Lane Medical Library

Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO).

Eur J Med Chem. 2015 Feb 7;93C:392-400

Authors: Banister SD, Beinat C, Wilkinson SM, Shen B, Bartoli C, Selleri S, Da Pozzo E, Martini C, Chin FT, Kassiou M

Abstract
Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay.

PMID: 25725375 [PubMed - as supplied by publisher]

Delayed and intermittent CPR for severe accidental hypothermia.

Resuscitation. 2015 Feb 25;

Authors: Gordon L, Paal P, Ellerton JA, Brugger H, Peek GJ, Zafren K

Abstract
INTRODUCTION: Cardiac arrest (CA) in patients with severe accidental hypothermia (core temperature <28°C) differs from CA in normothermic patients. Maintaining CPR throughout the prehospital period may be impossible, particularly during difficult evacuations. We have developed guidelines for rescuers who are evacuating and treating severely hypothermic CA patients.
METHODS: A literature search was performed. The authors used the findings to develop guidelines.
RESULTS: Full neurological recovery is possible even with prolonged CA if the brain was already severely hypothermic before CA occurred. Data from surgery during deep hypothermic CA and prehospital case reports underline the feasibility of delayed and intermittent CPR in patients who have arrested due to severe hypothermia.
CONCLUSIONS: Continuous CPR is recommended for CA due to primary severe hypothermia. Mechanical chest-compression devices should be used when available and CPR-interruptions avoided. Only if this is not possible should CPR be delayed or performed intermittently. Based on available data, a patient with a core temperature <28°C or unknown with unequivocal hypothermic CA, evidence supports alternating 5minutes CPR and ≤5minutes without CPR. With core temperature <20°C, evidence supports alternating 5minutes CPR and ≤10minutes without CPR.

PMID: 25725297 [PubMed - as supplied by publisher]

Helicobacter pylori Activate and Expand Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands.

Gastroenterology. 2015 Feb 25;

Authors: Sigal M, Rothenberg ME, Logan CY, Lee JY, Honaker RW, Cooper RL, Passarelli B, Camorlinga M, Bouley DM, Alvarez G, Nusse R, Torres J, Amieva MR

Abstract
BACKGROUND & AIMS: Helicobacter pylori infection is the main risk factor for gastric cancer. We characterized the interactions of H pylori with gastric epithelial progenitor and stem cells in humans and mice and investigated how these interactions contribute to H pylori-induced pathology.
METHODS: We used quantitative confocal microscopy and 3-dimensional reconstruction of entire gastric glands to determine the localizations of H pylori in stomach tissues from humans and infected mice. Using lineage tracing to mark cells derived from Lgr5+ stem cells (Lgr5-eGFP-IRES-CreERT2/Rosa26-TdTomato mice) and in situ hybridization, we analyzed gastric stem cell responses to infection. Isogenic H pylori mutants were used to determine the role of specific virulence factors in stem cell activation and pathology.
RESULTS: H pylori grow as distinct bacterial microcolonies deep in the stomach glands and interact directly with gastric progenitor and stem cells in tissues from mice and humans. These gland-associated bacteria activate stem cells, increasing the number of stem cells, accelerating Lgr5(+) stem cell proliferation, and upregulating expression of stem cell-related genes. Mutant bacteria with defects in chemotaxis that are able to colonize the stomach surface but not the antral glands in mice do not activate stem cells. Moreover, bacteria that are unable to inject the contact-dependent virulence factor CagA into the epithelium colonized stomach glands in mice, but did not activate stem cells or produce hyperplasia to the same extent as wild-type H pylori.
CONCLUSIONS: H pylori colonize and manipulate the progenitor and stem cell compartments, which alters turnover kinetics and glandular hyperplasia. Bacterial ability to alter the stem cells has important implications for gastrointestinal stem cell biology and H pylori-induced gastric pathology.

PMID: 25725293 [PubMed - as supplied by publisher]

Response to letter: more rigorous, not less, external validation is needed.

J Clin Epidemiol. 2015 Jan 31;

Authors: Siontis GC, Ioannidis JP

PMID: 25724895 [PubMed - as supplied by publisher]

Integrated Care Increases Treatment and Improves Outcomes of Patients with Chronic HCV Infection and Psychiatric Illness or Substance Abuse.

Clin Gastroenterol Hepatol. 2015 Feb 24;

Authors: Ho SB, Bräu N, Cheung R, Liu L, Sanchez C, Sklar M, Phelps TE, Marcus SG, Wasil MM, Tisi A, Huynh L, Robinson SK, Gifford A, Asch SM, Groessl EJ

Abstract
BACKGROUND AND AIMS: Patients with hepatitis C virus (HCV) infection with psychiatric disorders and/or substance abuse face significant barriers to antiviral treatment. New strategies might be needed to improve treatment rates and outcomes. We investigated whether an integrated care (IC) protocol, which includes multi-disciplinary care coordination and patient case management, could increase the proportion of patients with chronic HCV infection who receive antiviral treatment (a combination of interferon-based and direct acting antiviral agents) and achieve a sustained virologic response (SVR).
METHODS: We performed a prospective, randomized trial at 3 medical centers in the US. Participants (n=363 patients attending HCV clinics) had been screened and tested positive for depression, post-traumatic stress disorder, and/or substance use; they were randomly assigned (1:1) to groups that received IC or usual care (controls) from March 2009 through February 2011. A mid-level mental health practitioner was placed in each HCV clinic to provide IC with brief mental health interventions and case management, according to formal protocol. The primary endpoint was SVR.
RESULTS: Of the study participants, 63% were non-White, 51% were homeless in the last 5 years, 64% had psychiatric illness, 65% were substance abusers within 1 year before enrollment, 57% were at risk for post-traumatic stress disorder, 71% had active depression, 80% were infected with HCV genotype 1, and 23% had advanced fibrosis. Over a mean follow-up period of 28 months, a greater proportion of patients in the IC group began receiving antiviral therapy (31.9% vs 18.8% for controls; P=.005) and achieved a SVR (15.9% vs 7.7% of controls; odds ratio=2.26; 95% confidence interval, 1.15-4.44; P=.018). There were no differences in serious adverse events between groups.
CONCLUSION: Integrated care increases the proportions of patients with HCV infection and psychiatric illness and/or substance abuse who begin antiviral therapy and achieve SVRs, without serious adverse events.

PMID: 25724704 [PubMed - as supplied by publisher]

Long-term safety and efficacy of sapropterin: The PKUDOS registry experience.

Mol Genet Metab. 2015 Feb 16;

Authors: Longo N, Arnold GL, Pridjian G, Enns GM, Ficicioglu C, Parker S, Cohen-Pfeffer JL, Phenylketonuria Demographics, Outcomes and Safety (PKUDOS) registry

Abstract
The Phenylketonuria (PKU) Demographics, Outcomes and Safety (PKUDOS) registry is designed to provide longitudinal safety and efficacy data on subjects with PKU who are (or have been) treated with sapropterin dihydrochloride. The PKUDOS population consists of 1189 subjects with PKU: N=504 who were continuously exposed to sapropterin from date of registry enrollment, N=211 who had intermittent exposure to the drug, and N=474 with some other duration of exposure. Subjects continuously exposed to sapropterin showed an average 34% decrease in blood phenylalanine (Phe) - from 591±382μmol/L at baseline to 392±239μmol/L (p=0.0009) after 5years. This drop in blood Phe was associated with an increase in dietary Phe tolerance [from 1000±959mg/day (pre-sapropterin baseline) to 1539±840mg/day after 6years]. Drug-related adverse events (AEs) were reported in 6% of subjects, were mostly considered non-serious, and were identified in the gastrointestinal, respiratory, and nervous systems. Serious drug-related AEs were reported in ≤1% of subjects. Similar safety and efficacy data were observed for children<4years. Long-term data from the PKUDOS registry suggest that sapropterin has a tolerable safety profile and that continuous use is associated with a significant and persistent decrease in blood Phe and improvements in dietary Phe tolerance.

PMID: 25724073 [PubMed - as supplied by publisher]