Pharmacological characteristics and species-related variations of β3-adrenergic receptors

Summary— Beta-adrenergic receptors (β/-AR) belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three subtypes have been identified: β₁-, β₂- and β₃-AR. Much of the work delineating the precise pharmacological comparison of the three β-ARs has come from investigations with stably transfected Chinese hamster ovary cells (CHO cells). This review discusses the structure and function of β₃-AR in various species and presents new findings on a number of β₃-AR ligands including carazolol, tertatolol and CL 316,243 which were found to be selective and potent β₃-AR agonists and ZD 2079 and salmeterol which appear to display full but non-subtype selective agonistic activity. Species-related variations of the β₃-AR pharmacology have been shown for propranolol and bupranolol. With the ongoing characterization of the β₃-AR at the molecular and cellular level, and with the advent of computer-assisted molecular modelling to aid in the determination of the three-dimensional structure of the receptor, it is thought that novel β₃-AR compounds will become available with improved selectivity and potency.     

Nasal IgA response in wheezy infants

It is unknown why some infants wheeze during upper respiratory tract infections. One possibility is that secretory IgA, which has a major role in mucosal defence against viral infection, might be deficient in wheezy infants. The nasal IgA response to upper respiratory tract infection in 32 wheezy infants (median age 5.8 months) was compared with nine siblings (median age 2.6 years) who had nasal symptoms only. Nasal lavage was performed during infections and on follow up when free from symptoms, using inulin as a marker of dilution to determine absolute concentrations of IgA in the nasal secretions. The two groups showed a similar increase in total IgA and total protein levels during infection, but secretory IgA concentrations were unchanged. This study shows that wheezy infants have a normal nasal IgA response to infection and that the increase in total IgA during early infection is due to plasma exudation rather than increased production of secretory IgA.     

Differential interleukin-1 elaboration by density-defined human monocyte subpopulations

Interleukin-1 (IL-1) is an important immunoregulatory peptide produced by monocytes and macrophages. Because mononuclear phagocytes are morphologically and functionally heterogeneous, we examined whether they differ in their ability to elaborate IL-1. We used discontinuous Percoll gradients to obtain five density-defined human blood monocyte subpopulations. Unfractionated monocytes and their subsets were compared for their ability to stimulate thymocyte proliferation. Supernatants obtained from the denser monocytes consistently contained more IL-1 activity than did supernatants from the less dense cells. This difference in IL-1 activity was the result of differences in IL-1 elaboration, not the selective production of an inhibitor of IL-1- induced thymocyte proliferation. These data demonstrate that density- defined human monocyte subpopulations differ in their capacity to elaborate IL-1.     

Tibolone,transdermal estradiol or oral estrogen–progestin therapies: Effects on circulating allopregnanolone,cortisol and dehydroepiandrosterone levels

The aim of the present study was to evaluate, in healthy postmenopausal women, the impact of tibolone (2.5?mg), transdermal estradiol (50?μg) (TE) and different oral estrogen–progestin regimens, conjugated equine estrogens (0.625?mg) plus medroxyprogesterone acetate (5?mg) (CEE?+?MPA) and estradiol (2?mg) plus norethisterone acetate (1?mg) (E2?+?NETA) on circulating estradiol, progesterone, allopregnanolone, cortisol and dehydroepiandrosterone (DHEA) levels. Blood samples were collected before and after 1, 3, 6 and 9 months of treatment in 85 postmenopausal women. Estradiol levels increased (p?<?0.001) in the TE, CEE?+?MPA and E2?+?NETA groups after 1 month of therapy, but did not change in the tibolone group during the entire follow-up period. Both E2?+?NETA and tibolone treatments induced an increase in progesterone levels (p?<?0.05) after 1 year of therapy. Allopregnanolone levels showed an increase in all estrogen-based groups, being significant after 3 months of treatment (p?<?0.01). Patients receiving tibolone showed a significant increase in allopregnanolone levels at 3 months (p?<?0.05), but lower than in the other groups. Cortisol levels decreased significantly in the TE and CEE?+?MPA groups after 6 months and 12 months of treatment, respectively. Neither tibolone nor E2?+?NETA treatments modified circulating cortisol levels. DHEA levels significantly (p?<?0.05) decreased after 6 months of TE or estrogen–progestin therapies independently of the presence or the type of progestin used. In contrast, DHEA remained stable throughout the 12 months of treatment with tibolone. The increase of allopregnanolone, a steroid with sedative and anxiolytic properties, in response to these different treatments could underlie, at least in part, the central effects that hormone replacement therapy and tibolone have on anxiety, mood and behavior. Unlike estrogen-based therapy, tibolone treatment did not reduce the DHEA milieu in the menopause, and thus did not enhance the androgen deficiency syndrome in postmenopausal women.     

A systematic review and meta-analysis of complications following the posterior and lateral surgical approaches to total hip arthroplasty

IntroductionTotal hip arthroplasty is one of the most commonly performed orthopaedic procedures. Despite this, medical evidence to inform the choice of surgical approach is lacking. Currently in the UK, the two most frequently performed approaches to the hip are the posterior and the direct lateral.MethodsThis systematic review was performed according to Cochrane guidelines following an extensive search for prospective controlled trials published in any language before January 2014. Of the 728 records identified from searches, 6 prospective studies (including 3 randomised controlled trials) involving 517 participants provided data towards this review.FindingsCompared with the lateral approach, the posterior approach conferred a significant reduction in the risk of Trendelenburg gait (odds ratio [OR]: 0.31, p=0.0002) and stem malposition (OR: 0.24, p=0.02), and a non-significant reduction in dislocation (OR: 0.37, p=0.16) and heterotopic ossification (OR: 0.41, p=0.13). Neither approach conferred a functional advantage. We draw attention to the paucity of evidence and the need for a further randomised trial.