Analgesic profile of the sodium salt of pemedolac

Pemedolac Na, 1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)-pyrano [3,4-b] indole-1-acetic acid sodium salt, exhibited equipotent analgesic effects after oral, iv, and im administration, suggesting that it is well absorbed. In mouse writhing models, the ED₅₀ values ranged from 0.3 mg (0.81 μmol)/kg (vs. acetylcholine) to 4.3 mg (11.6 μmol)/kg (vs. paraphenylbenzoquinone [PBQ]). In the rat Randall-Selitto model, the ED₅₀ o the compound was approximately 0.001 mg (2.7 nmol)/kg, with a flat dose response curve. The peak effects lasted for 7–9 h, 10–18 h, and 5 h following oral, im, and iv injections, respectively. Intracerebroventricular (i.c.v.) injections of pemedolac Na inhibited the PBQ-induced writing in mice with an ED₅₀ of 43.5 μg (0.12 μmol)/mouse, and this effect was not antagonized by naloxone. It was inactive in the hot plate and tail flick tests, demonstrating that pemedolac Na does not act via an opiate mechanism. These results indicate that pemedolac Na is a viable parenteral and oral analgesic, typified by high analgesic potency, a rapid onset and long duration of action, and an extremely wide safety index. © Wiley-Liss, Inc.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

'Fat mass and obesity associated' gene (<Emphasis Type="Italic">FTO</Emphasis>): No significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents

Background  

We have previously identified strong association of six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) to early onset extreme obesity within the first genome wide association study (GWA) for this phenotype. The aim of this study was to investigate whether the obesity risk allele of one of these SNPs (rs9939609) is associated with weight loss in a lifestyle intervention program. Additionally, we tested for association of rs9939609 alleles with fasting blood parameters indicative of glucose and lipid metabolism.     

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.     

Antibiotic sensitivity of enteric pathogens in Vietnam

The in vitro antimicrobial susceptibilities of 675 common enteropathogenic isolates from faecal specimens of patients with diarrhea (E. coli, Shigella, Salmonella and V. cholerae), and 568 E. coli isolates from faecal flora of healthy persons, which were collected as part of a National antibiotic resistance surveillance in Vietnam, were determined. The agar dilution method was used for the following nine antibiotics: ampicillin, doxycycline, chloramphenicol, gentamicin, nalidixic acid, kanamycin, trimethoprim, trimethoprim in combination with sulfamethoxazole (1/20), and sulfisomidin. Gentamicin was the most active of the antibiotics tested against all bacterial species with MICs in the range 0.125-4 mg/l. All strains were susceptible to nalidixic acid (0.125-8 mg/l) and more than 90% were susceptible to kanamycin. Among E. coli and Shigella isolates from patients the frequencies of resistance to commonly used antibiotics were high: ampicillin 73% and 84%, doxycycline 83% and 94%, chloramphenicol 71% and 91%, sulfisomidin 82% and 92%, respectively. Resistance to trimethoprin, as well as to the combination with sulfamethoxazole was found in 21% and 23%, respectively. The frequencies of multiple resistance (resistance to three or more antibiotics) were also high (77% and 89%, respectively). Less than 10% of Salmonellae and V. cholerae isolates were resistant to ampicillin, sulfisomidin or trimethoprim. Among E. coli from healthy people the frequencies of resistance were lower than in isolates from patients: ampicillin 23%, doxycycline 40%, chloramphenicol 21% and sulfisomidin 34%. However, the same patterns of multiple resistance were found in both groups.     

Interspecies Recombination-Led Speciation of a Novel Geminivirus in Pakistan

Recombination between isolates of different virus species has been known to be one of the sources of speciation. Weeds serve as mixing vessels for begomoviruses, infecting a wide range of economically important plants, thereby facilitating recombination. Chenopodium album is an economically important weed spread worldwide. Here, we present the molecular characterization of a novel recombinant begomovirus identified from C. album in Lahore, Pakistan. The complete DNA- A genome of the virus associated with the leaf distortion occurred in the infected C. album plants was cloned and sequenced. DNA sequence analysis showed that the nucleotide sequence of the virus shared 93% identity with those of the rose leaf curl virus and the duranta leaf curl virus. Interestingly, this newly identified virus is composed of open reading frames (ORFs) from different origins. Phylogenetic networks and complementary recombination detection methods revealed extensive recombination among the sequences. The infectious clone of the newly detected virus was found to be fully infectious in C. album and Nicotiana benthamiana as the viral DNA was successfully reconstituted from systemically infected tissues of inoculated plants, thus fulfilling Koch’s postulates. Our study reveals a new speciation of an emergent ssDNA plant virus associated with C. album through recombination and therefore, proposed the tentative name ‘Chenopodium leaf distortion virus’ (CLDV).     

Safety for Human MR Scanners at 7T

After introduction of the first human 7 tesla (7T) system in 1999, 7T MR systems have been employed as one of the most advanced platforms for human MR research for more than 20 years. Currently, two 7T MR models are approved for clinical use in the U.S.A. The approval facilitated introduction of the 7T system, summing up to around 100 worldwide. The approval in Japan is much awaited. As a clinical MR scanner, the 7T MR system is drawing attention in terms of safety.Several large-sized studies on bioeffects have been reported for vertigo, dizziness, motion disturbances, nausea, and others. Such effects might also be found in MR workers and researchers. Frequency and severity of reported bioeffects will be presented and discussed, including their variances. The high resonance frequency and shorter RF wavelength of 7T increase the concern about the safety. Homogeneous RF pulse excitation is difficult even for the brain, and a multi-channel parallel transmit (pTx) system is considered mandatory. However, pTx may create a hot spot, which makes the estimation of specific absorption rate (SAR) to be difficult. The stronger magnetic field of 7T causes a large force of displacement and heating on metallic implants or devices, and the scan of patients with them should not be conducted at 7T. However, there are some opinions that such patients might be scanned even at 7T, if certain criteria are met. This article provides a brief review on the effect of the static magnetic field on humans (MR subjects, workers, and researchers) and neurons, in addition to scan sound, SAR, and metal implants and devices. Understanding and avoiding adverse effects will contribute to the reduction in safety risks and the prevention of incidents.