Studies on the Syntheses and Properties of 5′-Branched-sugar Isonucleosides and the Related Oligonucleotides

The chemistry of nucleosides and oligonucleotides is an actively investigated field in the search for new drugs. The syntheses and the properties of isonucleosides and oligonucleotides have been investigated to improve their stability, antitumor and antiviral activities, and to reduce their toxicity.The syntheses and properties of isonucleosidesA new class of isonucleoside analogues with branched-sugar 2(-deoxy-2(-nucleobase-5(-deoxy-1(,4(-anhydro-D-altritol(21, 23a～c) has been synthesized fr…     

Electroretinographic and Ophthalmologic Examinations in the Yucatan Micropig and in the Göttingen Minipig

Abstract

External gross observations of the eye and its adnexae, ocular reflexes, anterior ocular segment biomicroscopic examinations, fundic examinations performed with an indirect ophthalmoscope, and/or electroretinographic investigations (ERG) were carried out on 112 7-12-month-old Yucatan micropigs, on 18 6-8-week-old, and 81 2-10-month old Gottingen minipigs to evaluate the incidence of observed ocular abnormalities and to compare the ERG waves. A statistical comparison was performed for these findings.

The most important ocular defects were classified as remnants of embryological vascular tissue. The other findings were considered either as embryonic remnants or of nondeterminate etiology. The most noteworthy findings were, in decreasing order of incidence, for Yucatan micropigs, 6-8 week-old and 2-10-monfh-old Gottingen minipigs, respectively, hyaloid artery remnants (82.1%, 83.3%, and 46.3%), pupillary     

Studies on the Syntheses and Properties of 5＇-Branched-sugar Isonucleosides and the Related Oligonucleotides

The chemistry of nucleosides and oligonucleotides is an actively investigated field in the search for new drugs. Thesyntheses and the properties of isonucleosides and oligonucleotides have been investigated to improve their stability,antitumor and antiviral activities, and to reduce their toxicity.     

the epidemic diseases were very complex and mixed infection and

cine epidemic diseases;epidemiology investigation;control0广西农业科学Guangxi Agricultural Sciences105-107S858.28D05048D;D050_48黄夏;200-202二温式PCR检测猪传染性胸膜肺炎放线杆菌方法的建立与应用庞耀珊;谢芝勋;刘加波;邓显文;唐小飞;谢志勤;广西兽医研究所,广西兽医研究所,广西兽医研究所,广西兽医研究所,广西兽医研究所,广西兽医研究所 南宁530001,南宁530001,南宁530001,南宁530001,南宁530001,南宁530001猪;;传染性胸膜肺炎放线杆菌;;聚合酶链反应;;检测为了探索简便、快速确诊猪传染性胸膜肺炎的方法,根据猪传染性胸膜肺炎放线杆菌(APP)apx IV基因序列,设计合成1对特异性引物,建立聚合酶链反应(PCR)检测APP的方法。采用该方法对APP和其他6种猪病病原核酸进行检测,结果只对APP扩增出与预期大小相符的422bp DNA片段,而对其他6种猪病病原核酸的扩增结果为阴性。该PCR最低可检出10pg的APP DNA。对送检的46份可疑病猪组织进行检测,结果有19份样品为阳性,27份为其他病原感染。Establishment and application of a two-temperature polymerase chain reaction on detection of pig Actino     

TRPM8 and dyspnea: from the frigid and fascinating past to the cool future?

The transient receptor potential melastatin 8 (TRPM8) ion channel is gated by cool and noxious cold temperatures. The activation threshold is in the range of ≈25-28°C, which aligns well with the discharge of airway afferents. TRPM8 is widely expressed across species and evolutionary changes in the TRPM8 amino acid sequence may tune the temperatures at which it is gated. The discovery of TRPM8 and its molecular/biophysical characterization provides a robust candidate for airway afferents responding to cool/cold temperatures. TRPM8 may provide a mechanistic link for the manipulation of respiratory sensations such as dyspnea or mechanisms leading to cold-induced asthma and cough.     

How are the inner hair cells and auditory nerve fibers activated without the mediation of the outer hair cells and the cochlear amplifier?

The present study was designed to assess whether, in the presence of a depression of the cochlear amplifier i.e. a sensorineural hearing loss (SNHL), the inner hair cells (IHCs) require the presence of a normal endocochlear potential for transduction. An SNHL was induced by injecting salicylic acid (which binds to the motor protein prestin in the outer hair cells), and then furosemide (which depresses the endocochlear potential) was injected. Furosemide did not cause an additional elevation of the threshold of the auditory nerve brainstem evoked response (ABR) over that induced by the salicylic acid injection. Exposure to noise was also used to induce a SNHL in other mice, and then furosemide was injected. Here too furosemide did not cause an additional ABR threshold elevation over that induced by the noise. These results show that the IHCs (and the auditory nerve) can be excited in the presence of a SNHL (i.e. without the cochlear amplifier) and in the absence of an endocochlear potential. Possible mechanisms of excitation in such a state are discussed.     

Medical Toxicology and Public Health—Update on Research and Activities at the Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry

Evidence suggests that in-utero exposure to environmental chemicals, such as persistent organic pollutants (POPs), heavy metals, and radionuclides, that might bioaccumulate in the mother may increase a newborn's risk of adverse developmental, neurological, and immunologic effects. Chemical contamination of bodies of water and strong ocean currents worldwide can drive these chemicals from lower latitudes to Arctic waters where they accumulate in common traditional subsistence foods. In response to concerns of the people from Alaska of the effects of bio-accumulated chemicals on their children, the Maternal Organics Monitoring Study(MOMS) was developed. The objective of the study was to assess the risks and benefits associated with the population's subsistence diet. Data analysis of biological samples at the CDC's NCEH laboratory and maternal questionnaires is ongoing. Results will be provided to Alaska Native communities to help support public health actions and inform future interventions and research.     

Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer – recent developments and future directions

ABSTRACT

Introduction: Despite the heterogeneity of prostate cancer (PCa), androgen stimulation is fundamental to its development, growth, and lethality. Therefore, the blockade of androgen receptor (AR) signaling is critical to controlling the disease, even after progression with castrate levels of androgens.

Areas covered: We review the current understanding of new ways to block the AR, using novel antiandrogen inhibitors, which act on different parts of the AR signaling pathway in PCa. We also review new approaches, such as the use of poly(ADP–ribose) polymerase (PARP) inhibitors, targeting both the AR and the DNA repair pathway, potentially adding synergy and improving efficacy and the combination of AR inhibitors and immunotherapy. Bipolar androgen therapy (BAT), an innovative strategy to target the AR, has shown early evidence of efficacy in PCa is also discussed in detail. We highlight some of the key ongoing studies of greatest relevance to this topic.

Expert commentary: Clinical trials investigating new AR-targeted therapies should be encouraged in patients with PCa. While it is unlikely that one AR inhibitor will produce long-lasting responses in a substantial proportion of patients, there is evidence that some strategies, such as the BAT could resensitize the AR to antiandrogens, alternating therapies and delaying time to progression, maximizing benefit to patients.     

β-blockers and the risk of incident depression in the elderly

The hypothesis that β-blockers cause depression has been both confirmed and refuted in previous studies. However, in hardly any of these studies, depression was systematically and adequately assessed. The aim of this cohort study was to examine whether β-blockers, in general, highly lipid-soluble, nonselective, or serotonergic receptor-binding β-blockers, are associated with incident depression. Between 1993 and 2005, 5104 elderly persons were followed for incident depressions. Depressions were identified by regular interview and continuous monitoring of medical records. Cases were categorized as clinically relevant depressive symptoms or as depressive syndromes, the latter including Diagnostic and Statistical Manual of Mental Disorders-IV-defined depressive disorders. Pharmacies provided information on filled β-blockers. We used Cox regression with drug use as a time-dependent variable to analyze the data, adjusted for potential demographic covariates, activity of daily living, and (contra)indications for β-blockers. We found that use of β-blockers in general did not convey an increased risk of depressive symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.37-1.59) or depressive syndromes (HR, 0.99; 95% CI, 0.53-1.84). Highly lipid-soluble β-blockers, mostly propranolol in our study, were associated with depressive symptoms during the first 3 months of use (HR, 3.31; 95% CI, 1.03-10.6), but not with depressive syndromes. Nonselective or serotonergic receptor affinity was not associated with an increased risk of depressive symptoms or syndromes independent of high lipid solubility. We conclude that β-blockers in general do not convey an increased risk of depression. Lipophilic β-blockers are associated with an increased risk of depressive symptoms.     

Pharmacoepidemiology and the “Impact Factor”

The field of Pharmacoepidemiology/Drug Utilization research has been analysed by studying published research articles under the medical subject headings (MeSH terms) Pharmacoepidemiology, Drug Utilization and Drug Utilization Review. There were 1822 articles published, and stored in Medline, during the 32-month period between 1 January 2001 and 31 August 2003; these papers might represent a field of research, due to the similarity of MeSH terms used for coding and the set of journals in which the articles were published. A total of 457 articles, representing 25% of all articles in the field, were published in 14 different journals, and 50% of all articles (948) were collected in only 64 different journals. The two main journals publishing research in Pharmacoepidemiology/Drug Utilization are Pharmacoepidemiol Drug Saf and the Eur J Clin Pharmacol. These two publications are the official journals of the three main societies in the field and are at least partially focused on this subject, with 45.7% of all articles in Pharmacoepidemiol Drug Saf and 11.1% of all articles in Eur J Clin Pharmacol included under the studied MeSH terms; other journals only occasionally publish papers in this line of research. These two journals are the leaders in pharmacoepidemiology and drug utilization research, having impact factors (IFs) in 2002/2003 above (1.955/1.972 for EJCP) and a bit below (1.092/1.257 for PDS) the middle of the ranking of publications, according to the IF, in the Pharmacology and Pharmacy list of the Science Citation Index (SCI).     

Δ9-Tetrahydrocannabinol and the extrapyramidal system

The behavioural effects of stereotypy and catalepsy by ⁹-Tetrahydrocannabinol (⁹-THC) in the rat were estimated and the possible involvement of the basal ganglia in these behaviours was studied using brain lesion techniques. In addition, the interactions of ⁹-THC with a dopaminergic (amphetamine) and a cholinergic stimulant (RS-86) were evaluated using the above methods.The excitatory effects of ⁹-THC alone, i.e., circling, sniffing, and head movements, were of low intensity and short duration and they were not significantly affected by lesions in the basal ganglia. On the other hand, ⁹-THC was found to depress behaviour, including catalepsy and atonic muscular prostration, the former being markedly potentiated, while prostration was unaffected by such lesions.⁹-THC was also found to potentiate cholinergic-induced catalepsy, extrapyramidal lesions causing further potentiation.Amphetamine-induced circling, sniffing, and gnawing emerged as a triad of related behaviour fragments. This was altermated by pallidal lesions and ⁹-THC treatment, the combination of the two being additive. The potentiation by ⁹-THC of amphetamine-induced rhythmic head and body movements was unaffected by pallidal lesions and so could be mediated by another brain area.The hypothesis is proposed that ⁹-THC exerts its cataleptogenic and some of its amphetamine interaction effects by reducing dopaminergic transmission in the basal ganglia.     

Cellular and paracellular calcium transport in the rat ileum and the influence of 1α,25-dihydroxyvitamin D3 and dexamethasone

Summary Concentration dependence of unidirectional calcium fluxes across the rat ileum freed from the serosa and the muscularis externa were measured in a modified Ussingchamber. Mucosa (m) to serosa (s) calcium flux showed a saturable component, whereas s to m calcium flux was linearly related to the calcium concentration between 0.125 mmol/1 and 5 mmol/1. At all calcium concentrations used net secretion of calcium was observed. The s to m flux of the simultaneously measured paracellular marker mannitol at all calcium concentrations was remarkably higher than the m to s flux, resulting in net mannitol secretion. The results obtained from the calcium fluxes when clamping the transepithelial electrical potential agree well with those of the concentration dependence of the calcium fluxes: 1. Only m to s flux has a voltage independent, transcellular component. 2. Calcium s to m flux is totally voltage dependent, i.e. diffusive. 3. Diffusional s to m calcium flux is about 80% greater than the diffusional fraction of the m to s flux. Omitting glucose from the bathing solution effected a decrease of the transepithelial electrical potential and of the short circuit current by 91% and 85% respectively; net calcium secretion was almost abolished and net mannitol secretion remarkably reduced. Addition of glucose, which stimulates water absorption in the ileum as a metabolic substrate, activated m to s but significantly more pronounced s to m calcium flux parallel to that of mannitol. Dexamethasone, known to stimulate sodium and water absorption in the ileum by activation of the Na,K-ATPase, effected an increase of the transepithelial electrical potential difference and of the short circuit current by about 100% but had no influence on tissue resistance; m to s and more pronounced s to m calcium flux was stimulated after the induction by dexamethasone and net calcium secretion was increased by 70%. After pretreatment with 1,25-dihydroxyvitamin D3 tissue resistance was decreased by about 42%. The vitamin had no effect on net calcium or mannitol secretion but significantly increased bidirectional calcium and mannitol fluxes. Flux measurements in clamped preparations revealed: 1. 1,25-dihydroxyvitamin D₃ and dexamethasone has no effect on the cellular-mediated m to s calcium transport; 2. diffusive calcium flux in m to s and in the opposite direction, from s to m, is increased by the vitamin and by the hormone. In conclusion the net ileal calcium and mannitol secretion is the consequence of an asymmetry of the paracellular flux with a prevalence of the s to m flux over that in m to s direction. It is hypothesized that this prevalence is caused by an anomalous solvent drag effect. Paracellular calcium flux in both directions is increased by 1,25-dihydroxyvitamin D3 and dexamethasone by different mechanisms, as indicated by the changes in the electrical parameters of the tissue. Send offprint requests to U. Karbach at the above address     

Endocannabinoids and the gastrointestinal tract: what are the key questions?

Cannabinoid (CB1) receptor activation acts neuronally, reducing GI motility, diarrhoea, pain, transient lower oesophageal sphincter relaxations (TLESRs) and emesis, and promoting eating. CB2 receptor activation acts mostly via immune cells to reduce inflammation. What are the key questions which now need answering to further understand endocannabinoid pathophysiology? GPR55. Does this receptor have a GI role? Satiety, Nausea, Vomiting, Gastro-Oesophageal Reflux, Gastric Emptying. Endocannabinoids acting at CB1 receptors can increase food intake and body weight, exert anti-emetic activity, reduce gastric acid secretion and TLESRs; CB2 receptors may have a small role in emesis. Question 1: CB1 receptor activation reduces emesis and gastric emptying but the latter is associated with nausea. How is the paradox explained? Q2: Do non-CB receptor actions of endocannabinoids (for example TRPV1) also modulate emesis? Q3: Is pathology necessary (gastritis, gastro-oesophageal reflux) to observe CB2 receptor function? Intestinal Transit and Secretion. Reduced by endocannabinoids at CB1 receptors, but not by CB2 receptor agonists. Q1: Do the effects of endocannabinoids rapidly diminish with repeat-dosing? Q2: Do CB2 receptors need to be pathologically upregulated before they are active? Inflammation. CB1, CB2 and TRPV1 receptors may mediate an ability of endocannabinoids to reduce GI inflammation or its consequences. Q1: Are CB2 receptors upregulated by inflammatory or other pathology? Pain. Colonic bacterial flora may upregulate CB2 receptor expression and thereby increase intestinal sensitivity to noxious stimuli. Q1: Are CB2 receptors the interface between colonic bacteria and enteric- or extrinsic nerve sensitivity? Relevance of endocannabinoids to humans. Perhaps apart from appetite, this is largely unknown.     

Role of the MPTP in conditioning the heart – translatability and mechanism

Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia‐reperfusion injury (IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof‐of‐concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered – the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.

Linked Articles

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8

Abbreviations

ANT

adenine nucleotide translocase

CABG

coronary artery bypass graft

CsA

cyclosporin A

CypD

cyclophilin D

Drp1

dynamin‐related protein 1

GSK

glycogen synthase kinase

IPC

ischaemic preconditioning

IPost

ischaemic postconditioning

IRI

ischaemia‐reperfusion injury

LV

left ventricular

MI

myocardial infarct

MitoK_ATP

mitochondrial ATP‐sensitive potassium channel

MPTP

mitochondrial permeability transition pore

OMM

outer mitochondrial membrane

OPA1

optic atrophy 1

PMI

perioperative myocardial injury

PPCI

primary percutaneous coronary intervention

RIC

remote ischaemic conditioning

RISK

reperfusion injury salvage kinase

ROS

reactive oxygen species

SAFE

survivor activating factor enhancement

STEMI

ST segment elevation myocardial infarction

VDAC

voltage‐dependent anion channel

Tables of Links

GABAA ρ receptor mechanisms in the rat amygdala and its role in the modulation of fear and anxiety

Rationale  

Accumulating evidence for the presence of GABA_A ρ receptors within the amygdala which differ from other members of the GABA_A receptor family in both subunit composition and functional properties has been recently obtained.