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Andrea Vukić Dugac,1,2 Mirna Vergles,3 Sanda Škrinjarić Cincar,4 Ljiljana Bulat Kardum,5 Marina Lampalo,1 Sanja Popović-Grle,1,2 Jelena Ostojić,6 Tatjana Tokić Vuksan-Ćusa,7 Žarko Vrbica,8,9 Emilija Lozo Vukovac,10 Neven Tudorić11 1Clinic for Respiratory Diseases, University Hospital Centre Zagreb, Zagreb, Croatia; 2School of Medicine, University of Zagreb, Zagreb, Croatia; 3Department of Pulmonology, Clinical Hospital Dubrava, Zagreb, Croatia; 4Faculty of Medicine, University of Osijek, Osijek, Croatia; 5Department of Pulmonology, Clinical Hospital Centre Rijeka, Rijeka, Croatia; 6Pulmonary Outpatient Clinic, Special Hospital for Pulmonary Diseases, Zagreb, Croatia; 7Department of Internal Medicine, Karlovac General Hospital, Karlovac, Croatia; 8Department of Internal Medicine, Dubrovnik General Hospital, Dubrovnik, Croatia; 9University Study Programme Nursing, University of Dubrovnik, Dubrovnik, Croatia; 10Department of Pulmonology, University Hospital Split, Split, Croatia; 11Pulmonary Outpatient Clinic, St. Catherine Specialty Hospital, Zagreb, CroatiaCorrespondence: Neven Tudorić, St. Catherine Specialty Hospital, Branimirova Ul. 71E, Zagreb, 10000, Croatia, Tel +385915832449, Email neven.tudoric@gmail.comIntroduction: Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) lead to poor outcomes and increased burden for patients and healthcare systems. The Global Initiative for COPD (GOLD) includes specific recommendations for AECOPD interventions, discharge criteria, and follow-up. Aligning the AECOPD discharge letters (DL) with GOLD guidelines could facilitate dissemination of recommendations among general practitioners (GPs).Purpose: This study was conducted to assess the compliance of DL with the GOLD recommendations in Croatia.Methods: Pre-pandemic DL of patients presenting for AECOPD to emergency room (ER) were analyzed and stratified by clinical decision to hospitalize (HDL) or discharge patients for outpatient treatment (ERDL). Experienced pulmonologists checked the information from DL against guidelines by using online study-specific questionnaires.Results: In total, 225 HDL and 368 ERDL were analyzed. In most cases, the GOLD ABCD categories (85% HDL, 92% ERDL) or the spirometry-based degree of severity (90% HDL, 91% ERDL) were not included. The number of AEs in the previous year was recorded, but the specific frequent exacerbator phenotype not explicitly stated. The AE phenotype was included in two thirds of HDL and one third of ERDL. The blood eosinophil count was frequently available, but not considered decision-relevant information. Adjustments of previous maintenance therapy, mostly escalation, were recommended in 58.4% HDL and 27.9% ERDL, respectively. Education on proper use of inhalers was recommended only in 15.6% of HDL. Smoking cessation measures were advised in 23.1% HDL and 7.9% ERDL; pulmonary rehabilitation in 35.6% HDL and 0.8% ERDL. Early follow-up was frequently advised (> 50%), but rarely appointed.Conclusion: Significant deficiencies in compliance with the GOLD guidelines were identified, translating into a missed opportunity for GPs to become acquainted with GOLD recommendations. These findings emphasize the necessity to increase compliance with guidelines first at specialist level and consequent standardization of DL.Keywords: COPD, GOLD guidelines, acute exacerbation, discharge record

Background: Pretreatment differentiation between glioblastoma and metastasis is a frequently encountered dilemma in neurosurgical practice. Distinction is required for precise planning of resection or radiotherapy, and also for defining further diagnostic procedures. Morphology and spectroscopy imaging features are not specific and frequently overlap. This limitation of magnetic resonance imaging and magnetic resonance spectroscopy was the reason to initiate this study. The aim of the present study was to determine whether the dataset of diffusion tensor imaging metrics contains information which may be used for the distinction between primary and secondary intra-axial neoplasms. Methods: Two diffusion tensor imaging parameters were measured in 81 patients with an expansive, ring-enhancing, intra-axial lesion on standard magnetic resonance imaging (1.5 T system). All tumors were histologically verified glioblastoma or secondary deposit. For qualitative analysis, two regions of interest were defined: intratumoral and immediate peritumoral region (locations 1 and 2, respectively). Fractional anisotropy and mean difusivity values of both groups were compared. Additional test was performed to determine if there was a significant difference in mean values between two locations. Results: A statistically significant difference was found in fractional anisotropy values among two locations, with decreasing values in the direction of neoplastic infiltration, although such difference was not observed in fractional anisotropy values in the group with secondary tumors. Mean difusivity values did not appear helpful in differentiation between these two entities. In both groups there was no significant difference in mean difusivity values, neither in intratumoral nor in peritumoral location. Conclusion: The results of our study justify associating the diffusion tensor imaging technique to conventional morphologic magnetic resonance imaging as an additional diagnostic tool for the distinction between primary and secondary intra-axial lesions. Quantitative analysis of diffusion tensor imaging metric, in particular measurement of fractional anisotropy in peritumoral edema facilitates accurate diagnosis.

Total creatine concentration in the skeletal muscle and brain of long COVID patients were significantly lower when compared to the reference values for the general population, as measured with proton magnetic resonance spectroscopy at 1.5-T in vastus medialis muscle, thalamus, and three bilateral cerebral locations across the white and gray matter. [ABSTRACT FROM AUTHOR]

Severe climate alterations that seriously challenge fruit production, combined with the demand for healthy, pesticide-free fruits, continuously direct rootstock/cultivar selection towards high adaptable varieties breeding. This study aimed to investigate the rootstocks’ influence on the performance of grafted ‘Summit’ cherry trees, including potentially dwarfing Prunus cerasus, Prunus fruticosa and Prunus mahaleb rootstock candidates. Anatomical properties of rootstock and scion stems were investigated to determine variation among different rootstocks and scion-rootstock combinations and to establish the link between trunk hydraulic conductivity, effective tree crown volume and yielding potential. Cross-section anatomical characteristics varied significantly both in rootstock and scion stems, indicating a clear influence of rootstock genotype on grafted sweet cherry trees. It was observed that all investigated cherry rootstock candidates belong to the low-vigorous rootstocks, based on the estimated effective crown volume of grafted trees compared to ‘Gisela 5’, with values ranging from 0.86 to 2.97 m3 in the fifth year after planting. Results showed a statistically significant positive correlation between trunk hydraulic conductivity, effective tree crown volume and yielding potential, with correlation coefficients up to 0.96. Significantly higher effective crown volume and trunk hydraulic conductance of trees grafted on P. cerasus compared to the trees on control, as well as highest yielding potential, showed better adaptation of these rootstock candidates in the trial without irrigation implemented. It was found that PC_05_04 rootstock candidate could be considered as the most appropriate choice when raising the high-density sweet cherry plantations, due to assessed parameters of vegetative and generative growth.

Introduction. Synchronous multicentric cerebral gliomas are uncommon brain tumors, mostly malignant, with unknown pathogenesis, unfavorable prognosis and still controversial management. Preoperative differentiation from other multiple brain pathologies by conventional magnetic resonance imaging (MRI) is often difficult, but supplemental use of advanced magnetic resonance techniques should allow the tumor biology to be predicted and an appropriate treatment strategy planned. Case report. We reported a 59-yearold man with double synchronous multicentric cerebral lesions, which had initial MRI and diffusion-weighted imaging presentation as left parietal metastasis and ipsilateral amygdalo- hippocampal low-grade glioma. However, magnetic resonance spectroscopy (MRS) of both lesions showed different metabolite profiles of malignant glioma. En bloc resection of the easily accessible parietal lesion revealed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Subsequently, the patient was treated with temozolomide (TMZ)-based chemoradiation according to Stupp’s protocol, with continuous standard (5/28) adjuvant TMZ in 12 courses. Despite prolonged stabilization of the disease with good life-quality during treatment, the patient died 19 months after diagnosis. The time to tumor progression estimated by MRI was 17 months. Conclusion. MRS significantly improved the differential diagnostic accuracy of conventional MRI in our patient. In accordance with reviewed literature data, the younger age, good initial performance status and methylated MGMT gene promoter were all favorable predictors of longer survival in the reported case. Resection of at least one easily accessible tumor lesion, followed by TMZ-based chemoradiation, with continuous adjuvant TMZ in more than 6 standard courses, seems currently to be the most beneficial therapeutic option for such cases.

Magnetic resonance spectroscopy (MRS) is a diagnostic tool that provides information related to brain’s metabolic activity. Literature data suggest that elevation of the ratio between the choline and creatine (the Cho/Cr ratio), the reduction of the ratio between n-acetyl-aspartate acid and creatine (the NAA/Cr ratio), increase of the ratio between myo-inositol and creatine (the MI/Cr ratio), and the presence of lipids and lactate are useful diagnostic markers in grading tumors as well as in the prediction of tumor malignancy potential. Two additional important roles of MRS are differentiation between recurrent tumor and radiation necrosis and evaluation of peritumoral region. [ABSTRACT FROM AUTHOR]

We argue that small miracles and transition periods, notions that play part in Lewis's standard resolution of vagueness of counterfactuals, lead his theory to errors, either by giving conditionals wrong truth values, or by going against other Lewis's views. In fact, we do not believe that Lewis needs these notions. We suggest a way how his theory could be reformulated without them, in a way that does not disturb other parts of his system. More precisely, we argue that the asymmetry of counterfactual dependence can be reduced to the asymmetry of overdetermination even if the relation of similarity is determined without notions of small miracles and transition periods.

There is an increase in the number of patients with systemic lupus erythematosus (SLE) reported as developing progressive multifocal leukoencephalopathy (PML) while on intensive immunosuppressive therapy. A 39-year-old HIV-negative woman with a 10-year history of SLE presented with progressive left-side weakness while on maintenance therapy with oral prednisone and mycophenolate mofetil (MMF). On several occasions low CD4+ T-lymphocyte counts were found (68/µL). Brain magnetic resonance imaging (MRI) revealed a large lesion in the right subcortical fronto-parietal region and a smaller one in the left frontal subcortex, corresponding to the PML. In cerebrospinal fluid, polymerase chain reaction (PCR) for JC virus (JCV) was negative, but anti-JCV antibodies were highly positive. Diagnosis of probable PML was made and MMF was withdrawn. The patient's condition improved with marked reduction of left-side weakness and an increase in CD4+ T-lymphocyte count (141/µL). Follow-up MRI showed regression of lesions and over the next 6 months the patient remained stable. In spite of the grave prognosis associated with PML, SLE patients can have an excellent outcome if immunosuppressants are discontinued as soon as the correct diagnosis is made. SLE patients with associated low CD4+ T-lymphocyte counts should be monitored for the development of PML during immunosuppressive therapy in particular. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of medium-term supplementation with dihydrogen and pyrroloquinoline quinone (PQQ) on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals diagnosed with mild cognitive impairment., Design: A parallel-group, randomized, placebo-controlled, double-blind experimental design, maintaining a 1:1 allocation ratio between the experimental group (receiving the dihydrogen-producing minerals and PQQ) and the control group (receiving the placebo) throughout the trial., Setting and Participants: Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) voluntarily provided written consent to participate in this trial. Participants were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture (Alpha Hope®, CalerieLife, Irvine, CA) or placebo twice daily for a 6-week intervention period., Methods: The primary endpoint was the change in serum brain-derived neurotrophic factor (BDNF) from baseline to the 6-week follow-up; secondary outcomes included cognitive function indices, specific metabolites in brain tissue, brain oxygenation, and the prevalence and severity of side effects. Interaction effects (time vs. intervention) were evaluated using two-way ANOVA with repeated measures and Friedman's 2-way ANOVA by ranks, for normally distributed data with homogeneous variances and non-homogeneous variances, respectively., Results: Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group throughout the study duration (P = 0.27). A non-significant trend in the impact of interventions on BDNF levels was observed (treatment vs. time interaction, P = 0.14), suggesting a tendency for dihydrogen-PQQ to upregulate BDNF levels compared to the placebo. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo in enhancing this cognitive aspect. Cerebral oxygenation saturation exhibited a significant increase following the administration of the dihydrogen-PQQ mixture, from 48.4 ± 7.2% at baseline to 52.8 ± 6.6% at 6-week post-administration (P = 0.005). In addition, brain N-acetyl aspartate levels significantly increased at seven out of thirteen locations post-intervention in participants receiving the mixture (P ≤ 0.05)., Conclusions: Despite the limited number of participants included in the study for interpreting clinical parameters, the dihydrogen-PQQ mixture blend shows promise as a potential dietary intervention for enhancing mental orientation and brain metabolism in individuals with age-related mild cognitive decline., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/Objectives: The aim of this study was to evaluate brain metabolism using MR spectroscopy (MRS) after recovery from Coronavirus disease (COVID-19) and to test the impact of disease severity on brain metabolites. Methods: We performed MRS on 81 individuals (45 males, 36 females, aged 40-60), who had normal MRI findings and had recovered from COVID-19, classifying them into mild (17), moderate (36), and severe (28) groups based on disease severity during the acute phase. The study employed two-dimensional spectroscopic imaging above the corpus callosum, focusing on choline (Cho), creatine (Cr), and N-acetylaspartate (NAA). We analyzed Cho/Cr and NAA/Cr ratios as well as absolute concentrations using water as an internal reference. Results: Results indicated that the Cho/Cr ratio was higher with increasing disease severity, while absolute Cho and NAA/Cr ratios showed no significant differences across the groups. Notably, absolute Cr and NAA levels were significantly lower in patients with severe disease. Conclusions: These findings suggest that the severity of COVID-19 during the acute phase is associated with significant changes in brain metabolism, marked by an increase in Cho/Cr ratios and a reduction in Cr and NAA levels, reflecting substantial metabolic alterations post-recovery.

Despite constant achievements in treatment, acute kidney injury (AKI) remains a significant public health problem and a cause of mortality in the human population. In developed countries, AKI is a significant and frequent hospital complication, especially among patients admitted to intensive care units, where mortality rates can reach up to 50%. In addition, AKI has been implicated as an independent risk factor for the development of chronic kidney disease. Hyperbaric oxygenation (HBO) has been used as a primary or adjunctive therapy for the past 50 years, both in experimental and clinical studies. HBO is a treatment in which the patient is occasionally exposed to 100% oxygen at a pressure greater than atmospheric pressure at sea level. However, despite decades of extensive research, the potentially beneficial effects of this therapeutic approach are still not fully understood, although many potential mechanisms have been proposed, such as antioxidative, anti-inflammatory, anti-apoptotic, etc. Furthermore, the low cost and insignificant adverse events make HBO a potentially important strategy in the prevention and treatment of different diseases. Considering all of this, this review highlights the potential role of HBO in maintaining cellular homeostasis disrupted due to AKI, caused in different experimental models.

Neuromuscular excitability is a vital body function, and Mg 2+ is an essential regulatory cation for the function of excitable membranes. Loss of Mg 2+ homeostasis disturbs fluxes of other cations across cell membranes, leading to pathophysiological electrogenesis, which can eventually cause vital threat to the patient. Chronic subclinical Mg 2+ deficiency is an increasingly prevalent condition in the general population. It is associated with an elevated risk of cardiovascular, respiratory and neurological conditions and an increased mortality. Magnesium favours bronchodilation (by antagonizing Ca 2+ channels on airway smooth muscle and inhibiting the release of endogenous bronchoconstrictors). Magnesium exerts antihypertensive effects by reducing peripheral vascular resistance (increasing endothelial NO and PgI 2 release and inhibiting Ca 2+ influx into vascular smooth muscle). Magnesium deficiency disturbs heart impulse generation and propagation by prolonging cell depolarization (due to Na + /K + pump and K ir channel dysfunction) and dysregulating cardiac gap junctions, causing arrhythmias, while prolonged diastolic Ca 2+ release (through leaky RyRs) disturbs cardiac excitation-contraction coupling, compromising diastolic relaxation and systolic contraction. In the brain, Mg 2+ regulates the function of ion channels and neurotransmitters (blocks voltage-gated Ca 2+ channel-mediated transmitter release, antagonizes NMDARs, activates GABA A Rs, suppresses nAChR ion current and modulates gap junction channels) and blocks ACh release at neuromuscular junctions. Magnesium exerts multiple therapeutic neuroactive effects (antiepileptic, antimigraine, analgesic, neuroprotective, antidepressant, anxiolytic, etc.). This review focuses on the effects of Mg 2+ on excitable tissues in health and disease. As a natural membrane stabilizer, Mg 2+ opposes the development of many conditions of hyperexcitability. Its beneficial recompensation and supplementation help treat hyperexcitability and should therefore be considered wherever needed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives : Differentiating between a high-grade glioma (HGG) and solitary cerebral metastasis presents a challenge when using standard magnetic resonance imaging (MRI) alone. Magnetic resonance spectroscopy (MRS), an advanced MRI technique, may assist in resolving this diagnostic dilemma. N-acetylaspartate (NAA), an amino acid found uniquely in the central nervous system and in high concentrations in neurons, typically suggests HGG over metastatic lesions in spectra from ring-enhancing lesions. This study investigates exceptions to this norm. Materials and Methods : We conducted an MRS study on 49 histologically confirmed and previously untreated patients with brain metastases, employing single-voxel (SVS) techniques with short and long echo times, as well as magnetic resonance spectroscopic imaging (MRSI). Results: In our cohort, 44 out of 49 (90%) patients demonstrated a typical MR spectroscopic profile consistent with secondary deposits: a Cho peak, very low or absent Cr, absence of NAA, and the presence of lipids. A peak at approximately 2 ppm, termed the "NAA-like peak", was present in spectra obtained with both short and long echo times. Among the MRS data from 49 individuals, we observed a peak at 2.0 ppm in five brain metastases from mucinous carcinoma of the breast, mucinous non-small-cell lung adenocarcinoma, two metastatic melanomas, and one metastatic non-small-cell lung cancer. Pathohistological verification of mucin in two of these five cases suggested this peak likely represents N-acetyl glycoproteins, indicative of mucin expression in cancer cells. Conclusions: The identification of a prominent peak at 2.0 ppm could be a valuable diagnostic marker for distinguishing single ring-enhancing lesions, potentially associated with mucin-expressing metastases, offering a new avenue for diagnostic specificity in challenging cases.

Abstract: Eight long-COVID patients with moderate fatigue that had lasted for ≥3 months were recruited. All patients were allocated in a double-blind parallel-group design to receive either 4 g of creatine per day plus breathing exercises (study group) or breathing exercises only (control group) for 3 months. Creatine induced a significant increase in tissue total creatine levels for all 14 locations evaluated in the present study ( P < 0.05), while its levels significantly dropped in the right frontal gray matter and left parietal mesial gray matter at follow-up in the control group ( P < 0.05). No change in time to exhaustion was demonstrated in the control group (P > 0.05), while the mean time to exhaustion was significantly improved for 54 s in the study group post-administration (P = 0.05). These preliminary findings suggest that creatine is as an effective adjuvant therapeutic to breathing exercises for tackling the clinical features in long-COVID., (Copyright © 2023 Copyright: © 2023 Journal of Postgraduate Medicine.)

The central exacerbating factor in the pathophysiology of ischemic-reperfusion acute kidney injury (AKI) is oxidative stress. Lipid peroxidation and DNA damage in ischemia are accompanied by the formation of 3-nitrotyrosine, a biomarker for oxidative damage. DNA double-strand breaks (DSBs) may also be a result of postischemic AKI. γH2AX(S139) histone has been identified as a potentially useful biomarker of DNA DSBs. On the other hand, hypoxia-inducible factor (HIF) is the "master switch" for hypoxic adaptation in cells and tissues. The aim of this research was to evaluate the influence of hyperbaric oxygen (HBO) preconditioning on antioxidant capacity estimated by FRAP (ferric reducing antioxidant power) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assay, as well as on oxidative stress parameter 3-nitrotyrosine, and to assess its effects on γH2AX(S139), HIF-1α, and nuclear factor-κB (NF-κB) expression, in an experimental model of postischemic AKI induced in spontaneously hypertensive rats. The animals were divided randomly into three experimental groups: sham-operated rats (SHAM, n = 6), rats with induced postischemic AKI (AKI, n = 6), and group exposed to HBO preconditioning before AKI induction (AKI + HBO, n = 6). A significant improvement in the estimated glomerular filtration rate, eGFR, in AKI + HBO group ( p < 0.05 vs. AKI group) was accompanied with a significant increase in plasma antioxidant capacity estimated by FRAP ( p < 0.05 vs. SHAM group) and a reduced immunohistochemical expression of 3-nitrotyrosine and γH2AX(S139). Also, HBO pretreatment significantly increased HIF-1α expression ( p < 0.001 vs. AKI group), estimated by Western blot and immunohistochemical analysis in kidney tissue, and decreased immunohistochemical NF-κB renal expression ( p < 0.01). Taking all of these results together, we may conclude that HBO preconditioning has beneficial effects on acute kidney injury induced in spontaneously hypertensive rats.

Preliminary studies demonstrated beneficial effects of dietary creatine across different post-viral fatigue syndromes. Creatine is often co-administered with glucose to improve its potency yet whether glucose boost the efficacy of creatine in long COVID remains currently unknown. In this report, we investigate the effects of 8-wk creatine intake with and without glucose on patient-reported outcomes, exercise tolerance, and tissue creatine levels in patients with long COVID. Fifteen male and female long COVID adult patients (age 39.7±16.0 y; 9 women) with moderate fatigue and at least one of additional long COVID-related symptoms volunteered to participate in this randomized controlled parallel-group interventional trial. All patients were allocated in a double-blind parallel-group design (1 : 1 : 1) to receive creatine (8 g of creatine monohydrate per day), a mixture of creatine and glucose (8 g of creatine monohydrate and 3 g of glucose per day), or placebo (3 g of glucose per day) t.i.d. during an 8-wk intervention interval. Two-way ANOVA with repeated measures (treatment vs. time interaction) revealed significant differences in changes in total creatine levels between the groups, showing an interaction effect at two brain locations (right precentral white matter F=34.740, p=0.008; partial η 2 =0.72; left paracentral grey matter F=19.243, p=0.019; partial η 2 =0.88), with creatine and creatine-glucose outcompeted placebo to elevate creatine levels at these two locations. Several long COVID symptoms (including body aches, breathing problems, difficulties concentrating, headache, and general malaise) were significantly reduced in creatine-glucose group at 8-wk follow-up (p≤0.05); the effect sizes for reducing body aches, difficulties concentrating, and headache were 1.33, 0.80, and 1.12, respectively, suggesting a large effect of creatine-glucose mixture for these outcomes. Our preliminary findings suggest that supplying exogenous creatine with glucose could be recommended as an effective procedure in replenishing brain creatine pool and alleviating long COVID features in this prevalent condition.

Dietary creatine has been recently put forward as a possible intervention strategy to reduce post-COVID-19 fatigue syndrome yet no clinical study so far evaluated its efficacy and safety for this perplexing condition. In this parallel-group, randomized placebo-controlled double-blind trial, we analyzed the effects of 6-month creatine supplementation (4 g of creatine monohydrate per day) on various patient- and clinician-reported outcomes, and tissue creatine levels in 12 patients with post-COVID-19 fatigue syndrome. Creatine intake induced a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter compared to the baseline values at both 3-month and 6-month follow-ups ( p  < .05). Two-way analysis of variance with repeated measures revealed a significant difference (treatment vs. time interaction) between interventions in tissue creatine levels ( p  < .05), with the creatine group was superior to placebo to augment creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter. Creatine supplementation induced a significant reduction in general fatigue after 3 months of intake compared to baseline values ( p  = .04), and significantly improved scores for several post-COVID-19 fatigue syndrome-related symptoms (e.g., ageusia, breathing difficulties, body aches, headache, and difficulties concentrating) at 6-month follow-up ( p  < .05). Taking creatine for 6 months appears to improve tissue bioenergetics and attenuate clinical features of post-COVID-19 fatigue syndrome; additional studies are warranted to confirm our findings in various post-COVID-19 cohorts., Competing Interests: SMO serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). SMO co‐owns patent “Supplements Based on Liquid Creatine” at European Patent Office (WO2019150323 A1). SMO has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. SMO does not own stocks and shares in any organization. JS, MR, NT, JO, and VS declare no known competing financial interests or personal relationships that could have appeared to influence the authorship of this paper., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Renal cell carcinoma (RCC) is the deadliest urological neoplasm. Up to date, no validated biomarkers are included in clinical guidelines for the screening and follow up of patients suffering from RCC. Slug (Snail2) and Snail (Snail1) belong to the Snail superfamily of zinc finger transcriptional factors that take part in the epithelial-mesenchymal transition, a process important during embryogenesis but also involved in tumor progression. We examined Slug and Snail immunohistochemical expression in patients with different stages of renal cell carcinomas with the aim to investigate their potential role as staging and prognostic factors. A total of 166 samples of malignant renal cell neoplasms were analyzed using tissue microarray and immunohistochemistry. Slug and Snail expressions were evaluated qualitatively (presence or absence), in nuclear and cytoplasmic cell compartments and compared in relation to clinical parameters. The Kaplan-Meier survival analysis showed the impact of the sarcomatoid component and Slug expression on the survival longevity. Cox regression analysis separated Slug as the only independent prognostic factor ( p = 0.046). The expression of Snail was associated with higher stages of the disease ( p = 0.004), especially observing nuclear Snail expression ( p < 0.001). All of the tumors that had metastasized showed nuclear immunoreactivity ( p < 0.001). In clear cell RCC, we showed a significant relationship between a high nuclear grade and nuclear Snail expression ( p = 0.039). Our results suggest that Slug and Snail could be useful immunohistochemical markers for staging and prognosis in patients suffering from various RCCs, representing potential targets for further therapy strategies of renal cancer.

Introduction: We evaluated whether 12-week intake of molecular hydrogen (H 2 ) in 5 overweight adults (3 women; age: 50.2 ±11.9 years, body mass index: 29.4 ±2.1 kg/m 2 ) affects brain levels of the glutamate-glutamine-GABA cycle, critical amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation., Methods: A 1.5-T single-voxel proton magnetic resonance spectroscopy was used to assess the tissue concentrations of relevant metabolites., Results: The mean glutamate and glutamate-plus-glutamine levels at the posterior cingulate gyrus decreased significantly during the study; this was accompanied by a significant drop in GABA levels at left prefrontal white matter, and glutathione levels at anterior cingulate gyrus. No changes in the brain metabolites were found in the comparable group of overweight individuals ( n = 4, 2 women; age: 41.0 ±13.9, BMI 26.8 ±1.3 kg/m 2 ) followed-up in the past without this treatment., Conclusions: We showed a possible hydrogen-driven upregulation of neurotransmitters involved in appetite stimulation leading to hunger suppression and weight loss. Further studies analyzing appetite-controlling metabolic pathways affected by H 2 would require monitoring of additional biomarkers of satiation and satiety during different feeding regimens., Competing Interests: SMO co-owns patent “Agent for Inhibiting Deterioration of Recognition Function Comprising Hydrogen Gas” at the Japan Patent Office (2016-163322), and has received research support related to molecular hydrogen during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development, the Provincial Secretariat for Higher Education and Scientific Research, Natural Health Products Inc, EvoDrop, and SeaCret Direct. SMO is the founder of Centram, a biotechnology startup developing and commercializing innovative nutraceuticals that can support and rejuvenate energy metabolism, the gut-brain-muscle axis, and immunity across various health domains. SMO does not own stocks and shares in any organization. DK, JO, and NT declare no conflict of interest., (Copyright: © 2023 Termedia & Banach.)

Background: Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature., Results: Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465&#95;466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements., Conclusion: We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders., (© 2023. The Author(s).)

Ischemia-reperfusion injury (IRI) is a frequent cause of AKI, resulting in vasoconstriction, cellular dysfunction, inflammation and the induction of oxidative stress. DNA damage, including physical DNA strand breaks, is also a potential consequence of renal IRI. The histone H2A variants, primary H2AX and H2AZ participate in DNA damage response pathways to promote genome stability. The aim of this study was to evaluate the immunohistochemical pattern of histone H2A variants' (H2AX, γH2AX(S139), H2AXY142ph and H2AZ) expression in an experimental model of ischemia-reperfusion-induced acute kidney injury in spontaneously hypertensive rats. Comparing the immunohistochemical nuclear expression of γH2AX(S139) and H2AXY142ph in AKI, we observed that there is an inverse ratio of these two histone H2AX variants. If we follow different regions from the subcapsular structures to the medulla, there is an increasing extent gradient in the nuclear expression of H2AXY142ph, accompanied by a decreasing nuclear expression of γH2AX. In addition, we observed that different structures dominated when γH2AX and H2AXY142ph expression levels were compared. γH2AX was expressed only in the proximal tubule, with the exception of when they were dilated. In the medulla, H2AXY142ph is predominantly expressed in the loop of Henle and the collecting ducts. Our results show moderate sporadic nuclear H2AZ expression mainly in the cells of the distal tubules and the collecting ducts that were surrounded by dilated tubules with PAS (periodic acid-Schiff stain)-positive casts. These findings may indicate the degree of DNA damage, followed by postischemic AKI, with potential clinical and prognostic implications regarding this condition.

Introduction: ST2 is the receptor for interleukin (IL)-33, the last discovered member of the IL-1 cytokine family. Acute inflammation is an early response of vascularized tissue to injury, in which alteration of micro- and macro-elements occurs. This study aimed to examine the alteration of cobalt, sodium, potassium, and calcium concentration at the site of acute inflammation and the role of ST2 in these alterations., Material and Methods: Wild-type (WT) and ST2 knockout (ST2-/-) mice were divided into groups: WT control group (WT-C), ST2 knockout control group (KO-C), WT inflammatory group (WT-I), and ST2 knockout inflammatory group (KO-I). We induced acute inflammation by intramuscular injection of turpentine oil or saline in the case of the control group. After 12 h, we anesthetized mice and collected treated tissues for histopathological analysis and determination of cobalt, sodium, potassium, and calcium concentration by atomic absorption spectrometer., Results: Histopathological analysis showed the inflammatory infiltrate and cell necrosis in the treated tissue in WT-I and KO-I. The concentration of sodium was significantly lower in WT-I than in WT-C. The concentration of potassium and cobalt was significantly lower in WT-I and KO-I when compared to WT-C and KO-C, respectively. However, the concentration of potassium and cobalt in the tissue was significantly lower in WT-I than in KO-I. The concentration of calcium in the tissue did not significantly differ between groups., Conclusion: We reported, to our knowledge for the first time, that ST2 is involved in decreasing sodium, potassium, and cobalt concentration at the site of acute inflammation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Transcription factor PAX8, expressed during embryonic kidney development, has been previously detected in various kidney tumors. In order to investigate expression of PAX8 transcription factor in acute kidney injury (AKI) and chronic kidney diseases (CKD), immunohistochemical analysis was performed. Presence, location and extent of PAX8 expression were analyzed among 31 human kidney samples of AKI (25 autopsy cases, 5 kidney biopsies with unknown etiology and 1 AKI with confirmed myoglobin cast nephropathy), as well as in animals with induced postischemic AKI. Additionally, expression pattern was analyzed in 20 kidney biopsy samples of CKD. Our study demonstrates that various kidney diseases with chronic disease course that results in the formation of tubular atrophy and interstitial fibrosis, lead to PAX8 expression in the nuclei of proximal tubules. Furthermore, patients with PAX8 detected within the damaged proximal tubuli would be carefully monitored, since deterioration in kidney function was observed during follow-up. We also showed that myoglobin provoked acute kidney injury followed with large extent of renal damage, was associated with strong nuclear expression of PAX8 in proximal tubular cells. These results were supported and followed by data obtained in experimental model of induced postischemic acute kidney injury. Considering these findings, we can assume that PAX8 protein might be involved in regeneration process and recovery after acute kidney injury. Thus, accordingly, all investigation concerning PAX8 immunolabeling should be performed on biopsy samples of the living individuals.

Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical outpatient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spectroscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate-creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.