Search

ABSTRACTIntroduction: Therapeutic goals in inflammatory bowel diseases (IBD) have evolved, over the last decades, from clinical response to complete remission (clinical and endoscopic remission).Areas covered: Development of biologics and small molecules has been associated with the development of new endpoints in IBD trials that could not have been achieved in the pre-biologics era. Herein, we focus on evolving endpoints for approved biologics and small molecules. We searched for relevant publications using Medline/PubMed, Embase and the Cochrane Library from their inception to 1 July 2019.Expert opinion: Endpoints differ between induction (clinical and endoscopic response) and maintenance trials (clinical and endoscopic remission) because the goal is to evaluate the anti-inflammatory effect of a given drug during induction, whereas full disease control is the ultimate goal during the maintenance phase in order to change patients’ life and disease course. Histological healing has recently emerged as a new co-primary endpoint in ulcerative colitis, and is now part of the definition of mucosal healing in these trials. Whether new endpoints such as transmural and radiologic healing could become an endpoint and replace endoscopy in Crohn’s disease trials in the near future requires further investigation.

Effective communication between healthcare staff and patients is central to development of the patient-professional relationship. Many barriers influence this communication, often resulting in patients' lack of understanding and retention of information, particularly affecting advice regarding lifestyle habits, such as alcohol consumption and smoking. Alcohol and smoking misuse are potentially modifiable risk factors known to adversely affect a variety of gastroenterological conditions and improvements in communication with patients regarding this is an important management component. This review discusses the clinical impact of these factors and how healthcare professionals can improve communication. We discuss how enhancing verbal communication skills through medical training leads to greater outcomes in patient satisfaction and adherence to treatment and advice. In addition, with the rapid digitalisation of society, platforms such as social media and smartphone applications may be considered as adjuncts to traditional forms of communication.

In the era of increasing use of immunosuppressive and biologic therapy for inflammatory bowel disease, environmental influences remain important independent risk factors to modify the course of the disease, affect the need for surgery and recurrence rates post-surgical resection. The effect of smoking on inflammatory bowel disease has been established over the decades, however the exact mechanism of how smoking affects remains as area of research. Alcohol is also among the socio-environmental factors which has been recognised to cause a flare of symptoms in inflammatory bowel disease patients. Nonetheless, the exact relation to date is not fully understood, and various paradoxical results from different studies are still a point of controversy.

Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

The activity and trafficking of the Na+,K+-ATPase are regulated by several hormones, including dopamine, vasopressin, and adrenergic hormones through the action of G-protein–coupled receptors (GPCRs). Arrestins, GPCR kinases (GRKs), 14-3-3 proteins, and spinophilin interact with GPCRs and modulate the duration and magnitude of receptor signaling. We have found that arrestin 2 and 3, GRK 2 and 3, 14-3-3 , and spinophilin directly associate with the Na+,K+-ATPase and that the associations with arrestins, GRKs, or 14-3-3 are blocked in the presence of spinophilin. In COS cells that overexpressed arrestin, the Na+,K+-ATPase was redistributed to intracellular compartments. This effect was not seen in mock-transfected cells or in cells expressing spinophilin. Furthermore, expression of spinophilin appeared to slow, whereas overexpression of β-arrestins accelerated internalization of the Na+,K+-ATPase endocytosis. We also find that GRKs phosphorylate the Na+,K+-ATPase in vitro on its large cytoplasmic loop. Taken together, it appears that association with arrestins, GRKs, 14-3-3 , and spinophilin may be important modulators of Na+,K+-ATPase trafficking.

Agonist activation regulates reciprocal interactions of spinophilin and arrestin with the α2A- and α2B -adrenergic receptor (AR) subtypes via their 3i loop. Because arrestin association with G protein-coupled receptor is preceded by redistribution of arrestin to the cell surface, the present studies explored whether agonist activation of the α2A- and α2B -AR subtypes also led to spinophilin enrichment at the cell surface. Live cell imaging studies using a green fluorescent protein-tagged spinophilin examined spinophilin localization and its regulation by α2 -AR agonist. Agonist activation of α2A-AR preferentially, compared with the α2B-AR, led to spinophilin enrichment at the cell surface in human embryonic kidney 293 cells and in mouse embryo fibroblasts derived from spinophilin null mice. Activation of the ΔLEESSSSα2A-AR, which has enriched association with spinophilin compared with the wild-type (WT) α2A-AR, does not show an enhanced redistribution of spinophilin to the surface compared with WT α2A-AR, demonstrating that the ability or affinity of the receptor in binding spinophilin may be independent of the ability of the receptor to effect spinophilin redistribution to the surface. Agonist-evoked enrichment of spinophilin at the cell surface seems to involve downstream signaling events, manifested both by the pertussis toxin sensitivity of the process and by the marked attenuation of spinophilin redistribution in cells expressing the β-adrenergic receptor kinase-C tail, which sequesters βγ subunits of G proteins. Together, the data suggest that agonist-evoked spinophilin enrichment at the cell surface is caused by receptor-evoked signaling pathways and is independent of the affinity of the receptor for the spinophilin molecule.

The activity of the serotonin (5‐hydroxytryptamine, 5‐HT) system is sensitive to estradiol and progesterone. During the ovarian cycle, dendritic spines on CA1 pyramidal neurons of the dorsal hippocampus are increased by estradiol and later decreased by progesterone. We sought to determine whether 5‐HT is involved in maintaining CA1 spine density and/or in steroid regulation of synaptic plasticity in dorsal hippocampus. Ovariectomized rats were treated (sc) over 10 days with the tryptophan hydroxylase inhibitor parachlorophenylalanine (pCPA) to deplete 5‐HT, followed by estradiol benzoate on days 10 and 11. A subset of animals received progesterone on day 12. The day after the last treatment, rats were perfused and brains were processed for Golgi impregnation. Separate groups were processed for radioimmunocytochemistry (RICC) for the spine‐associated protein, spinophilin, or high‐performance liquid chromatography (HPLC) for monoamine analysis. Golgi and RICC data indicate that CA1 apical spine density was significantly decreased by pCPA (17–20%). Estradiol increased spine density in both saline‐ and pCPA‐treated rats compared to respective controls (30%); however, pCPA animals maintained significantly fewer spines. No differences in spine densities were observed between saline‐ and pCPA‐treated rats given estradiol and progesterone. Depletion of 5‐HT by pCPA was confirmed in the CA1 (−90%) and dorsal raphe (−80%) by HPLC analysis. While 5‐HT depletion was associated with a 57% decrease in CA1 norepinephrine (NE), there was no difference in dorsal raphe NE. Thus, whereas 5‐HT is involved in maintaining spine density in the adult female rat CA1, it is not crucial for steroid‐mediated plasticity. 5‐HT‐regulated spines/synapses may represent distinct populations from those modulated by estradiol and progesterone in dorsal hippocampus. Synapse 45:143–151, 2002. © 2002 Wiley‐Liss, Inc.

ABSTRACTIncreases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired β-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of β-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.

1The Ca2+sensitivity of smooth muscle contractility is modulated via regulation of phosphatase activity. Protein phosphatase inhibitor‐1 (I‐1) is the classic type‐1 phosphatase inhibitor, but its presence and role in cAMP‐dependent protein kinase (PKA) modulation of smooth muscle is unclear. To address the relevance of I‐1 in vivo, we investigated smooth muscle function in a mouse model lacking the I‐1 protein (I‐1(‐/‐)mice).2Significant amounts of I‐1 protein were detected in the wild‐type (WT) mouse aorta and could be phosphorylated by PKA, as indicated by 32P‐labelled aortic extracts from WT mice.3Despite the significant presence of I‐1 in WT aorta, phenylephrine and KCl concentration‐ isometric force relations in the presence or absence of the PKA pathway activator isoproterenol (isoprenaline) were unchanged compared to I‐1(‐/‐)aorta. cGMP‐dependent protein kinase (PKG) relaxation pathways were also not different. Consistent with these findings, dephosphorylation rates of the 20 kDa myosin light chains (MLC20), measured in aortic extracts, were nearly identical between WT and I‐1(‐/‐)mice.4In the portal vein, I‐1 protein ablation was associated with a significant (P <0.05) rightward shift in the EC50of isoproterenol relaxation (EC50= 10.4 ± 1.4 nm) compared to the WT value (EC50= 3.5 ± 0.2 nm). Contraction in response to acetylcholine as well as Ca2+sensitivity were similar between WT and I‐1(‐/‐)aorta.5Despite the prevalence of I‐1 and its activation by PKA in the aorta, I‐1 does not appear to play a significant role in contractile or relaxant responses to any pharmacomechanical or electromechanical agonists used. I‐1 may play a role as a fine‐tuning mechanism involved in regulating portal vein responsiveness to β‐adrenergic agonists.

Traditionally, nitric oxide-mediated alteration in blood vessel tone has been inferred from changes in flow in response to physical and pharmacological interventions using plethysmographic or ultrasonic techniques. We hypothesized that alteration in pulsatile arterial function may represent a more sensitive measure to detect and monitor nitric oxide-mediated modulation of arterial smooth muscle tone. Healthy male volunteers (n = 15) had radial artery pressure pulse waveforms recorded using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was employed to quantify changes in arterial waveform morphology in terms of altered pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. NG-nitro-L-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, was infused intravenously in incrementally increasing doses of 0.25, 0.5 and 0.75 mg/kg for 8 min each. Subjects then received either L-arginine or D-arginine (200 mg/kg over 15 min) intravenously in a blinded fashion. On a separate day, subjects had radial artery pressure pulse waveforms recorded before and after the sublingual administration of glyceryl trinitrate, an exogenous donor of nitric oxide. Cardiac output and heart rate decreased and mean arterial blood pressure increased significantly (P < 0.01 for all) in response to the incremental intravenous infusion of L-NAME. Small artery compliance decreased, whereas systemic vascular resistance increased in response to nitric oxide synthesis inhibition (P < 0.01 for both). The intravenous infusion of L-arginine restored the pulsatile and steady-state haemodynamic parameters to pre-treatment values, whereas D-arginine had no effect. Sublingual glyceryl trinitrate decreased systemic vascular resistance by 11%, whereas large artery- and small artery-compliance increased by 25% and 44% respectively. Pressure pulse contour analysis represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries accompanying nitric oxide-mediated alteration in arterial smooth muscle tone.

Glycogen synthase is an excellent in vitrosubstrate for protein phosphatase-1 (PP1), which is potently inhibited by the phosphorylated forms of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, Mr= 32,000) and Inhibitor-1. To test the hypothesis that the activation of glycogen synthase by insulin is due to a decrease in the inhibition of PP1 by the phosphatase inhibitors, we have investigated the effects of insulin on glycogen synthesis in skeletal muscles from wild-type mice and mice lacking Inhibitor-1 and DARPP-32 as a result of targeted disruption of the genes encoding the two proteins. Insulin increased glycogen synthase activity and the synthesis of glycogen to the same extent in wild-type and knockout mice, indicating that neither Inhibitor-1 nor DARPP-32 is required for the full stimulatory effects of insulin on glycogen synthase and glycogen synthesis in skeletal muscle.

The article presents the history of the Rocky Mountain Bonsai Society (RMBS). The Denver Bonsai Club, organized by eight Japanese men in 1945 raised interest on bonsai in Denver, Colorado and resulted in the club having up to 75 members. The club meetings were held in the homes of members and were conducted in Japanese. An English speaking bonsai club, called the Denver Junior Bonsai club was formed with 55 charter members in 1969.