Interactions of sodium pentobarbital with d-glucose and l-sorbose transport in human red cells

AbstractPentobarbital acts as a mixed inhibitor of net d-glucose exit, as monitored photometrically from human red cells. At 30°C the Ki of pentobarbital for inhibition of Vmax of zero-trans net glucose exit is 2.16±0.14 mM; the affinity of the external site of the transporter for d-glucose is also reduced to 50% of control by 1.66±0.06 mM pentobarbital. Pentobarbital reduces the temperature coefficient of d-glucose binding to the external site. Pentobarbital (4 mM) reduces the enthalpy of d-glucose interaction from 49.3±9.6 to 16.24±5.50 kJ/mol (P<0.05). Pentobarbital (8 mM) increases the activation energy of glucose exit from control 54.7±2.5 kJ/mol to 114±13 kJ/mol (P<0.01). Pentobarbital reduces the rate of l-sorbose exit from human red cells, in the temperature range 45°C–30°C (P<0.001). On cooling from 45°C to 30°C, in the presence of pentobarbital (4 mM), the Ki (sorbose, glucose) decreases from 30.6±7.8 mM to 14±1.9 mM; whereas in control cells, Ki (sorbose, glucose) increases from 6.8±1.3 mM at 45°C to 23.4±4.5 mM at 30°C (P<0.002). Thus, the glucose inhibition of sorbose exit is changed from an endothermic process (enthalpy change=+60.6±14.7 kJ/mol) to an exothermic process (enthalpy change=−43±6.2 7 kJ/mol) by pentobarbital (4 mM) (P<0.005). These findings indicate that pentobarbital acts by preventing glucose-induced conformational changes in glucose transporters by binding to ‘non-catalytic’ sites in the transporter

An integrated care pathway for menorrhagia across the primary–secondary interface : patients' experience, clinical outcomes, and service utilisation

Background: ‘‘Referral’’ characterises a significant area of interaction between primary and secondary care. Despite advantages, it can be inflexible, and may lead to duplication. Objective: To examine the outcomes of an integrated model that lends weight to general practitioner (GP)-led evidence based care. Design: A prospective, non-random comparison of two services: women attending the new (Bridges) pathway compared with those attending a consultant-led one-stop menstrual clinic (OSMC). Patients’ views were examined using patient career diaries, health and clinical outcomes, and resource utilisation. Follow-up was for 8 months. Setting: A large teaching hospital and general practices within one primary care trust (PCT). Results: Between March 2002 and June 2004, 99 women in the Bridges pathway were compared with 94 women referred to the OSMC by GPs from non-participating PCTs. The patient career diary demonstrated a significant improvement in the Bridges group for patient information, fitting in at the point of arrangements made for the patient to attend hospital (ease of access) (p,0.001), choice of doctor (p = 0.020), waiting time for an appointment (p,0.001), and less ‘‘limbo’’ (patient experience of non-coordination between primary and secondary care) (p,0.001). At 8 months there were no significant differences between the two groups in surgical and medical treatment rates or in the use of GP clinic appointments. Significantly fewer (traditional) hospital outpatient appointments were made in the Bridges group than in the OSMC group (p,0.001). Conclusion: A general practice-led model of integrated care can significantly reduce outpatient attendance while improving patient experience, and maintaining the quality of care

A protocol for developing, disseminating, and implementing a core outcome set for adenomyosis research

BACKGROUND: Adenomyosis is a common benign gynaecological condition that has been associated with heavy and/or painful periods, subfertility and poor obstetric outcomes including miscarriage and preterm delivery. Studies evaluating treatments for adenomyosis have reported a wide range of outcomes and outcome measures. This variation in outcomes and outcome measures prevents effective data synthesis, thereby hampering the ability of meta-analyses to draw useful conclusions and inform clinical practice. OBJECTIVES: Our aim is to develop a minimum set of outcomes to be reported in all future studies that investigate any uterus-sparing intervention for treating uterine adenomyosis. Wide adoption of ‘core outcomes’ into research on adenomyosis would reduce the heterogeneity of studies and make data synthesis easier. This will ultimately lead to comparable, prioritised, and patient-centred conclusions from meta-analyses and guidelines. MATERIALS AND METHODS: Outcomes identified from a systematic review of the literature will form a long list, agreed by an international steering group representing key stakeholders, including healthcare professionals, researchers, and public research partners. Through a modified Delphi process, key stakeholders will score outcomes from the agreed long list on a nine-point Likert scale that ranges from 1 (not important) to 9 (critical). Following the Delphi process, the refined outcome set will be finalised by the steering group. Finally, the steering group will develop recommendations for high-quality measures for each outcome. The study was prospectively registered with Core Outcome Measures in Effectiveness Trials Initiative; number 1649. CONCLUSION: The implementation of the core outcome set for adenomyosis in future trials will enhance the availability of comparable data to facilitate more patient-centred evidence-based care. WHAT IS NEW? The core outcome set will facilitate the generation of clinically important and patient centred outcomes for studies evaluating treatments for adenomyosis

Modelling of an aza-Michael reaction from crystalline naphthalene derivatives containing peri–peri interactions: very long N–C bonds?

The separation between a pair of peri-located dimethylamino and ethene-2,2-dinitrile groups in a naphthalene molecule, which models the progress of a Michael reaction, can be controlled by the installation of a short ethylene bridge or the introduction of repulsive interactions at the opposite set of peri positions. Introduction of a dimethylammonium substituent produced a hydrated chloride salt in which the Me2N⋯C(H)[double bond, length as m-dash]C(CN)2 separation between reactive groups decreases, reversibly, from 2.167 Å at 200 K to 1.749 Å at 100 K, with the maximum rate of change in the range 128–140 K, which was studied by variable temperature X-ray crystallography and solid state NMR. From these and other crystallographic data a correlation between Me2N⋯C bond formation and alkene bond breaking was constructed for the first step of an aza-Michael reaction

A Reflection on Types

The ability to perform type tests at runtime blurs the line between statically-typed and dynamically-checked languages. Recent developments in Haskell’s type system allow even programs that use reflection to themselves be statically typed, using a type-indexed runtime representation of types called \{}\textit{TypeRep}. As a result we can build dynamic types as an ordinary, statically-typed library, on top of \{}\textit{TypeRep} in an open-world context

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy

Evidence for modulation of pericryptal sheath myofibroblasts in rat descending colon by Transforming Growth Factor β and Angiotensin II.

BACKGROUND: Absorption of water and Na(+) in descending colonic crypts is dependent on the barrier function of the surrounding myofibroblastic pericryptal sheath. Here the effects of high and low Na(+) diets and exposure to whole body ionising radiation on the growth and activation of the descending colonic pericryptal myofibroblasts are evaluated. In addition the effect of a post-irradiation treatment with the angiotensin converting enzyme inhibitor Captopril was investigated. METHODS: The levels of Angiotensin II type 1 receptor (AT1), ACE, collagen type IV, transforming growth factor-β type 1 receptor (TGF-βR1), OB cadherin and α-smooth muscle actin in both descending colon and caecum were evaluated, using immunocytochemistry and confocal microscopy, in rats fed on high and low Na(+) diets (LS). These parameters were also determined during 3 months post-irradiation with 8Gy from a (60)Co source in the presence and absence of the angiotensin converting enzyme inhibitor, Captopril. RESULTS: Increases in AT1 receptor (135.6% ± 18.3, P < 0.001); ACE (70.1% ± 13.1, P < 0.001); collagen type IV (49.6% ± 15.3, P < 0.001); TGF-β1 receptors (291.0% ± 26.5, P < 0.001); OB-cadherin (26.3% ± 13.8, P < 0.05) and α-smooth muscle actin (82.5% ± 12.4, P < 0.001) were observed in the pericryptal myofibroblasts of the descending colon after LS diet. There are also increases in AT1 receptor and TGF-β1 receptor, smooth muscle actin and collagen type IV after irradiation. Captopril reduced all these effects of irradiation on the pericryptal sheath and also decreased the amount of collagen and smooth muscle actin in control rats (P < 0.001). CONCLUSIONS: These results demonstrate an activation of descending colonic myofibroblasts to trophic stimuli, or irradiation, which can be attenuated by Captopril, indicative of local trophic control by angiotensin II and TGF-β release