The institutional experience of the implementing 4DCT in NSCLC radiotherapy planning.

Background: The study was to evaluate the effectiveness of dose distribution of four-dimensional computed tomography (4DCT) simulation. Materials and methods: The gross tumor volume (GTV) and clinical target volume (CTV) were contoured in all 10 respiratory phases of 4DCT in 30 patients with non-small cell lung cancer (NSCLC). Both 3D and 4D treatment plans were made individually for each patient using the planning volume (PTV). The PTV3D was taken from a single CTV plus the recommended margin, and the PTV4D was taken from the 4D internal target volume, including all 10 CTVs plus the setup margins. Results: The mean PTV was 460 ± 179 (69-820) cm3 for 3DCT and 401 ± 167 (127-854) cm3 for 4DCT (p = 0.0018). The dose distribution (DD) of organs at risk, especially the lungs, was lower for the 4DCT simulation. The V5%, V10%, and V20% of the total lung dose for 4DCT were significantly lower for the 3DCT. However, lung V30% the heart, esophagus, and spinal cord were not significantly different. In addition, the conformity index and the dose heterogeneity index of the PTV were not significantly different. The normal tissue complication probability (NTCP) of the lung and heart was significantly lower for 4DCT than for 3DCT. Conclusions: The 4DCT simulation gives better results on the NTCP. The organs at risk, especially the lungs, receive a significantly lower DD compared with the 3DCT. The conformity index (CI), heterogeneity index (HI) and the DD to the heart, spinal cord, and esophagus were not significantly different between the two techniques.

Sputum culture and antibiotic resistance in elderly inpatients with exacerbation of chronic obstructive pulmonary disease at a tertiary geriatric hospital in southern Vietnam.

OBJECTIVE: To determine the rate of positive culture sputum and related factors as well as the microorganism features and antibiotic susceptibility of pathogens in elderly inpatients with exacerbation of chronic obstructive pulmonary disease (COPD) in Thong Nhat Hospital, Vietnam. METHODS: This cross-sectional study included elderly patients admitted to the hospital because of exacerbation of COPD. Data of their medical history, symptoms and signs were collected, and the patients were instructed to collect sputum sample. A positive culture was identified with the growth of ≥ 105 colony-forming units per milliliter. Antibiotic susceptibility testing was performed according to the European Committee on Antimicrobial Susceptibility Testing. RESULTS: There were 167 participants (mean age: 77.5 ± 8.8 years, 87.4% male). The culture-positive rate was 25.1%. A higher proportion of positive culture was among participants with purulent sputum (p = 0.029) and with severe and very severe airflow obstruction (p = 0.005). Three most common agents were Acinetobacter baumannii (24.4%), Klebsiella pneumoniae (22.2%), and Pseudomonas aeruginosa (15.6%). Despite high resistance to almost other antibiotics (> 50% resistance), Acinetobacter baumannii and Pseudomonas aeruginosa were sensitive to colistin, tobramycin, and gentamicin (> 80% susceptibility). Klebsiella pneumoniae was highly sensitive to almost common antibiotics (> 80% susceptibility). Among Gram-positive pathogens, methicillin-resistant Staphylococcus aureus (MRSA) was completely sensitive to vancomycin, teicoplanin, and linezolid. CONCLUSION: The sputum culture-positive rate in this study was not high. Most prevalent isolated pathogens were Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Acinetobacter baumannii and Pseudomonas aeruginosa were sensitive to tobramycin, gentamicin, and colistin. Commonly used antibiotics remained effective against Klebsiella pneumoniae. MRSA was sensitive to vancomycin, teicoplanin, and linezolid.

Effects of Donepezil Treatment on Brain Metabolites, Gut Microbiota, and Gut Metabolites in an Amyloid Beta-Induced Cognitive Impairment Mouse Pilot Model.

Accumulated clinical and biomedical evidence indicates that the gut microbiota and their metabolites affect brain function and behavior in various central nervous system disorders. This study was performed to investigate the changes in brain metabolites and composition of the fecal microbial community following injection of amyloid ß (Aß) and donepezil treatment of Aß-injected mice using metataxonomics and metabolomics. Aß treatment caused cognitive dysfunction, while donepezil resulted in the successful recovery of memory impairment. The Aß + donepezil group showed a significantly higher relative abundance of Verrucomicrobia than the Aß group. The relative abundance of 12 taxa, including Blautia and Akkermansia, differed significantly between the groups. The Aß + donepezil group had higher levels of oxalate, glycerol, xylose, and palmitoleate in feces and oxalate, pyroglutamic acid, hypoxanthine, and inosine in brain tissues than the Aß group. The levels of pyroglutamic acid, glutamic acid, and phenylalanine showed similar changes in vivo and in vitro using HT-22 cells. The major metabolic pathways in the brain tissues and gut microbiota affected by Aß or donepezil treatment of Aß-injected mice were related to amino acid pathways and sugar metabolism, respectively. These findings suggest that alterations in the gut microbiota might influence the induction and amelioration of Aß-induced cognitive dysfunction via the gut-brain axis. This study could provide basic data on the effects of Aß and donepezil on gut microbiota and metabolites in an Aß-induced cognitive impairment mouse model.

Pharmacokinetic improvement provided by microneedle patch in delivering bee venom, a case study in combating scopolamine-induced neurodegeneration in mouse model.

Much research has shown Bee venom to be an effective neuroprotective agent. However, the usual transdermal injection of bee venom poses many pharmacokinetic disadvantages. Here, we compared the administration of bee venom via subcutaneous injection (SC) and via Microneedle patch (MN). Both administrated routes produce significant recovery effects, however: the MN significantly prolongs the bio-significant-and-yet-lower concentration of bee venom in mice bodies. In contrast, SC could produce only a short period of much higher bee venom levels in the blood and brain. We also see that due to the concentration-response-curve of bee venom (represented by melittin): mice bodies do not require much higher bee venom concentration (seen in the SC group) to produce a much more significant neuroprotective effect (than seen in those treated with the MN method). Therefore, a MN could maintain bee venom levels in mice bodies at lower-yet-more-efficient concentrations. This is important, as bee venom can cause more adverse effects and pain sensations, at higher concentrations. For the first time, we confirmed that the pharmacokinetic advantages of MN delivered bee venom also guarantee a holistic neuroprotection effect (which was shown by SC delivered bee venom in previous research). This was proven via the results of the water maze experiments for long-term learning memory assessment and protein analysis of key neuronal regulatory proteins: BDNF, p-CREB, iNOS, and mArhR 1. In conclusion, for situations where we ought to administrate drugs at a more downward amount, such as bee venom, MN can keep the therapeutic concentrations at a lower, yet interestingly, more-efficient level.

Insamgobonhwan Protects Neuronal Cells from Lipid ROS and Improves Deficient Cognitive Function.

Iron is an essential element in the central nervous system that is involved in many of its important biological processes, such as oxygen transportation, myelin production, and neurotransmitter synthesis. Previous studies have observed the selective accumulation of iron in Aß aggregates and neurofibrillary tangles in the brains of patients with Alzheimer's disease, and excess of this accumulation is associated with accelerated cognitive decline in Alzheimer's patients. Emerging evidence suggests that ferroptosis, cell death due to iron accumulation, is a potential therapeutic target for treating Alzheimer's disease. Insamgobonhwan (GBH) is a well-regarded traditional medicine from Donguibogam that possess antioxidant properties and has been suggested to slow the aging process. However, the neuroprotective role of GBH against lipid peroxidation-induced ferroptosis and its positive cognitive effects remain unexplored. Here, we investigated the ability of GBH to protect against RSL3-induced ferroptosis in vitro and to suppress amyloid-ß-induced cognitive impairment in vivo. First, we treated HT22 cells with RSL3 to induce ferroptosis, which is an inhibitor of glutathione peroxidase 4 (GPX4) and induces lethal lipid hydroperoxide accumulation, reactive oxygen species (ROS) production, and ferroptotic cell death. GBH treatment inhibited cell death and lipid peroxidation, which were increased by RSL3 administration. In addition, GBH restored the expression of ferroptosis marker proteins, such as GPX4, HO-1 and COX-2, which were altered by RSL3. Next, we examined whether the protective ability of GBH in cells was reproduced in animals. We concluded that GBH treatment inhibited Aß-induced lipid peroxidation and improved Aß-induced cognitive impairment in mice.

Bee Venom Activates the Nrf2/HO-1 and TrkB/CREB/BDNF Pathways in Neuronal Cell Responses against Oxidative Stress Induced by Aß1-42.

Honeybee venom has recently been considered an anti-neurodegenerative agent, primarily due to its anti-inflammatory effects. The natural accumulation of amyloid-beta (Aß) in the brain is reported to be the natural cause of aging neural ability downfall, and oxidative stress is the main route by which Aß ignites its neural toxicity. Anti-neural oxidative stress is considered an effective approach for neurodegenerative therapy. To date, it is unclear how bee venom ameliorates neuronal cells in oxidative stress induced by Aß. Here, we evaluated the neuroprotective effect of bee venom on Aß-induced neural oxidative stress in both HT22 cells and an animal model. Our results indicate that bee venom protected HT22 cells against apoptosis induced by Aß1-42. This protective effect was explained by the increased nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2), consequently upregulating the production of heme oxygenase-1 (HO-1), a critical cellular instinct antioxidant enzyme that neutralizes excessive oxidative stress. Furthermore, bee venom treatment activated the tropomyosin-related kinase receptor B (TrkB)/cAMP response element-binding (CREB)/brain-derived neurotrophic factor (BDNF), which is closely related to the promotion of cellular antioxidant defense and neuronal functions. A mouse model with cognitive deficits induced by Aß1-42 intracerebroventricular (ICV) injections was also used. Bee venom enhanced animal cognitive ability and enhanced neural cell genesis in the hippocampal dentate gyrus region in a dose-dependent manner. Further analysis of animal brain tissue and serum confirmed that bee venom reduced oxidative stress, cholinergic system activity, and intercellular neurotrophic factor regulation, which were all adversely affected by Aß1-42. Our study demonstrates that bee venom exerts antioxidant and neuroprotective actions against neural oxidative stress caused by Aß1-42, thereby promoting its use as a therapeutic agent for neurodegenerative disorders.

Neuroprotective Activity of Melittin-The Main Component of Bee Venom-Against Oxidative Stress Induced by Aß25-35 in In Vitro and In Vivo Models.

Melittin, a 26-amino acid peptide, is the main component of the venom of four honeybee species and exhibits neuroprotective actions. However, it is unclear how melittin ameliorates neuronal cells in oxidative stress and how it affects memory impairment in an in vivo model. We evaluated the neuroprotective effect of melittin on Aß25-35-induced neuro-oxidative stress in both in vitro HT22 cells and in vivo animal model. Melittin effectively protected against HT22 cell viability and significantly deregulated the Aß25-35-induced overproduction of intracellular reactive oxygen species. Western blot analysis showed that melittin suppressed cell apoptosis and regulated Bax/Bcl-2 ratio, as well as the expression of proapoptotic related factors: Apoptosis-inducing factor (AIF), Calpain, Cytochrome c (CytoC), Cleaved caspase-3 (Cleacas3). Additionally, melittin enhanced the antioxidant defense pathway by regulating the nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2) thus upregulated the production of the heme oxygenase-1 (HO-1), a major cellular antioxidant enzyme combating neuronal oxidative stress. Furthermore, melittin treatment activated the Tropomyosin-related kinase receptor B (TrkB)/cAMP Response Element-Binding (CREB)/Brain-derived neurotrophic factor (BDNF), contributing to neuronal neurogenesis, and regulating the normal function of synapses in the brain. In our in vivo experiment, melittin was shown to enhance the depleted learning and memory ability, a novel finding. A mouse model with cognitive deficits induced by Aß25-35 intracerebroventricular injection was used. Melittin had dose-dependently enhanced neural-disrupted animal behavior and enhanced neurogenesis in the dentate gyrus hippocampal region. Further analysis of mouse brain tissue and serum confirmed that melittin enhanced oxidant-antioxidant balance, cholinergic system activity, and intercellular neurotrophic factors regulation, which were all negatively altered by Aß25-35. Our study shows that melittin exerts antioxidant and neuroprotective actions against neural oxidative stress. Melittin can be a potential therapeutic agent for neurodegenerative disorders.

[A randomized double-blind therapeutic trial of enalapril versus timed-release nifedipine in mild to moderate essential hypertension]. / Essai thérapeutique randomisé en double aveugle de l'énalapril versus nifédipine retard dans L'hypertension essentielle légère á modérée.

In a multicentre, randomized, double-blind, double-placebo therapeutic trial, the effectiveness and safety of enalapril and slow-release nifedipine were studied in two groups of ambulatory patients with mild to moderate essential hypertension. Following a 2-week placebo period, 136 patients were allocated at random to either enalapril 20 mg/day in one evening dose (group 1, n = 68) or to nifedipine 40 mg/day in two doses, one a.m. the other p.m. (group II). Each treatment was administered for 12 weeks. Patients in both groups whose diastolic arterial pressure remained above 90 mmHg were given hydrochlorothiazide 25 mg/day from the 4th week onward. When blood pressure did not return to normal, the dose of hydrochlorothiazide was increased to 50 mg/day in the 8th week. After 4 weeks of treatment, no significant difference in reduction of supine diastolic arterial pressure was observed between the two groups (- 12.1 +/- 9.9 mmHg in groups I vs - 10.3 +/- 9.0 mmHg in group II). At the end of the 12-week treatment the decrease of diastolic blood pressure was more pronounced in patients on enalapril than in those on nifedipine (- 16.3 +/- 8.0 mmHg vs - 13.9 +/- 7.1 mmHg), although the difference was not statistically significant (P = 0.06). The number of patients with undesirable side-effects was greater in the nifedipine group (33 patients; 48.5 per cent) than in the enalapril group (18 patients; 26.5 per cent). Treatment was discontinued on account of side-effects in 3 patients of the enalapril group and 10 patients of the nifedipine group.

Diagnostic and prognostic significance of myelomonocytic cell surface antigens in acute myeloid leukaemia.

Thirty-six cases of acute myeloid leukaemia (AML) were tested with a large battery of monoclonal antibodies (moAbs) detecting surface markers normally expressed by myelomonocytic, T and B lymphoid, megakaryocytic and erythroid lineages. Differences in antigenic expression were observed among the various FAB subgroups: HLA-class II molecules were found in almost all AML cases but not in the promyelocytic subgroup (M3); CD14 and CD36 antigens were detected in monocytic leukaemias (M4 and M5); the CD34 moAb (MY10) recognizing an epitope described on myeloid stem cells was positive in 88% of the M1 and 80% of the M3 cases. By a multivariate analysis, only the CD14b (MY4) discriminated significantly between M1-M2 and M4-M5 subgroups. Using Cox's model to assess the prognostic importance of variables including immunophenotyping on survival, we undertook a one by one analysis and found that the presence of CD17 antigen predicted for a shorter survival (P = 0.03). In addition this marker appeared more significant than other clinical and biological parameters.