislation and Mother/Infant Friendly Worksite Designations (MIFWD) that provide additional protections to working, breastfeeding mothers. We reviewed websites from the United States Breastfeeding Committee and state health departments, and found 27 states have legislation related to breastfeeding in the workplace, and eight states have active MIFWD program. State laws and designation programs are important additions to federal legislation to support employees not covered by the ACA provision.


Lipoxins: update and impact of endogenous pro-resolution lipid mediators.
Lipoxins (LXs) are endogenously produced eicosanoids that are typically generated by transcellular biosynthesis. These trihydroxytetraene-containing lipid mediators and their stable synthetic analogues possess a wide spectrum of anti-inflammatory and pro-resolution bioactions both in vitro and in vivo. More recently, LXs have emerged as potential anti-fibrotic mediators that may influence pro-fibrotic cytokines and matrix-associated gene expression in response to platelet-derived growth factor (PDGF). Here we review the biosynthesis, metabolism and bioactions of LXs and LX analogues and their therapeutic potential.


Single-channel studies on linear gramicidins with altered amino acid sequences. A comparison of phenylalanine, tryptophane, and tyrosine substitutions at positions 1 and 11.
The relation between chemical structure and permeability characteristics of transmembrane channels has been investigated with the linear gramicidins (A, B, and C), where the amino acid at position 1 was chemically replaced by phenylalanine, tryptophane or tyrosine. The purity of most of the compounds was estimated to be greater than 99.99%. The modifications resulted in a wide range of conductance changes in NaCl solutions: sixfold from tryptophane gramicidin A to tyrosine gramicidin B. The conductance changes induced by a given amino acid substitution at position 1 are not the same as at position 11. The only important change in the Na+ affinity was observed when the first amino acid was tyrosine. No major conformational changes of the polypeptide backbone structure could be detected on the basis of experiments with mixtures of different analogues and valine gramicidin A (except possibly with tyrosine at position 1), as all the compounds investigated could form hybrid channels with valine gramicidin A. The side chains are not in direct contact with the permeating ions. The results were therefore interpreted in terms of modifications of the energy profile for ion movement through the channel, possibly due to an electrostatic interaction between the dipoles of the side chains and ions in the channel.


A new role for zinc in the brain.
Certain neurons in the auditory cortex release zinc to influence how the brain processes sounds.


Effectiveness of a fenofibrate 145-mg nanoparticle tablet formulation compared with the standard 160-mg tablet in patients with coronary heart disease and dyslipidemia.
To compare the effectiveness of a fenofibrate 145-mg nanoparticle tablet formulation with the standard 160-mg tablet in patients with dyslipidemia and coronary heart disease. Retrospective medical record review. Outpatient university-affiliated cardiology clinic. One hundred thirty patients with dyslipidemia and coronary heart disease treated for a minimum of 6 months with fenofibrate 160 mg/day (with or without 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor [statin] therapy) who were then switched to a minimum of 3 months of treatment with fenofibrate 145 mg/day. Low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride levels were compared during treatment with each formulation. In patients not taking statins, statistically significant reductions of 4.6% and 2.3%, respectively, were noted in mean triglyceride and LDL levels after the switch to fenofibrate 145 mg/day. In patients taking statins, statistically significant reductions of 5.1% and 2.8%, respectively, were observed in mean triglyceride and LDL levels. In total, a larger proportion of patients had 10% or greater improvement in LDL (14/130 [11%]) and triglyceride (32/130 [25%]) levels compared with the proportion of patients who had 10% or greater worsening in LDL (3/130 [2%]) and triglyceride (9/130 [7%]) levels, and a net additional 14 patients (11%) achieved National Cholesterol Education Program (NCEP) lipid panel targets after the switch to fenofibrate 145 mg/day. Mean HDL level was not significantly different after the switch to fenofibrate 145 mg/day. Safety parameters of fenofibrate 145-mg/day therapy were not examined, although fenofibrate 160 mg/day is generally well tolerated. Eleven percent of the patients in our study had improvements in their lipid profiles that resulted in achievement of NCEP lipid panel targets after treatment with the 145-mg nanoparticle formulation of fenofibrate. This improvement in lipid levels may have been related to increased bioavailability of the 145-mg formulation. However, the exact mechanism of the improvement in lipid levels is unknown.


Preauricular pull through flap for reconstruction of the auricle.
Reconstruction of the crus of the antihelix after tumor resection is a significant surgical challenge and to date no ideal method has been described. The authors present a novel approach using a pedicled flap from preauricular excess skin, which is tunneled through the helix to the anterior auricular surface. The presented technique was successfully applied in a series of three patients requiring reconstruction of the superior and inferior crus of the antihelix after resection of skin malignancies. Technique and outcomes are described in detail. Postoperative course was uneventful in all patients and all flaps healed with excellent esthetic results. Initial flap edema was observed in two cases that resolved spontaneously. The preauricular pull-through flap is a versatile, straightforward, and reliable method for reconstruction of auricular defects located at the superior and inferior crus of the antihelix, including the triangular fossa, using the natural preauricular skin excess.


Comparison of the degradation mechanisms of diclofenac in the presence of iron octacarboxyphthalocyanine and myeloperoxidase.
The degradation process of diclofenac (DCF) by hematoprotein myeloperoxidase (MPO) and iron octacarboxyphthalocyanine (FePcOC) in the presence of hydrogen peroxide was compared. During the oxidation of diclofenac, in the presence of iron octacarboxyphthalocyanine (FePcOC) and hydroxyl radicals (HO•) (from H2O2), an intermediate product (dimer with an m/z value of 587) with the characteristic yellow colouration and an intense band at λmax = 451 nm is formed. Iron octacarboxyphthalocyanine oxidises in the presence of hydrogen peroxide, following the first-order reaction kinetics for FePcOC and H2O2. The concentration of diclofenac does not affect the initial reaction rate. For comparison, the oxidation of DCF in the presence of myeloperoxidase and hydrogen peroxide also provided yellow-coloured solutions with an absorption maximum at λmax = 451 nm. However, LC-MS/MS analysis indicates the presence of at least seven main products of the diclofenac oxidation process in the final reaction mixture, including two dimers with the ion mass [M-H]¯ = 587.01. The mechanism of the diclofenac degradation with hematoprotein myeloperoxidase is more complex than with iron octacarboxyphthalocyanine. Furthermore, the biological activity of diclofenac and DCF dimer (iron octacarboxyphthalocyanine and hydroxyl radicals degradation product) was tested. In this case, the long-term assayed in vitro against E. coli, colorectal HCT116 and melanoma Me45 cancer cells were performed.


The bidirectional impact of perceived and enacted support on mood in bipolar outpatients: A two-year prospective study.
Bipolar disorder (BD) is a chronic illness, and a great need has been expressed to elucidate factors affecting the course of the disease. Social support is one of the psychosocial factors that is assumed to play an important role in the course of BD, but it is largely unknown whether the depressive and/or manic symptoms also affect the patients' support system. Further, the perception of one's social support appears to have stronger effects on disease outcomes than one's enacted or received support, but whether this also applies to BD has not been investigated. The objective of this study is to examine temporal, bidirectional associations between mood states (depression and mania) and both enacted and perceived support in BD patients. The current study was conducted among 173 BD I and II outpatients, with overall light to mild mood symptoms. Severity of mood symptoms and social support (enacted as well as perceived) were assessed every 3months, for 2years (1146 data points). Multilevel regression analyses (linear mixed-models) showed that lower perceived support during 3months was associated with subsequent higher levels of depressive, but not of manic symptoms in the following 3months. Vice versa, depressive symptoms during 3months were associated with less perceived support in the following 3months. Further, manic symptoms during 3months were associated with less enacted support in the subsequent 3 months. The current study suggests that perceived, but not enacted, support is consistently related to depressive symptoms in a bidirectional way, while mania is specifically associated with a subsequent loss of enacted support. Clinical implications of the current findings are discussed.


The use of erythromycin in a general practice.
It would appear that erythromycin is a safe drug to use in general practice; it is indicated, and has advantages, in the treatment of infections of both the upper and lower respiratory tracts.


Size-specific reproductive parameters in red algae: a comparative analysis for two sympatric species from Central Chile.
Ahnfeltia durvillaei and Gymnogongrus furcellatus, two intertidal red algae from central Chile, often grow sympatrically and their gametophytic phases are dominant in the field, but recruitment is low. A shortterm comparative analysis of the reproductive behavior of their gametophytes was carried out to determine quantitative levels of reproduction and their degree of functional similarity. Size, rather than age, was evaluated as predictor of fecundity. Both species showed the same qualitative patterns, although maintaining quantitative differences. Reproductive plants were recorded throughout the size range, and fecundity increased continuously and directly with size. A size-independent threshold in reproductive effort was found for each species, and the variance of effort values decreased inversely with size. Vertical, size-specific life tables revealed low dependence of survivorship with size, and reproductive values exhibited a maximum at the same size class for both species. This last pattern, and a negative relationship found between fecundity and survivorship, suggest the existence of costs or trade-offs operating at the phenotypic level, but they would not be supported in a selective context.