Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism.

Cell metabolism reprogramming to sustain energy production, while reducing oxygen and energy consuming processes is crucially important for the adaptation to hypoxia/ischemia. Adaptive metabolic rewiring is controlled by hypoxia-inducible factors (HIFs). Accumulating experimental evidence indicates that timely activation of HIF in brain-resident cells improves the outcome from acute ischemic stroke. However, the underlying molecular mechanisms are still incompletely understood. Thus, we investigated whether HIF-dependent metabolic reprogramming affects the vulnerability of brain-resident cells towards ischemic stress. Methods: We used genetic and pharmacological approaches to activate HIF in the murine brain in vivo and in primary neurons and astrocytes in vitro. Numerous metabolomic approaches and molecular biological techniques were applied to elucidate potential HIF-dependent effects on the central carbon metabolism of brain cells. In animal and cell models of ischemic stroke, we analysed whether HIF-dependent metabolic reprogramming influences the susceptibility to ischemic injury. Results: Neuron-specific gene ablation of prolyl-4-hydroxylase domain 2 (PHD2) protein, negatively regulating the protein stability of HIF-α in an oxygen dependent manner, reduced brain injury and functional impairment of mice after acute stroke in a HIF-dependent manner. Accordingly, PHD2 deficient neurons showed an improved tolerance towards ischemic stress in vitro, which was accompanied by enhanced HIF-1-mediated glycolytic lactate production through pyruvate dehydrogenase kinase-mediated inhibition of the pyruvate dehydrogenase. Systemic treatment of mice with roxadustat, a low-molecular weight pan-PHD inhibitor, not only increased the abundance of numerous metabolites of the central carbon and amino acid metabolism in murine brain, but also ameliorated cerebral tissue damage and sensorimotor dysfunction after acute ischemic stroke. In neurons and astrocytes roxadustat provoked a HIF-1-dependent glucose metabolism reprogramming including elevation of glucose uptake, glycogen synthesis, glycolytic capacity, lactate production and lactate release, which enhanced the ischemic tolerance of astrocytes, but not neurons. We found that strong activation of HIF-1 in neurons by non-selective inhibition of all PHD isoenzymes caused a HIF-1-dependent upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 redirecting glucose-6-phosphate from pentose phosphate pathway (PPP) to the glycolysis pathway. This was accompanied by a reduction of NADPH production in the PPP, which further decreased the low intrinsic antioxidant reserve of neurons, making them more susceptible to ischemic stress. Nonetheless, in organotypic hippocampal cultures with preserved neuronal-glial interactions roxadustat decreased the neuronal susceptibility to ischemic stress, which was largely prevented by restricting glycolytic energy production through lactate transport blockade. Conclusion: Collectively, our results indicate that HIF-1-mediated metabolic reprogramming alleviates the intrinsic vulnerability of brain-resident cells to ischemic stress.

Surgical Antimicrobial Prophylaxis Compliance in Turkey: Data from the Prospective, Observational, Multicenter Survey Including 7,978 Surgical Patients.

Background: Surgical antimicrobial prophylaxis (SAP) is the peri-operative administration of antimicrobial agents. Compliance rates vary worldwide from 15% to 84.3%, with studies in Turkey not exceeding 35%. The aim of this multicenter study was to determine the rate of appropriate antibiotic class, timing, and duration as well as discharge prescriptions in Turkey. Thus, we aimed to determine the rate of full compliance with SAP procedures in our country Patients and Methods: This multicenter, prospective, observational, descriptive study was conducted in 47 hospitals from 28 provinces in seven different regions of Turkey. Patients over 18 years of age in all surgical units between June 6, 2022, and June 10, 2022, were included in the study. Results: Of the 7,978 patients included in the study, 332 were excluded from further analyses because of pre-existing infection, and SAP compliance analyses were performed on the remaining 7,646 cases. The antibiotic most commonly used for SAP was cefazolin (n = 4,701; 61.5%), followed by third-generation cephalosporins (n = 596; 7.8%). The most common time to start SAP was within 30 minutes before surgery (n = 2,252; 32.5%), followed by 30 to 60 minutes before surgery (n = 1,638; 23.6%). Surgical antimicrobial prophylaxis duration was <24 hours in 3,516 (50.7%) patients and prolonged until discharge in 1,505 (21.7%) patients. Finally, the actual proportion of patients compliant with SAP was 19% (n = 1,452) after omitting 4,458 (58.3%) patients who were prescribed oral antibiotic agents at discharge as part of a prolonged SAP. Conclusions: Surgical antimicrobial prophylaxis compliance rates are still very low in Turkey. Prolonged duration of SAP and especially high rate of antibiotic prescription at discharge are the main reasons for non-compliance with SAP.

Could Systemic Inflammation in Healthy Individuals With Obesity Indicate Subclinical Atherosclerosis?

Obesity is one of today's pandemics. The link between obesity and inflammation is well established and contributes to atherogenesis. We aimed to determine the relationship between carotid intima-media thickness (cIMT) and inflammation in healthy obese patients (n = 289). The patients were referred to the outpatient clinic due to obesity but had no chronic diseases. Subclinical atherosclerosis was defined as present in participants with cIMT values greater than those expected according to their age group. In patients with subclinical atherosclerosis, the neutrophil-lymphocyte ratio (1.86 ± .65 vs 1.57 ± .45, P < .01), platelet-lymphocyte ratio (120.0 ± 41.2 vs 106.8 ± 30.5, P ≤ .01), and systemic immune-inflammatory index (SII) (550.0 ± 232.8 vs 430.4 ± 135.0, P ≤ .01) were found to be higher. SII was the only independent risk factor for developing subclinical atherosclerosis (odds ratio (OR): 1.995, odds ratio (95% confidence interval): 1.692-4.099), P = .004). The area under the curve (AUC) was .664 (95% CI: .605-.729, P ≤ .001), and the optimal cut-off value was 436.7 (69.3% sensitivity and 61.6% specificity). In conclusion, SII may indicate subclinical atherosclerosis in healthy obese patients, thus leading to early initiation of treatment to reduce cardiovascular morbidity and mortality.

Comparison of diagnostic performances in the evaluation of breast microcalcifications: synthetic mammography versus full-field digital mammography.

BACKGROUND: Although several studies proved that SM could substitute for FFDM, the efficacy of SM in microcalcification evaluation remains controversial. AIMS: To investigate the diagnostic performance of synthetic mammography (SM) in the evaluation of microcalcifications in comparison with full-field digital mammography (FFDM). METHODS: In this retrospective study, 76 mammograms of 76 patients who underwent FFDM and digital breast tomosynthesis (DBT) acquisitions concomitantly between 2018 and 2019 and whose final mammography interpretation revealed microcalcifications (28 malignant microcalcifications and 48 benign microcalcifications) were included. All mammograms were reviewed independently by three radiologists with different levels of breast imaging experience. Readers were blinded to patient outcomes and interpreted each case in two separate reading sessions (first FFDM, second SM + DBT), according to the BI-RADS lexicon. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated using ROC analysis in all cases for FFDM and SM + DBT sessions. The readers also assigned conspicuity scores to mammograms. The interobserver agreement was calculated using intraclass correlation coefficients (ICC). RESULTS: The overall AUCs for malignant microcalcifications were 0.80 (95% CI: 0.75-0.85) in FFDM and 0.85 (95% CI: 0.80-0.89) in SM, and no significant difference was found between the groups (p = 0.0603). The sensitivity of the readers increased slightly with experience. The ICC values of BI-RADS categorization between readers were 0.93 (95% CI: 0.90-0.95) and 0.94 (95% CI: 0.91-0.96) for FFDM and SM, respectively. CONCLUSIONS: SM had similar diagnostic performance in the evaluation of breast microcalcifications in comparison with FFDM, regardless of reader experience levels.

The effect of bronchiectasis on the exacerbation and mortality of chronic obstructive pulmonary disease.

BACKGROUND: Coexistence of bronchiectasis with chronic obstructive pulmonary disease (COPD) may lead to the worsening of the functional parameters in exacerbations and may negatively affect the outcomes. METHODS: This study is a retrospective cross-sectional study that aims to investigate the relationships between bronchiectasis with COPD exacerbation and all-cause of mortality. We retrospectively enrolled 122 cases hospitalized for COPD exacerbation from 2010 to 2016. Patients who underwent thoracic tomography in the previous year of the index exacerbation were included in the study. Patients who admitted to the intensive care unit and patients with infected bronchiectasis and with conditions that mimic COPD exacerbation were excluded from the study. Demographic, clinical, and laboratory findings, comorbidities and the number of exacerbations in the previous year and the presence of bronchiectasis were recorded using hospital electronic registry. The radiological evaluation of bronchiectasis was made by the modified Reiff score (MRS). RESULTS: Bronchiectasis was found in 66 (54%) of 122 patients included in the study. The mean age was 67.5 ± 10.3 in the whole group, 108 (88.5%) of the patients were male, and 14 (11.5%) were female. When patients were stratified according to the presence of bronchiectasis, no statistically significant difference was found in terms of comorbidity scores, respiratory functions, exacerbation parameters, laboratory values and all cause of mortality between the groups (p > 0.05). There was no statistical relation between the presence of bronchiectasis and long-term survival (log-rank test p = 0.83). CONCLUSIONS: This study shows that patients with bronchiectasis did not cause a poor outcome in patients with COPD exacerbation.

Evaluation of schwannoma using the 3D-SPACE sequence: comparison with the 3D-CISS sequence in 3T-MRI

Background/aim: The purpose of this study is to compare the diagnostic accuracy and interobserver reliability of the T2-weighted 3D-SPACE (three-dimensional sampling perfection with application-optimized contrasts by using different flip angle evolutions) sequence in comparison with T2-weighted 3D-CISS (three-dimensional constructive interference in steady state) sequences for diagnosis of schwannomas. Materials and methods: Forty patients with cerebellopontine angle (CPA), internal acoustic canal (IAC), and cochlear schwannoma who had undergone magnetic resonance imaging (MRI) using the 3D-CISS and 3D-SPACE sequences were identified. The sequences were retrospectively evaluated by two radiologists for the qualitative analyses, which were subsequently compared using the Mann­Whitney U test. Following this, kappa values were used for interobserver agreement. P < 0.05 was considered to be of statistical significance. Results: The interobserver agreement was found to be excellent between the two observers for the interpretation of all qualitative analyses for both sequences (kappa value > 0.8). The 3D-SPACE sequences demonstrated significantly better qualitative scores and fewer artifacts compared with the 3D-CISS sequences (p < 0.05). Conclusion: Our results demonstrate that 3D-SPACE is superior to 3D-CISS in the imaging process of the schwannoma in terms of image quality, description of the relationship between the lesion and cranial nerve, signal differentiation between lesion and cistern, and signal differentiation between the lesion and adjacent brain.

Evaluation of effects of aging on skeletal muscle elasticity using shear wave elastography.

PURPOSE: To evaluate the effects of aging on skeletal muscle stiffness in relaxed and contracted status using shear wave elastography (SWE). MATERIALS AND METHODS: A total of 57 participants were enrolled to this institutional review board approved prospective study. Medial head of the gastrocnemius muscle (GM) of all participants were examined bilaterally by a single radiologist in prone position. Muscle thickness, stiffness values in both relaxed and contracted status were measured. Stiffness increase rate (SIR) was calculated for all muscles. The Spearman's correlation test was used for correlation analyses. Mann-Whitney U test was used to compare subgroups. RESULTS: The mean age of the participants was 41.15 ±â€¯16.19 (range, 18-74). The means of stiffness values of medial head of GM were 12.51 ±â€¯2.56 kPa and 81.74 ±â€¯15.77 kPa in relaxed and contracted status, respectively. The mean of SIR values was 5.62 ±â€¯1.05 (range, 3.18-8.66). The stiffness values of relaxed and contracted medial head of GM had moderate to strong inverse correlations with age for both dominant and non-dominant extremities (r range: -0.703 to -0.590). Age subgroup analyses revealed significant differences in muscle thickness and stiffness values, whereas no significant difference was found in SIR values. CONCLUSION: In conclusion, despite the decrease in stiffness of skeletal muscle with advancing age, SIR remained similar. Any improvement in stiffness values of skeletal muscle in relaxed status may play pivotal role in the management of sarcopenia.

Comparison of Mass Size Measurements: Synthesized Mammography Versus Full-Field Digital Mammography.

OBJECTIVES: To compare mass size measurements between synthesized mammography (SM) and full-field digital mammography (FFDM), and to assess interobserver agreement for those measurements. MATERIALS AND METHODS: One hundred and forty-three patients who underwent FFDM and digital breast tomosynthesis acquisitions during the same compression session were included in the study. Two observers with four-and 1-year experience with digital breast tomosynthesis and SM images, respectively, measured mass sizes independently in two different sessions that were 2 weeks apart, and were blinded to each other. The first session included only FFDM images, and the second session included only SM images. Largest dimension of masses was measured in millimeters. Paired t test was used to compare differences in size measurements between FFDM and SM images. Intraclass correlation coefficient test was used to analyze interobserver agreement. Bland-Altman analyses were performed to evaluate agreements between the imaging techniques and between the observers. RESULTS: The mean mass sizes on FFDM and SM images were 20.27 ± 14.10 and 18.50 ± 13.05 mm, respectively, for the first observer and 21.56 ± 14.84 and 19.89 ± 13.68 mm, respectively, for the second observer. The mass size measurements were significantly different between FFDM and SM for both observers (p < 0.001). Range of measurement errors, defined as 95% limits of agreements between two imaging techniques for observers 1 and 2 were ±1.96*1.36 mm, and ±1.96*1.53 mm, respectively. Range of measurement errors, defined as 95% limits of agreements between two observers for SM and FFDM were ±1.96*3.68 mm, and ±1.96*3.35 mm, respectively. CONCLUSION: The measured mass sizes were significantly smaller on SM than FFDM images, and the interobserver differences for both of the imaging techniques were greater than the differences measured between FFDM and SM images.

Design of meloxicam and lornoxicam transdermal patches: Preparation, physical characterization, ex vivo and in vivo studies.

Transdermal patches of meloxicam (MX) and lornoxicam (LX) were aimed to be prepared in order to overcome their side effects by oral application. The strategy was formulation of optimized films to prepare transdermal patches by determination of physical properties and investigation of drug-excipient compatibility. As the next step, in vitro drug release, assesment of anti-inflammatory effect on Wistar Albino rats, ex vivo skin penetration and investigation of factors on drug release from transdermal patches were studied. Hydroxypropyl methylcellulose (HPMC) was concluded to be suitable polymer for formulation of MX and LX transdermal films indicating pharmaceutical quality required. MX and LX transdermal patches gave satisfactory results regarding to the edema inhibition in the assessment of anti-inflammatory effect. MX was found out to be more effective compared to LX on relieving of edema and swelling. These results were supported by data obtained from ex vivo penetration experiments of drug through rat skin. Indicative parameters like log P, molecular weight and solubility constraint on penetration rate of drugs also indicated good skin penetration. Transdermal patches of MX and LX can be suggested to be used especially for the immediate treatment of inflammated area since it displays anti-inflammatory effect, soon.