To meet high cellular demands, the energy metabolism of cardiac muscles is organized by precise and coordinated functioning of intracellular energetic units (ICEUs). ICEUs represent structural and ...functional modules integrating multiple fluxes at sites of ATP generation in mitochondria and ATP utilization by myofibrillar, sarcoplasmic reticulum and sarcolemma ion‐pump ATPases. The role of ICEUs is to enhance the efficiency of vectorial intracellular energy transfer and fine tuning of oxidative ATP synthesis maintaining stable metabolite levels to adjust to intracellular energy needs through the dynamic system of compartmentalized phosphoryl transfer networks. One of the key elements in regulation of energy flux distribution and feedback communication is the selective permeability of mitochondrial outer membrane (MOM) which represents a bottleneck in adenine nucleotide and other energy metabolite transfer and microcompartmentalization. Based on the experimental and theoretical (mathematical modelling) arguments, we describe regulation of mitochondrial ATP synthesis within ICEUs allowing heart workload to be linearly correlated with oxygen consumption ensuring conditions of metabolic stability, signal communication and synchronization. Particular attention was paid to the structure–function relationship in the development of ICEU, and the role of mitochondria interaction with cytoskeletal proteins, like tubulin, in the regulation of MOM permeability in response to energy metabolic signals providing regulation of mitochondrial respiration. Emphasis was given to the importance of creatine metabolism for the cardiac energy homoeostasis.
Osteoarthritis and other degenerative joint diseases are common causes of chronic pain in cats. Frunevetmab is a felinized monoclonal antibody that binds to nerve growth factor (NGF) and provides ...relief from pain by blocking the receptor-mediated signaling cascade induced by NGF. Results from three studies were combined to provide an overview of frunevetmab pharmacokinetics (PK) and immunogenicity. The objective of the first study was to establish the pharmacokinetic parameters resulting from intravenous (IV) and subcutaneous (SC) administration of frunevetmab to the feline patient population at 3 mg/kg. Ten adult cats with naturally-occurring osteoarthritis were administered frunevetmab in a crossover design at 28 day intervals. Non-compartmental pharmacokinetic analysis of the plasma concentration-time data showed that the half-life was 10.1 ± 1.9 days after IV dosing and the SC bioavailability was 60.3 ± 15.8% with maximum drug levels observed at 3-7 days after dosing. Plasma samples were collected at ~28 days after dosing during two field safety and effectiveness studies of cats with degenerative joint disease. The doses ranged from 1.0 to 2.8 mg/kg; 2 or 3 doses were administered either SC/IV, SC/SC, or SC/SC/SC. The data from these studies along with the data from the laboratory pharmacokinetic study were analyzed using non-linear mixed-effects (NLME) modeling. The model closely predicted the trough concentrations from the two field studies, including the IV treatment in the pilot field study. The trough concentrations were predicted to be close to steady-state after 2 doses. A second objective was to determine the incidence and clinical relevance of frunevetmab immunogenicity. A three-tier anti-drug antibody assay (screen, confirm, titer) was developed and validated. Immunogenicity was assessed in 259 frunevetmab-treated animals enrolled in the two field studies. Only 4 of these animals (1.5%) appeared to develop immunogenicity to frunevetmab. None of the four exhibited adverse events attributed to immunogenicity and no impact on drug levels or efficacy was observed in three of the animals. In the placebo animals, 2.3% (3/131) appeared to develop treatment-emergent immunogenicity. Overall, frunevetmab administration resulted in a very low incidence of treatment-emergent immunogenicity with no safety findings and minimal effect on drug exposure and efficacy.
This study conveys striking findings regarding the operando structural behavior of the Na/FePO4 system during a charge and discharge cycle. From Rietveld refinements of synchrotron operando X-ray ...diffraction data, it appears that the active material presents large, non-stoichiometric domains while undergoing structural phase transformation. The corresponding extended limits of solubility are characterized by continuous variations in the metrics that mirror the entry of Na occupancy values into thermodynamically forbidden regions. A major consequence of this smoothed phase transformation is a significant decrease in the lattice volume mismatch, which could well compensate for the less efficient Na-based systems with respect to SEI and adverse effect of cation size in comparison to Li batteries. Comparison of the lattice volume mismatch on charge and discharge revealed an explanation for the asymmetry of the electrochemical curve.
•We examine the influence of dynamics on the phase diagram of Na/FePO4.•We used operando synchrotron X-ray diffraction during electrochemical cycling.•Thermodynamic phase diagram needs thorough reassessment within an operating battery.•Striking extended limits of solubility have been evidenced.•Lattice volume mismatch are therefore strongly reduced during cycling.
Vibrio cholerae, the causative agent of cholera, is a well-studied species, whereas Vibrio metoecus is a recently described close relative that is also associated with human infections. The ...availability of V. metoecus genomes provides further insight into its genetic differences from V. cholerae. Additionally, both species have been co-isolated from a cholera-free brackish coastal pond and have been suggested to interact with each other by horizontal gene transfer (HGT).
The genomes of 17 strains from each species were sequenced. All strains share a large core genome (2675 gene families) and very few genes are unique to each species (< 3% of the pan-genome of both species). This led to the identification of potential molecular markers-for nitrite reduction, as well as peptidase and rhodanese activities-to further distinguish V. metoecus from V. cholerae. Interspecies HGT events were inferred in 21% of the core genes and 45% of the accessory genes. A directional bias in gene transfer events was found in the core genome, where V. metoecus was a recipient of three times (75%) more genes from V. cholerae than it was a donor (25%).
V. metoecus was misclassified as an atypical variant of V. cholerae due to their resemblance in a majority of biochemical characteristics. More distinguishing phenotypic assays can be developed based on the discovery of potential gene markers to avoid any future misclassifications. Furthermore, differences in relative abundance or seasonality were observed between the species and could contribute to the bias in directionality of HGT.
The management of 10 cases of penile inflammatory granulomas following a subcutaneous injection of non-absorbable substance for the purpose of penile augmentation is presented. We subsequently used ...the bilateral scrotal flaps to cover the post-excision skin defect. A simple decision aid chart outlining the management of penile foreign body injections is proposed.
A total of 10 patients were included in this study. All required surgical management by penile degloving, followed by complete excision of the inflammatory granuloma and overlying skin. The dissection of 14 cadavers was carried out to study the blood supply to the anterior scrotal flap. Penile reconstruction was then performed using a bilateral scrotal flap in all but two cases. Post-operatively, the patients were followed up for a 1 year period.
We obtained good results in terms of the aesthetic outcome with all of our ten patients with the area covered having similar color to penile skin. There were no major post-operative complications. There were two minor complications involving wound healing. Sensory function was maintained and no penile shortening or curvatures were noted, in addition all patients were satisfied with both the shape and function of the penis.
Although much rarer, penile augmentation related complications are still seen in western countries. The treating doctor should be aware of its management. We had achieved acceptable outcomes in our experience with the bilateral scrotal flap. We believe it is a good and simple option for soft tissue coverage of the penis in cases following the complete inflammatory granuloma excision. It can achieve satisfactory aesthetic and functional results for this group of patients.
La prise en charge de 10 cas de lipogranulomes péniens suite à l’injection sous-cutanée de substance non résorbable a des fins d’augmentation pénienne est présentée dans cet article. Des lambeaux scrotaux bilatéraux ont été utilisés pour couvrir la perte de substance cutanée suite à l’excision de la peau atteinte. Un arbre décisionnel simple concernant la prise en charge de ces patients est proposé.
10 patients ont été inclus dans cet étude. Tous les patients ont bénéficié d’un dégantage de la peau pénienne suivi d’une excision complète du lipogranulome et de la peau le surplombant. 14 dissections cadavériques ont été réalisées pour étudier l’anatomie vasculaire du lambeau scrotal antérieur. La reconstruction de la perte de substance a été réalisée par l’utilisation de lambeaux scrotaux bilatéraux chez tous les patients sauf deux. Les patients ont été suivis 1 an après la chirurgie.
Nous avons obtenu de bons résultats esthétiques chez tous les patients opérés avec notamment une bonne concordance en termes de couleur de peau. Aucune complication majeure n’est à déplorer. Deux patients ont présenté un retard de cicatrisation. La sensibilité pénienne a été conservée et aucun raccourcissement ou courbement du pénis n’a été observé. Tous les patients ont été satisfaits par la forme et la fonction de leur pénis.
Bien que rares, des complications liées à des augmentations péniennes réalisées sans contrôle médical sont encore vues dans les pays occidentaux. Les chirurgiens plasticiens devraient donc être au courant des moyens de prise en charge. Nous avons obtenu des résultats très acceptables à l’aide du lambeau scrotal bilatéral, nous pensons donc que c’est une technique de choix pour la prise en charge des pertes de substance cutanées suite à l’excision de ces granulomes inflammatoires de verge.
BACKGROUNDWithin the framework of mammary reconstruction, since 2012 when Allen first described it, the profunda femoral artery perforator flap (PAP) takes an important place in the current ...therapeutic options. OBJECTIVEThis anatomical study aims to analyze the anatomy and morphologic consideration of the PAP : position of the perforating artery; length of the pedicle, area and volume of vascularization. METHODSSixteen flaps were harvested on fresh subjects at the University Department of Anatomy of Rockfeller, Lyon. The first direct cutaneous branch from the deep femoral vessels was located between or through the adductor magnus and gracilis muscles. Pedicle location, diameter, length and position regard to the great saphenous vein were recorded. A flap based on this vessel was designed. Height, width, and surface of the skin paddle were recorded. Three-dimensional computed tomographic angiography was used to analyze the area and volume of cutaneous territory supplied by the studied perforator. RESULTSOn the 16 analyzed flaps, localization of the perforating artery is on average to 8.2cm of the pubic tuber and 3.7cm behind a line connecting the pubic tuber to the internal femoral condyle. The length of the pedicle is on average of 11.7cm and the average area of skin perfused was 94,68cm2. The way of this perforating arterty is primarily through the adductor magnus. On the radiological images of the 8 flaps, the analysis shows an average surface of 111,25cm2 and a mean volume of 325.3cm3. DISCUSSIONPAP is an interesting therapeutic choice within the framework of a mammary reconstruction. Its surface and its volume associated with a discrete scar make a valid indication within the framework of this surgery.
The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ...ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly.
Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×.
Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs.
PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.
Cholera is a severe diarrheal disease caused by
, a natural inhabitant of brackish water. Effective control of cholera outbreaks depends on prompt detection of the pathogen from clinical specimens ...and tracking its source in the environment. Although the epidemiology of cholera is well studied, rapid detection of
remains a challenge, and data on its abundance in environmental sources are limited. Here, we describe a sensitive molecular quantification assay by qPCR, which can be used on-site in low-resource settings on water without the need for DNA extraction. This newly optimized method exhibited 100% specificity for total
as well as
O1 and allowed detection of as few as three target CFU per reaction. The limit of detection is as low as 5 × 10
CFU/L of water after concentrating biomass from the sample. The ability to perform qPCR on water samples without DNA extraction, portable features of the equipment, stability of the reagents at 4 °C and user-friendly online software facilitate fast quantitative analysis of
. These characteristics make this assay extremely useful for field research in resource-poor settings and could support continuous monitoring in cholera-endemic areas.
A third serotype of human parechovirus (HPeV) has been recently isolated from stool specimens of a young Japanese child with transient paralysis. We report 3 additional cases of neonatal sepsis ...caused by HPeV-3 in the fall of 2001 in Canadian infants 7-27 days old. All children were hospitalized with high fever, erythematous rash, and tachypnea for a median of 5 days. The viruses isolated from nasopharyngeal aspirates grew slowly on tertiary monkey kidney cells and were successfully passaged on Vero cells. The predicted amino acid identity of the VP0-VP3-VP1 region of the three viruses was 74.6%-74.8%, 73.4%-73.6%, and 97.0%-97.1% when compared to HPeV-1, -2, and -3 prototype strains, respectively. Although different, our isolates were closely related; amino acid identity was 99.6%-100% for the last 3 proteins.
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