Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood–brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.     

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Despite caregivers' impact on suicidal patients' compliance with treatment and suicide prevention, little is known about mental-health professionals' perceptions of work with suicidal patients. The roles of psychiatric staff's training and supervision in the care of suicidal patients were investigated by means of a postal questionnaire sent to a random sample of 1543 psychiatric staff members. The response rates were 71% for psychiatrists and 57% for nurses and assistant nurses. The responses of 53 psychiatrists, 164 nurses and 333 assistant nurses working with suicidal patients on a regular basis were compared and analysed using the Kruskal-Wallis test. Thirty-five per cent of the assistant nurses, 43% of the nurses and 74% of the psychiatrists who worked with suicidal patients on a regular basis perceived that they were sufficiently trained for this work, while 75% of the assistant nurses, 72% of the nurses and 34% of the psychiatrists received supervision in their work with suicidal patients. In spite of receiving supervision, nursing staff who perceived that they lacked training reported uncertainties in their work with suicidal patients to a larger extent than those who perceived that their training was sufficient. Uncertainties were significantly more prevalent among nursing staff than among psychiatrists. Basic and specific training in suicidology is needed and cannot be replaced solely by supervision, since psychiatric staff often have to deal with suicidal patients in emergency situations and must be able to rely on their own skills.     

Suicide-preventive activities in psychiatric care: Evaluation of an educational programme in suicide prevention

To promote implementation of suicide-preventive activities, the Swedish National Centre for Suicide Research and Prevention of Mental Ill-Health (NASP) introduced a 200-h academic, postgraduate educational programme (based on the training-of-trainers model) in suicide prevention. This programme was provided at Karolinska Institute, Stockholm, for key persons in psychiatric care. Twenty-nine key persons from 11 psychiatric intervention clinics in Stockholm County attended the first course. Preconditions for implementing suicide-preventive activities were assessed by means of semi-structured interviews with all course participants still working in the intervention clinics (n=10). In all but one of these 10 clinics, a wide range of suicide-preventive activities had been implemented as a result of the NASP course. Activities varied in scope, but the key persons seemed to have succeeded in pinpointing the key elements in suicide prevention – the need for specific knowledge about the suicidal process and for well-defined suicide-preventive routines. However, organizational factors and staff turnover were obstacles to maintaining and making the activities routine. There is a need to strengthen the course participants’ formal roles as implementers and encourage the clinical management in their continuous implementation of suicide-preventive activities.     

Low-level laser irradiation effect on endothelial cells under conditions of hyperglycemia

Diabetes mellitus is considered to be a very serious lifestyle disease leading to cardiovascular complications and impaired wound healing observed in the diabetic foot syndrome. Chronic hyperglycemia is the source of the endothelial activation. The inflammatory process in diabetes is associated with the secretion of inflammatory cytokines by endothelial cells, e.g., tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). The method of phototherapy using laser beam of low power (LLLT—low-level laser therapy) effectively supports the conventional treatment of diabetic vascular complications such as diabetic foot syndrome. The aim of our study was to evaluate the effect of low-power laser irradiation at two wavelengths (635 and 830 nm) on the secretion of inflammatory factors (TNF-α and IL-6) by the endothelial cell culture—HUVEC line (human umbilical vein endothelial cell)—under conditions of hyperglycemia. It is considered that adverse effects of hyperglycemia on vascular endothelial cells may be corrected by the action of LLLT, especially with the wavelength of 830 nm. It leads to the reduction of TNF-α concentration in the supernatant and enhancement of cell proliferation. Endothelial cells play an important role in the pathogenesis of diabetes; however, a small number of studies evaluate an impact of LLLT on these cells under conditions of hyperglycemia. Further work on this subject is warranted.     

Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands

Toll-like receptor ligands (TLRLs) produced by various pathogens activate mitogen-activated protein kinases (MAPKs). While the dependence on p38 MAPK activation for the induction of inflammatory genes by the TLR4L, lipopolysaccharide (LPS), has been well documented, the importance of the p38 pathway in gene regulation by other TLRLs is less well understood. We have focused our analysis on two TLRLs with therapeutic potential, imidazoquinoline S28463 (TLR7L) and CpG DNA (TLR9L), to explore in detail their effects on the regulation of gene expression in macrophages. Here we report that activation of the p38 MAPK/MK2 pathway is crucial for both S28463- and CpG-induced cytokine and chemokine production. We show that the stability of TNF mRNA induced by CpG DNA and S28463 is not dependent on the p38 MAPK/MK2 pathway, in contrast to LPS-induced TNF mRNA. Using a GFP reporter construct under the control of the 3' untranslated region of the TNF gene, we demonstrate that S28463 and CpG DNA-induced MK2 signalling regulates TNF mRNA primarily at the translational level, whereas LPS-induced MK2 signalling regulates both the stability and translational efficiency of TNF mRNA. Overall, these data provide insight into distinct molecular mechanisms of gene expression regulation by different Toll-like receptor ligands.     

In-vitro activity of the novel fluorocycline eravacycline against carbapenem non-susceptible Acinetobacter baumannii

The activity of eravacycline was compared with that of anti-Acinetobacter reference antimicrobials against carbapenem non-susceptible Acinetobacter baumannii isolates associated with an acquired OXA or up-regulation of the intrinsic OXA-51-like enzyme. Antimicrobial susceptibility testing was performed by broth microdilution of 286 non–duplicate, carbapenem non-susceptible A. baumannii isolates to eravacycline, amikacin colistin, doxycycline, imipenem, levofloxacin, meropenem, minocycline, sulbactam, tigecycline and tobramycin.Eravacycline showed greater activity than the comparators of the tetracycline class, levofloxacin, amikacin, tobramycin and colistin. The eravacycline MIC_50/90 values were 0.5/1?mg/L and those for tigecycline, minocycline and doxycycline were 1/2, 4/8 and 32/?≥?64?mg/L, respectively. In conclusion, eravacycline was the most potent antibiotic of those tested against A. baumannii, including isolates that were resistant to sulbactam, imipenem/meropenem, levofloxacin and amikacin/tobramycin. Eravacycline has the potential to become a useful addition to the limited armamentarium of drugs that can be used to treat this problem pathogen.     

Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) often colonize the anterior nares, and nasal carriage remains the main source of bacterial dissemination. The aim of this study was to assess the in vivo activity of the lantibiotic mersacidin against MRSA colonizing nasal epithelia. METHODS: The efficiency of mersacidin in the eradication of MRSA was tested employing mice pre-treated with hydrocortisone and inoculated intranasally either three or six times with a bacterial suspension. RESULTS: In mersacidin-treated animals, pre-colonized with MRSA, bacteria could not be detected in blood, lungs, liver, kidney, spleen or nasal scrapings and there were no lesions manifested after intraperitoneal drug application. Blood samples from infected mice obtained 2 h after mersacidin therapy revealed anti-MRSA activity in a serum bactericidal test. Moreover, elevated interleukin-1beta and tumour necrosis factor-alpha titres were noticed in the pre-infected but not in cured animals. In contrast, mersacidin did not induce differences in the cytokine profiles of treated uninfected control mice. CONCLUSIONS: In the mouse rhinitis model, mersacidin was able to eradicate MRSA colonization. The site of action (epithelium versus blood) of mersacidin needs to be further explored.     

Dynamic Response of Angle Ply Laminates with Uncertainties Using MARS,ANN-PSO,GPR and ANFIS

In the present work, for the first time, free vibration response of angle ply laminates with uncertainties is attempted using Multivariate Adaptive Regression Spline (MARS), Artificial Neural Network-Particle Swarm Optimization (ANN-PSO), Gaussian Process Regression (GPR), and Adaptive Network Fuzzy Inference System (ANFIS). The present approach employed 2D C⁰ stochastic finite element (FE) model based on the Third Order Shear Deformation Theory (TSDT) in conjunction with MARS, ANN-PSO, GPR, and ANFIS. The TSDT model used eliminates the requirement of shear correction factor owing to the consideration of the actual parabolic distribution of transverse shear stress. Zero transverse shear stress at the top and bottom of the plate is enforced to compute higher-order unknowns. C⁰ FE model makes it commercially viable. Stochastic FE analysis done with Monte Carlo Simulation (MCS) FORTRAN inhouse code, selection of design points using a random variable framework, and soft computing with MARS, ANN-PSO, GPR, and ANFIS is implemented using MATLAB in-house code. Following the random variable frame, design points were selected from the input data generated through Monte Carlo Simulation. A total of four-mode shapes are analyzed in the present study. The comparison study was done to compare present work with results in the literature and they were found in good agreement. The stochastic parameters are Young’s elastic modulus, shear modulus, and the Poisson ratio. Lognormal distribution of properties is assumed in the present work. The current soft computation models shrink the number of trials and were found computationally efficient as the MCS-based FE modelling. The paper presents a comparison of MARS, ANN-PSO, GPR, and ANFIS algorithm performance with the stochastic FE model based on TSDT.     

Diffuse lymphoma of the intestines with a monoclonal gammopathy of IgG3 kappa type

Monoclonal gammopathy of IgG₃ kappa type is described in a young man with diffuse lymphoid infiltration of the stomach duodenum and intestines.     

Role ofl-arginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing

Nitric oxide (NO) synthesized froml-arginine interacts with prostaglandins (PG) and sensory neuropeptides in the regulation of mucosal integrity, but the role ofl-arginine, a substrate for NO-synthase, in gastroprotection and healing of chronic gastric ulcers has been little studied. In this study we compared the effects of intragastric (i.g.) and systemic (i.v.) administration ofl-arginine ord-arginine on gastric secretion and acute gastric lesions provoked in rats by i.g. application of 100% ethanol, acidified aspirin (ASA), or the exposure to 3.5h of water immersion and restraint stress (WRS). In addition, the effects ofl-arginine on ulcer healing and the formation of new vessels (angiogenesis) were determined, using monoclonal antibody (MAb E-9).l-arginine (10–200 mg/kg i.g.) failed to significantly affect gastric secretion but dose-dependently reduced the gastric lesions induced by 100% ethanol, ASA, and WRS, the doses inhibiting 50% of these lesions being 65, 94, and 72 mg/kg, respectively. This protection was accompanied by a significant rise in the gastric blood flow (GBF), whereasl-arginine given i.v. failed to affect the ethanol-lesions and the GBF.d-arginine or the NO-related amino acids—l-glutamine,l-citrulline, orl-ornithine—failed to significantly influence these lesions. Suppression of the generation of mucosal PG by indomethacin or capsaicin-denervation attenuated the protection and hyperemia induced byl-arginine. The inhibition of constitutive NO synthase byl-NNA had no significant effect on the protection afforded byl-arginine, but reduced the gastric hyperemia accompanying this protection.l-arginine (150 mg/kg per day, i.g.) accelerated the ulcer healing and increased GBF at the ulcer margin, and angiogenesis, whereas treatment with L-NNA had an opposite effect.l-arginine added to N^G-nitro-l-arginine (L-NNA) restored the ulcer healing, hyperemia, and angiogenesis. We conclude that: (1) the protective activity ofl-arginine involves gastric hyperemia mediated by NO and a mild irritant effect due to enhanced generation of endogenous PG, and (2) the ulcer healing properties ofl-arginine depend upon its hyperemic and angiogenic actions, possibly involving NO.