The value of pre-operative outpatient flexible sigmoidoscopy in patients with deep infiltrating endometriosis.

Background: Deep infiltrating endometriosis (DE) is a particularly severe disease which affects 10-20% of women with endometriosis. 90% of DE is rectovaginal and when suspected, some clinicians have suggested the routine use of flexible sigmoidoscopy to identify intraluminal disease. We aimed to assess the value of sigmoidoscopy prior to surgery for rectovaginal DE, both in terms of diagnosis and planning management. Objectives: We aimed to assess the value of sigmoidoscopy prior to surgery for rectovaginal DE. Materials and Methods: A retrospective case series study was performed from a consecutive cohort of patients with DE referred for outpatient flexible sigmoidoscopy between January 2010 and January 2020. All patients were under the care of a specialist endometriosis multidisciplinary team. Main outcome measures: The primary outcome measure was the incidence of luminal disease. Results: 102 consecutive cases were analysed with no cases confirming intraluminal disease. Non-specific evidence of endometriosis such as tight angulation of the bowel was found in 36.3%. Following sigmoidoscopy 100 patients proceeded to surgery and the risk of bowel resection during surgery was 4%. Conclusions: Due to the low incidence of luminal endometriosis, performing sigmoidoscopy routinely is of limited benefit. We recommend the selective use of sigmoidoscopy where serious pathology such as colorectal neoplasia is considered or to determine the location of endometriosis lesions which aids subsequent resectional surgery planning. What is new?: This large case series details a very low incidence of intraluminal disease and makes recommendations for the specific scenarios where flexible sigmoidoscopy should be used.

Disaster declarations associated with bushfires, floods and storms in New South Wales, Australia between 2004 and 2014.

Australia regularly experiences disasters triggered by natural hazards and New South Wales (NSW) the most populous State is no exception. To date, no publically available spatial and temporal analyses of disaster declarations triggered by hazards (specifically, bushfires, floods and storms) in NSW have been undertaken and no studies have explored the relationship between disaster occurrence and socio-economic disadvantage. We source, collate and analyse data about bushfire, flood and storm disaster declarations between 2004 and 2014. Floods resulted in the most frequent type of disaster declaration. The greatest number of disaster declarations occurred in 2012-2013. Whilst no significant Spearman's correlation exists between bushfire, flood and storm disaster declarations and the strength of the El Niño/Southern Oscillation (ENSO) phase, we observe that bushfire disaster declarations were much more common during El Niño, and flood disaster declarations were five times more common during La Niña phases. We identify a spatial cluster or 'hot spot' of disaster declarations in the northeast of the State that is also spatially coincident with 43% of the most socio-economically disadvantaged Local Government Areas in NSW. The results have implications for disaster risk management in the State.

Hypothemycin inhibits the proliferative response and modulates the production of cytokines during T cell activation.

Hypothemycin, a resorcylic acid lactone antibiotic, was identified as active in a screen for inhibitors of T cell activation. It was found to inhibit the proliferation of mouse and human T cells stimulated with anti-CD3 mAb + PMA and of human PBMC stimulated with anti-CD3 mAb alone. This inhibition was partially reversed by exogenous IL-2 indicating that it is not due to non-specific toxicity. Hypothemycin potently suppressed the production of IL-2 (IC50: 9 nM) but affected IL-2-induced proliferation to a lesser extent (IC50: 194 nM). Hypothemycin also inhibited IL-6, IL-10, IFN-gamma and TNF-alpha production. By contrast, it markedly enhanced the production of IL-4, IL-5 and IL-13. These effects were seen both at the mRNA and protein secretion levels. Analysis of the effect of hypothemycin on CD69 induction suggested that it disrupts calcineurin-independent rather than calcineurin-dependent signaling. Furthermore, hypothemycin was able to inhibit the phosphorylation of ERK1/2 induced by PMA treatment of T cells. Therefore, hypothemycin represents an inhibitor of T cell activation with a novel mode of action and unique modulatory activity on cytokine production.

Inhibition of calcineurin by a novel FK-506-binding protein.

FK-506, a potent immunosuppressive drug, acts during the commitment phase of T-lymphocyte activation to block a subset of calcium-associated events necessary for transcription of certain early lymphokine genes. The drug binds to an abundant, cytosolic 11.8-kDa protein termed the FK-506-binding protein (FKBP12). The FKBP12.FK-506 complex inhibits calcineurin, a calcium-dependent phosphatase that is a component of the signal transduction pathway leading to early lymphokine gene transcription. FKBP12 is one member of a growing gene family. Prior to this report, all other FKBP family members had been irrelevant to the mechanism of action of FK-506 because no other FKBP.FK-506 complexes were able to bind and inhibit calcineurin. Here, we report the purification and characterization of a novel FK-506-binding protein, FKBP12.6. Having 85% amino acid sequence identity to FKBP12, FKBP12.6 is, among the FKBPs, most closely related to FKBP12. When complexed with FK-506, FKBP12.6 binds to and inhibits calcineurin, making it only the second FKBP discovered thus far to do so. The ability to inhibit calcineurin establishes the potential relevance of FKBP12.6 to the immunosuppressive or toxic side effects of FK-506.

The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin.

FK-506 inhibits Ca(2+)-dependent transcription of lymphokine genes in T cells, and thereby acts as a powerful immunosuppressant. However, its potential therapeutic applications may be seriously limited by several side effects, including nephrotoxicity and neurotoxicity. At present, it is unclear whether these immunosuppressive and toxic effects result from interference with related biochemical processes. FK-506 is known to interact with FK-binding protein-12 (FKBP-12), an abundant cytosolic protein with cis-trans peptidyl-prolyl isomerase activity (PPIase) activity. Because rapamycin (RAP) similarly binds to FKBP-12, although it acts in a manner different from FK-506, by inhibiting T cell responses to lymphokines, such an interaction with FKBP-12 is not sufficient to mediate immunosuppression. Recently, it was found that the complex of FKBP-12 with FK-506, but not with RAP, inhibits the phosphatase activity of calcineurin. Here, we used L-685,818, the C18-hydroxy, C21-ethyl derivative of FK-506, to explore further the role of FKBP-12 in the immunosuppressive and toxic actions of FK-506. Although L-685,818 bound with high affinity to FKBP-12 and inhibited its PPIase activity, it did not suppress T cell activation, and, when complexed with FKBP-12, did not affect calcineurin phosphatase activity. However, L-685,818 was a potent antagonist of the immunosuppressive activity of both FK-506 and RAP. Moreover, L-685,818 did not induce any toxicity in dogs and rats or in a mouse model of acute FK-506 nephrotoxicity, but it blocked the effect of FK-506 in this model. Therefore, FK-506 toxicity involves the disruption of biochemical mechanisms related to those implicated in T cell activation. Like immunosuppression, this toxicity is not due to the inhibition of the PPIase activity of FKBP-12, but may be linked to the inhibition of the phosphatase activity of calcineurin by the drug FKBP-12 complex.

Growth and academic achievement in inner-city kindergarten children. The relationship of height, weight, cognitive ability, and neurodevelopmental level.

Measures of height, weight, nonverbal cognitive ability (Ravens progressive matrix), visual-motor-perceptual ability (Beery-Buktenica test of Visual Motor Integration [VMI]), the imitation-of-gestures technique, and academic achievement (Stanford Early Achievement) were obtained for a sample of 82 children from a poor inner-city community. In contrast to prior reports from the United States and about other developed countries, anthropometric measures were related both to academic achievement and to these measures of neurodevelopment. They were not consistently related to measures of nonverbal cognitive ability. Regression analyses revealed that general cognitive ability contributed more variance (39%) to predictions of achievement than all other variables, including weight for age (13%) and VMI (6%). Children with reduced somatic growth were likely to do poorly in school, but the data do not show that undernutrition causes learning failure. Rather, they suggest that environmental problems affecting the development of thought processes and nutrient intake precede both growth and learning failure.

Human monoclonal antibodies that protect mice against challenge with Pseudomonas aeruginosa.

Lymphocytes from healthy volunteers and from cystic fibrosis patients were transformed with Epstein-Barr virus and cultured at a limiting dilution to generate lymphoblastoid cell lines that secreted human monoclonal antibodies specific for lipopolysaccharide (LPS) from Pseudomonas aeruginosa. Three cell lines (RM5, FDD7, and 11F9) produced immunoglobulin M (IgM) antibody species that reacted specifically with P. aeruginosa Fisher immunotypes 2, 4, and 5, respectively, and with LPS extracted from these immunotypes. A fourth cell line (9H10) produced a single IgM antibody species that recognized P. aeruginosa immunotypes 3, 6, and 7 and LPS extracted from them. Monoclonal antibodies secreted by cell lines RM5, FDD7, and 11F9 protected neutropenic mice prophylactically against challenge with P. aeruginosa immunotypes 2, 4, and 5, and those secreted by 9H10 protected against P. aeruginosa immunotypes 3 and 6 but did not protect against immunotype 7. In vivo experiments indicated that antibodies protected mice against infection by increasing the rate of bacterial clearance.

X-linked immunodeficient mice as a model for testing the protective efficacy of monoclonal antibodies against Pseudomonas aeruginosa.

(DBA/N[female] X CBA/2[male])F1 males have been reported to be deficient in producing antibodies against a number of antigens, including carbohydrates (I. Scher, Adv. Immunol. 35:1-71, 1982). We show that F1 male mice, in contrast to females, made less lipopolysaccharide (LPS)-specific antibodies after immunization with heat-inactivated Pseudomonas aeruginosa and had significantly less naturally occurring LPS-specific antibodies. Furthermore, neutropenic males were 50 to 1,000 times more sensitive to challenge with representative isolates belonging to the seven Fisher immunotypes. Administration to neutropenic F1 males of a human monoclonal antibody specific for the O carbohydrates of P. aeruginosa immunotype 2 LPS or administration of serum from rabbits immunized with heat-inactivated P. aeruginosa immunotype 1 raised the level of resistance to bacterial challenge close to that of females. The results show that the X-linked immunodeficient mouse is an excellent model with which to test the protective efficacy of P. aeruginosa-specific monoclonal antibodies.

Anxiety, cognitive style, and mathematics achievement.

This study examined the relationship among state and trait anxiety, cognitive style, and mathematics achievement. The Ss were 50 junior college students enrolled in a mathematics course. The results confirmed the hypothesis that high state anxiety would be associated with poor mathematics achievement; trait anxiety showed no significant relationship to achievement. The need to develop learning aids and strategies to counteract the possible debilitating effects of state anxiety in learning and mathematics assessment was discussed.

Self-regulation and external reinforcement in problem-solving strategies of black adolescents.

Examined the relationships among self-regulatory behaviors, perceptions of social reinforcement from significant persons, and the problem-solving performance of black adolescents (N = 33). The components of self-regulatory processes--self-reinforcement, self-evaluation and self-monitoring--were interrelated highly. Ss' perception of neither positive nor negative social reinforcement was related significantly to problem-solving performance. Discussion centered around the effects of self-responsibility and affective factors in the achievement orientation of minority children.

American and British data on a three dimensional assessment of personality in college students.

Reported data on American and British college student samples for the new Psychoticism, Extraversion, and Neuroticism (PEN) Inventory. Descriptive statistics for PEN dimensions for five American female samples (total 492 subjects), five American male samples (total 399 subjects), one British female sample (700 subjects) and one British male sample (700 subjects) were summarized. Intercorrelations of PEN dimensions for most of the American samples were reported. The pattern of significant intercorrelations tended to be in accord with previous work on prior related inventories. Similarities and differences among the sample descriptive statistics were discussed.

X-ray analysis and circular dichroism of the acid protease from Endothia parasitica and chymosin.

The structure of an acid proteinase from Endothia parasitica has been solved by x-ray diffraction using multiple isomorphous replacement. A 3 A resolution map was interpreted in terms of a bilobal structure with a long 25 A cleft. The secondary structure is mostly distorted beta-sheet. The circular dichroism was measured and model curves for different secondary structures were fitted by least squares indicating a large component of beta-structure. The structure was seen to be homologous with that of the acid proteinase from R. Chinensis and hence with pepsin and chymosin. A rotation function against diffraction data from chymosin crystals confirm confirm this and suggested an approach to the solution of this structure.