G protein-coupled receptors (GPCRs) convert extracellular stimuli in the form of hormones, odorants and light into profound changes in cell homeostasis. Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling. Seven GPCR kinases (GRKs) phosphorylate and regulate the activity of most of the ~800 GPCRs in the human genome. Although GRKs normally play an adaptive role, in conditions such as chronic heart failure they are overexpressed and linked to disease progression. GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy, respectively. Our lab has determined atomic structures representing all three vertebrate GRK subfamilies, and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design. We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor, determined the crystal structure of the GRK2·paroxetine complex and, in collaboration with the Koch lab, showed that the drug improves contractility in myocytes and, most impressively, recovery in post-myocardial infarcted mice. Since then, we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5. Using a ″hybrid″ inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models. Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds, allowing for the design of future generations of GRK chemical probes.

The Woven EndoBridge (WEB) is an intrasaccular flow-disrupting device for the treatment of wide-necked saccular cerebral aneurysms. As with any neuroendovascular device, complications in the form of malpositioning and migration must be managed quickly and safely. Few studies have reported complication management techniques in instances of dislocated or migrated WEB devices. We retrospectively describe a case of a malpositioned WEB device that was successfully adjusted with the use of a gooseneck snare. Multiple other intra-procedural bailout strategies for management of WEB malposition and migration were considered, and are herein discussed. Operators should be aware of the causes of WEB malposition and a variety of bailout strategies.

The Singapore public healthcare system has increasingly used the term "right-siting" to describe the principle that stable chronic disease patients should be managed in primary care rather than specialist settings. The majority of primary healthcare providers in Singapore are general practitioners (GPs). The aims of this paper were to measure the quality of diabetes care in specialist and GP settings, and assess right-siting efforts in a tertiary centre in Singapore. Three hundred eighty-three consecutive patients with type 2 diabetes referred to the Singapore General Hospital Diabetes Centre (SGH DBC) between January and March 2005 were analysed. At the first visit, 51 patients (13.3%) were classified as inappropriate referrals and discharged back to the referral source or to primary care. After 12 months, 136 patients (group A = 35.5%) remained on follow-up at SGH DBC. In these patients, significant improvements were seen in mean HbA1c but not blood pressure (BP) or low density lipoprotein-cholesterol (LDL-C). One hundred twenty-eight (group B = 33.4%) patients were discharged from DBC within the 12 months of the study period. Mean follow-up duration in group B was 5.5 months and HbA1c, blood pressure and LDL-cholesterol had improved significantly in these patients. Glycaemic control of group B patients at the time of discharge was significantly better than group A at 12 months (mean HbA1c = 7.15% vs 8.16%; P <0.001). More than half (55.6%) of group B patients achieved HbA1c targets compared to 32.4% from group A (P <0.001). Although mean BP and LDL-C levels fell in group B patients, the percentage of patients achieving BP and LDL-C targets did not improve significantly in both groups. From August 2005 to January 2008, GPs participating in SingHealth's Delivering on Target (DOT) programme enrolled 579 patients under their care for additional diabetic counselling by community nurse educators. Pre- and post-programme HbA1c results were submitted for 370 patients (64%). Mean HbA1c levels of these patients decreased from 8.23% to 7.32% (P <0.001). The proportion of patients who achieved HbA1c <7% increased from 26% to 51% (P <0.01). However, BP and LDL-C levels did not improve. It is difficult to base referral or discharge decisions solely on these indicators. Our studies show that both in the specialist and GP settings, significant improvements in HbA1c are seen. Results for BP and LDL-C, however, showed little improvement. Some degree of rightsiting was seen at SGH DBC with discharged patients showing greater improvements than patients who were retained. However, >30% of patients remained in SGH DBC despite achieving HbA1C targets. Our results indicate the need for better strategies to address the underlying obstacles to right-siting. Of greater concern, the lack of improvement in BP and LDL-C indicates a high degree of clinical inertia to these issues among specialists and GPs treating diabetes in Singapore.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Blood Glucose ; metabolism ; Blood Pressure ; Cholesterol, LDL ; blood ; Delivery of Health Care, Integrated ; methods ; standards ; Diabetes Mellitus ; blood ; physiopathology ; therapy ; Female ; Follow-Up Studies ; Glycated Hemoglobin A ; metabolism ; Humans ; Middle Aged ; Outcome Assessment (Health Care) ; methods ; Primary Health Care ; methods ; standards ; Retrospective Studies ; Singapore ; Young Adult

OBJECTIVETo study, at the cytological level, the basic concept of Chinese medicine that "the Kidney (Shen) controls the bone".

METHODSKaempferol was isolated form Rhizoma Drynariae (Gu Sui Bu, GSB) and at several concentrations was incubated with opossum kidney (OK) cells, osteoblasts (MC3T3 E1) and human fibroblasts (HF) at cell concentrations of 2×10(4)/mL. Opossum kidney cell-conditioned culture media with kaempferol at 70 nmol/L (70kaeOKM) and without kaempferol (0OKM) were used to stimulate MC3T3 E1 and HF proliferation. The bone morphological protein receptors I and II (BMPR I and II) in OK cells were identified by immune-fluorescence staining and Western blot analysis.

RESULTSKaempferol was found to increase OK cell growth (P<0.05), but alone did not promote MC3T3 E1 or HF cell proliferation. However, although OKM by itself increased MC3T3 E1 growth by 198% (P<0.01), the 70kaeOKM further increased the growth of these cells by an additional 127% (P<0.01). It indicates that the kidney cell generates a previously unknown osteoblast growth factor (OGF) and kaempferol increases kidney cell secretion of OGF. Neither of these media had any significant effect on HF growth. Kaempferol also was found to increase the level of the BMPR II in OK cells.

CONCLUSIONSThis lends strong support to the original idea that the Kidney has a significant influence over bone-formation, as suggested by some long-standing Chinese medical beliefs, kaempferol may also serve to stimulate kidney repair and indirectly stimulate bone formation.

3T3 Cells ; Animals ; Cell Line ; Culture Media, Conditioned ; Intercellular Signaling Peptides and Proteins ; secretion ; Kaempferols ; pharmacology ; Kidney Tubules ; physiology ; secretion ; Medicine, Chinese Traditional ; Mice ; Opossums ; Osteoblasts ; chemistry

A cirrhosis risk score (CRS) comprised of single nucleotide polymorphisms (SNPs) in seven genes that predicts the risk of cirrhosis in Caucasian hepatitis C has been reported. The present study was to evaluate the association of 11 separate but related SNPs and the CRS with cirrhosis risk in Chinese hepatitis B patients. A total of 563 Chinese subjects with persistent HBV infection (349 with evident liver cirrhosis and 214 without cirrhosis clinically or pathologically) were studied. The candidate SNPs were detected with a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) method. The allele frequency and genotype distribution of each polymorphism as well as the CRS value within the cirrhosis and non-cirrhosis subjects were compared. The rs2679757 polymorphism of the antizyme inhibitor 1 (AZIN1) gene was associated with the risk of cirrhosis (x2 = 6.79, P = 0.03, odds ratio for GG+AG versus AA = 1.63, 95% confidence interval = 1.13-2.35). A gene variant (rs886277) in the transient receptor potential cation channel subfamily M, member 5 gene (TRPM5) was associated with liver cirrhosis, but did not reach statistical significance (x2 = 5.77, P = 0.06). Two SNPs (rs4986791, rs62522600) are not polymorphic in Chinese. Genotype frequencies of other SNPs were not different between the cirrhosis and non-cirrhosis groups. The overall CRS values were not different between the cirrhotic and non-cirrhotic groups (median value 0.57 versus 0.62, Z = -1.05, P = 0.29). SNP rs2679757 in the AZIN1 gene is associated with the risk of HBV-related liver cirrhosis in Chinese. The CRS for Caucasian population has limited applicability for predicting liver cirrhosis in Chinese hepatitis B patients. SNPs associated with cirrhosis prognosis in hepatitis B patients and liver diseases with other etiologies warrant further clinical validation.
Adult ; Carrier Proteins ; genetics ; Female ; Gene Frequency ; Genotype ; Hepatitis B ; genetics ; Humans ; Liver Cirrhosis ; genetics ; Male ; Middle Aged ; Ornithine Decarboxylase Inhibitors ; Polymorphism, Single Nucleotide

Prompt, effective treatment is necessary following aneurysmal subarachnoid hemorrhage to prevent recurrent rupture, which is thought to double mortality. Atypical ruptured aneurysms, such as blister or dissecting pseudoaneurysms, or those that are unusually distal in the middle cerebral artery (MCA) are challenging to treat with either open or endovascular options, though the pipeline embolization device (PED) has shown promise in multiple case series. We present a case of a ruptured dissecting pseudoaneurysm in the distal MCA (distal M3/proximal M4) prefrontal division in an healthy young patient (<60 years) successfully treated with a PED. The PED was chosen both as the only vessel sparing option in the young patient as well as for its potential as a vessel sacrifice tool if the pseudoaneurysm was felt to be incompletely treated, which in this case was not necessary—though would have leveraged the thrombogenicity of the device as a therapeutic advantage.

Background: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS. Objectives: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology. Methods: Eight dogs with a confirmed cPSS were included in the study. Results: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes. Conclusions This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.

OBJECTIVE: Garcinia mangostana Linn., commonly known as mangosteen, is a tropical fruit with a thick pericarp rind containing bioactive compounds that may be beneficial as an adjunctive treatment for schizophrenia. The biological underpinnings of schizophrenia are believed to involve altered neurotransmission, inflammation, redox systems, mitochondrial dysfunction, and neurogenesis. Mangosteen pericarp contains xanthones which may target these biological pathways and improve symptoms; this is supported by preclinical evidence. Here we outline the protocol for a double-blind randomized placebo-controlled trial evaluating the efficacy of adjunctive mangosteen pericarp (1,000 mg/day), compared to placebo, in the treatment of schizophrenia. METHODS: We aim to recruit 150 participants across two sites (Geelong and Brisbane). Participants diagnosed with schizophrenia or schizoaffective disorder will be randomized to receive 24 weeks of either adjunctive 1,000 mg/day of mangosteen pericarp or matched placebo, in addition to their usual treatment. The primary outcome measure is mean change in the Positive and Negative Symptom Scale (total score) over the 24 weeks. Secondary outcomes include positive and negative symptoms, general psychopathology, clinical global severity and improvement, depressive symptoms, life satisfaction, functioning, participants reported overall improvement, substance use, cognition, safety and biological data. A 4-week post treatment interview at week 28 will explore post-discontinuations effects. RESULTS: Ethical and governance approvals were gained and the trial commenced. CONCLUSION: A positive finding in this study has the potential to provide a new adjunctive treatment option for people with schizophrenia and schizoaffective disorder. It may also lead to a greater understanding of the pathophysiology of the disorder.
Cognition ; Depression ; Fruit ; Garcinia mangostana ; Garcinia ; Inflammation ; Neurogenesis ; Outcome Assessment (Health Care) ; Oxidation-Reduction ; Oxidative Stress ; Psychopathology ; Psychotic Disorders ; Schizophrenia ; Synaptic Transmission ; Xanthones