Acute metabolic actions of des-(B27–B30)-insulin and related analogues in adult rats

Metabolic potencies of the destetrapeptide insulin analogues des-(B27–B30)-insulin, des-(B27–B30)-insulin-B26-amide, [Thr^B26] des-(B27–B30)-insulin-B26-amide and [Glu^B26] des-(B27-B30)-insulin-B26-amide were studied in anaesthetized adult rats and in primary cultures of rat hepatocytes and compared with that of the native hormone. Hypoglycaemic effects following intravenous bolus injection of insulin or analogues were similar, as were the stimulatory actions on total body glucose disposal during euglycaemic clamping. In these latter studies a maximal stimulation in the range 16–20 mg glucose/kg per hour was observed and identical half-maximally effective serum concentrations for all peptides of about 1 pmol/ml were obtained. Analogue actions on individual peripheral tissues estimated by the uptake of 2-deoxyglucose were not different from those of insulin. In hepatocyte cultures the stimulatory action of destetrapeptide analogues on glycogenesis and on aminoisobutyric acid transport was indistinguishable from that of native insulin, with identical half-maximally effective concentrations. These data demonstrate that des-(B27–B30)-insulin and related destetrapeptide analogues have high biological activity. Since the truncated non-amidated analogue appeared to be monomeric in solution, this peptide could be a candidate for an insulin preparation potentially showing rapid absorption from subcutaneous tissue.     

Initiation of parturition and lactation in the sow: effects of delaying parturition with medroxyprogesterone acetate

The synthetic progestagen, medroxyprogesterone acetate (MPA), was administered to sows in late pregnancy with the objective of slightly delaying the time of farrowing and thereby providing more marked associations between hormonal changes and the termination of pregnancy, and the initiation of farrowing and lactation in this species. MPA was administered orally (140 mg, twice daily) to eight sows in late pregnancy on days 112, 113 and 114 of gestation. Parturition was then induced to occur on day 116 by injecting 200 micrograms cloprostenol i.m. on day 115 of gestation. The peripartum changes in the plasma concentrations of progesterone, cortisol, oestradiol-17 beta, relaxin, prolactin, lactose and 13,14-dihydro-15-keto prostaglandin F2 alpha (PGFM) were measured in these sows together with a group of untreated sows. The gestational length for the MPA-treated sows (116.3 +/- 0.3 days, mean +/- S.E.M.) was significantly (P less than 0.01) greater compared with the untreated sows (114.9 +/- 0.3 days). Plasma progesterone declined earlier (P less than 0.05) with respect to the time of parturition in the treated sows compared with the untreated group. With respect to the timing of parturition, the time at which maximal concentrations of relaxin were attained and the timing of the subsequent decline were earlier in the MPA-treated sows. In both groups of sows, the concentration of relaxin increased before the decline in plasma progesterone. In the untreated sows, the concentration of PGFM increased either slightly before or at the same time as the decline in plasma progesterone, whereas in sows treated with MPA, progesterone concentrations began to decline before any significant increase in the plasma concentration of PGFM. The profiles of cortisol, oestradiol-17 beta and PGFM were similar in both groups of sows. In both groups of sows, the timing of the initial increase in the concentration of plasma prolactin coincided with a similar rise in plasma lactose (P less than 0.01). Plasma progesterone either declined earlier or at the same time as the rise in plasma lactose (P less than 0.01) in the treated group of sows only. We conclude that since the prepartum changes in the concentration of progesterone and relaxin occurred before significant changes in the concentration of PGFM in the MPA-treated sows, the nature of the luteolytic factor and the mechanism by which it exerts its action remains obscure. The higher concentration of lactose in the mammary secretion at birth in the MPA-treated sows compared with the untreated group suggested that lactogenesis was initiated earlier with respect to parturition following MPA treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intragastric pH during continuous infusion with pantoprazole in patients with bleeding peptic ulcer

OBJECTIVES: In managing patients with bleeding peptic ulcers, prevention of rebleeding is a particular challenge to hemostasis and fibrinolysis, both of which involve reactions that are impaired in acidic gastric environment. Therefore, such patients are expected to benefit from profound acid suppression. The present investigation aimed to establish a safe and, with regard to pH elevation, effective treatment that, based on in vitro evidence, should provide clinical benefit in this patient population. METHODS: Patients with acute bleeding peptic ulcers (Forrest Ia, Ib, IIa) after successful endoscopic hemostasis were enrolled in two pilot studies (N = 20 each). They were given an intravenous bolus injection of 80 mg of pantoprazole immediately followed by continuous infusion of either 6 mg/h or 8 mg/h pantoprazole for 72 h. Intragastric pH was measured continuously over 24 h and, if possible, for up to 48 h. RESULTS: Intragastric pH increased rapidly to values of about 6 with both treatments. For the 0-24 h period, the median pH values were 6.1 (68% range 4.5-7.4) and 6.1 (68% range 5.2-6.7) in patients receiving 6 mg/h and 8 mg/h continuous infusion, respectively; the values for the 0-48 h period were 5.9 (4.9-6.7) and 6.3 (5.5-7.0), respectively. The median percentage time that pH was > or =6 during the 0-48 h interval was 47% (68% range 28-89) for the 6 mg/h treatment group and 64% (68% range 41-84) for the 8 mg/h treatment group. Both treatment regimens with pantoprazole were well tolerated based on electrocardiographic measurements, vital signs, clinical laboratory values, and adverse events. CONCLUSIONS: Compared with the infusion with 6 mg/h pantoprazole, the continuous infusion of 8 mg/h pantoprazole showed a lower interindividual variability of the intragastric pH and a greater percentage of time that pH was >/ or =6. Thus, with regard to safety and efficacy, an initial 80-mg bolus injection, followed by 8 mg/h continuous infusion, seems to be the adequate treatment in patients with a high risk of rebleeding.     

Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.     

Natürlicher Verlauf bei Hüftdysplasie und Operationsergebnisse

Background

The prevalence of hip dysplasia in epidemiological studies ranges from 1–20%. The associated deformity is a risk factor for secondary osteoarthritis (OA) of the hip.

Objective

What is the natural course of hip dysplasia and is it influenced by cofactors? How successful are corrective surgical procedures?

Material and methods

Analysis of published investigations up to 2018 which provide data about the natural course of hip dysplasia and the results of the most important surgical treatment procedures.

Results

The vast majority of published studies confirm a correlation between hip dysplasia and OA. The risk of OA increases with reduced acetabular coverage and severity of instability (subluxation). Long-term survival and functional results after pelvic osteotomies are meanwhile very good, if the procedure is performed in young or middle-aged patients with good congruency of the joints and no relevant OA. Additional deformities (e.?g. cam deformity or femoral torsional malalignment) should be simultaneously addressed and the acetabular fragment needs optimal positioning. Only a few studies with small patient cohorts and short observation times are currently available on the isolated arthroscopic treatment of borderline dysplasia.

Discussion

The importance of hip dysplasia as an established risk factor for secondary OA and the good results of reorientation pelvic osteotomies justify surgical correction when considering the identified indication criteria. Due to a low but relevant potential for complications, surgery should currently not be recommended for asymptomatic patients in adulthood. Potentially relevant cofactors are important for estimation of the natural course as well as the indications for surgical correction.

     

The Role of Families in Adolescent and Young Adults’ PrEP Use

AIDS and Behavior - While pre-exposure prophylaxis (PrEP) is a key HIV prevention tool for adolescents and young adults (AYAs), its initiation and sustained use is shaped by AYAs’ unique...