Creatine supplementation combined with breathing exercises reduces respiratory discomfort and improves creatine status in patients with long-COVID.

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.

"The Red Flags" in Clinical Approach to Acute Ataxia-the Experience in Cohort of 76 Children.

The aim of our study is to define the most frequent etiology, clinical presentation, and predictive factors of outcome in children with acute ataxia (AA) and to determine "the red flags" in the diagnostic approach to children with AA. The retrospective study included the patients with AA treated in the institute from 2015 to 2021. The inclusion criteria were children aged 1-18 years, evolution time of ataxia within 72 h, and diagnosis made by a physician. The exclusion criteria were anamnestic data about ataxia without confirmation by any physician, chronic/persistent ataxia, and psychogenic or postictal ataxia. Clinical presentation was divided into two categories: (1) isolated cerebellar signs (CS): ataxic gait, dysmetria, dysdiadochokinesia, intention tremor, dysarthria, and nystagmus; (2) CS-plus symptoms which included CS associated with any of other symptoms such as encephalopathy (GCS < 15), awareness disturbances, vomiting, headache, a new onset limb or facial paresis, torticollis, hypotonia, and opsoclonus. The outcome was assessed at the end of hospitalization and was defined as complete or incomplete recovery. The study included 76 children, with a mean age of 5.7 years (IQR 2.1-8.3). The most frequent causes of AA were immune-mediated/infective cerebellar ataxia in 27 (35.5%), and intoxication in 24 (31.6%) cases, followed by vestibular ataxia, opsoclonus-myoclonus-ataxia syndrome, and intracranial expansive process. Forty-two (56%) cases experienced isolated CS, and 35 (46%) cases had CS-plus. Complete recovery was experienced by 62 (81.6%) patients. Analysis of some risk factors (sex, age, presence of previous infection, "cerebellar plus symptoms," and structural abnormalities/neuroimaging abnormalities) and their relation to outcome was performed. Analysis showed that presence of additional symptoms to ataxia, so called "cerebellar plus symptoms" (p = 0.002) and structural abnormalities (p < 0.001), had statistically higher frequency of poor outcome. Statistical significance remained in the univariate analysis. Significant data was included in multivariate logistic regression analysis which also showed that presence of "cerebellar plus symptoms" (p = 0.021) and structural abnormalities (p = 0.002) is related to a poor outcome. Most of the children with AA have "benign" etiology such as intoxication and post/parainfectious cerebellar ataxia with favorable outcomes. On the other hand, AA might be the first manifestation of CNS neoplasm or paraneoplastic phenomena. "The red flags" associated with cerebellar signs are limbs or facial palsy, hypotonia, GCS < 15, vomiting, opsoclonus, headache, myoclonus, visual impairment, torticollis, and vertigo. The presence of those signs and/or structural brain abnormalities was related to poor outcomes in children with AA.

Sensorineural Hearing Loss in a Child with Succinic Semialdehyde Dehydrogenase Deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal-recessive disorder of gamma-aminobutyric acid (GABA) metabolism, resulting in accumulation of GABA and gamma-hydroxybutyric acid (GHB) in physiological fluids. Approximately 450 patients have been diagnosed worldwide with this inherited neurotransmitter disorder. We report on a five-year-old male patient, homozygous for the pathogenic variant (NM_170740:c.1265G>A) in ALDH5A1 presenting with an unexpected association of typical SSADH deficiency manifestations with bilateral sensorineural hearing loss (SNHL). Brainstem evoked response audiometry (BERA) testing showed mid-frequency sensorineural hearing damage that suggested a hereditary component to SNHL. Whole exome sequencing (WES) failed to discern other genetic causes of deafness. Several variants of uncertain significance (VUS) detected in genes known for their role in hearing physiology could not be verified as the cause for the SNHL. It is known that central auditory processing depends on a delicate balance between excitatory and inhibitory neurotransmission, and GABA is known to play a significant role in this process. Additionally, excessive concentrations of accumulated GABA and GBH are known to cause a down-regulation of GABA receptors, which could have an adverse influence on hearing function. However, these mechanisms are very speculative in context of SNHL in a patient with inherited disorder of GABA metabolism. Injury of the globi pallidi, one of hallmarks of SSADH deficiency, could also be a contributory factor to SNHL, as was suspected in some other inborn errors in metabolism. We hope that this case will contribute to the understanding of phenotypic complexity of SSADH deficiency.

Reduced tissue creatine levels in patients with long COVID-19: A cross-sectional study.

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.

Expanding the Phenotypic Spectrum: Chronic Kidney Disease in a Patient with Combined Oxidative Phosphorylation Defect 21.

Introduction: Pathogenic variants in TARS2 are associated with combined oxidative phosphorylation deficiency 21 (COXPD21), an autosomal recessive disorder usually presenting as mitochondrial encephalomyopathy. Kidney impairment has been documented in a minority of COXPD21 patients, mostly with distal renal tubular acidosis. Case report: We report on the first COXPD21 patient with generalized tubular dysfunction and early childhood progression to chronic kidney disease (CKD). Thorough diagnostic evaluation was initiated at six months of age due to failure to thrive, muscular hypotonia, motor delay and recurrent bronchiolitis. The boy was lost to follow-up until the age of two years, when he was readmitted with elevated creatinine level, reduced estimated glomerular filtrate rate, normochromic anaemia, metabolic acidosis and hyperkalaemia. Urine abnormalities pointed to generalized tubular dysfunction. Two novel heterozygous missense variants in TARS2 gene were detected by the means of whole exome sequencing: c.1298T>G (p.Phe438Cys) of maternal origin and c.1931A>T (p.Asp644Val) of paternal origin. Currently, at 4.5 years of age, the boy has failure to thrive, severe motor and verbal delay and end stage of CKD. We referred the patient to paediatric centre that provides renal replacement therapy. Conclusion: The overall clinical course in the patient we report on corresponds well to the previously reported cases of TARS2 related COXPD21, especially in regard to neurological and developmental aspects of the disease. However, we point out the generalized tubulopathy and early occurrence of CKD in our patient as atypical renal involvement in COXPD21. Additionally, this is the first report of hypothyroidism and hypoparathyroidism in a COXPD21 patient.

Diagnostic challenge and surgical management of multiple pancreatic neuroendocrine tumors - A case report.

Insulinoma is the most common functional solitary, benign pancreatic neuroendocrine tumor. In this paper, we share our experience of triple pancreatic insulinomas, with an idea to highlight the fact that despite the high frequency of solitary insulinoma, there is the possibility of multiple lesions and point out the need for a systematic and detailed radiographic and clinical examination. A 33-year-old woman was admitted to our clinic due to chronic fatigue, sweating, sporadic episodes of palpitations, unsteady hands, and blurred images, which resolve spontaneously after a few minutes. A comprehensive radiological examination revealed two lesions in the pancreatic tail, highly indicative of neuroendocrine tumor - insulinoma, so we elected for surgical treatment. Intraoperative exploration by manual palpation and ultrasonography revealed two more lesions. In the case of sporadically distributed lesions in the pancreas and if it is not possible to accurately differentiate those that represent the insulinoma for sure, the surgical procedure should be delayed. Additionally, tests such as selective arterial calcium stimulation testing should be carried out, and then, with more information in hands, make a re-plan of the potential surgical treatment which should be made.

A Novel Likely Pathogenic Variant in the RUNX1 Gene as the Cause of Congenital Thrombocytopenia.

Introduction: Heterozygous pathogenic and likely pathogenic sequence variants in the RUNX1 (Runt-related Transcription Factor 1) gene are a common genetic cause of decreased platelet count and/or platelet dysfunction and an increased risk of developing myelodysplasia and acute myeloid leukemia. The majority of causative variants are substitutions, which rarely occur de novo. The aim of this case report is to present a patient with congenital thrombocytopenia caused by a deletion variant in exon 9 in the RUNX1 gene. Case report: A one-month-old male infant was admitted to the Clinical Hospital Center Rijeka because of anemia and thrombocytopenia verified in the course of an acute viral infection. During follow-up, he occasionally had petechiae and ecchymoses on the lower extremities after mild trauma, with no other symptoms. The patient had persistent slightly decreased values of platelets with normal morphology, but with pathological aggregation with adrenaline and adenosine diphosphate. Due to the unclear etiology of persistent mild thrombocytopenia, he was referred for genetic testing at the age of five. Genomic DNA was isolated from the patient's peripheral blood and whole-exome sequencing was performed using the next-generation sequencing method. A heterozygous frameshift variant, c.1160delG (NM_001754.4), was identified in exon 9. The variant is classified as likely pathogenic. Conclusion: To the best of our knowledge, the heterozygous variant c.1160delG in the RUNX1 gene was first described in our patient. Although pathogenic variants in the RUNX1 genes are very rare, persistently low platelet counts of unclear etiology should raise suspicion of an underlying genetic disorder.

Age-Related Changes in Serum Guanidinoacetic Acid in Women.

Guanidinoacetic acid (GAA) is a fundamental intermediate in cellular bioenergetics, with circulating levels of GAA often reflects disturbances in its conversion due to many intrinsic and extrinsic factors, including gender or age. Here, we evaluated serum GAA in 172 healthy women aged 18 to 65 years, with age found to significantly predict serum GAA concentrations (r=0.29; P=0.03). This perhaps nominates serum GAA as a novel gender-specific proxy of impaired bioenergetics with aging.

Molecular hydrogen affects body composition, metabolic profiles, and mitochondrial function in middle-aged overweight women.

BACKGROUND: Molecular hydrogen (H2) effectively treats obesity-related disorders in animal models, yet no studies have investigated the effectiveness and safety of H2 for improving biomarkers of obesity in humans. AIM: In this double blind, placebo-controlled, crossover pilot trial, we evaluated the effects of H2 intervention on body composition, hormonal status, and mitochondrial function in ten (n = 10) middle-aged overweight women. METHODS: Volunteers received either hydrogen-generating minerals (supplying ~6 ppm of H2 per day) or placebo by oral administration of caplets for 4 weeks. The primary end-point of treatment efficacy was the change in the body fat percentage from baseline to 4 weeks. In addition, assessment of other body composition indices, screening laboratory studies, and evaluation of side effects were performed before and at follow-up. Clinical trial registration www.clinicaltrials.gov , ID number NCT02832219. RESULTS: No significant differences were observed between treatment groups for changes in weight, body mass index, and body circumferences at 4-week follow-up (P > 0.05). H2 treatment significantly reduced body fat percentage (3.2 vs. 0.9%, P = 0.05) and arm fat index (9.7 vs. 6.0%, P = 0.01) compared to placebo administration, respectively. This was accompanied by a significant drop in serum triglycerides after H2 intervention comparing to placebo (21.3 vs. 6.5%; P = 0.04), while other blood lipids remained stable during the study (P > 0.05). Fasting serum insulin levels dropped by 5.4% after H2 administration, while placebo intervention augmented insulin response by 29.3% (P = 0.01). CONCLUSIONS: It appears that orally administered H2 as a blend of hydrogen-generating minerals might be a beneficial agent in the management of body composition and insulin resistance in obesity.

Abstract Context Representations in Primate Amygdala and Prefrontal Cortex.

Neurons in prefrontal cortex (PFC) encode rules, goals, and other abstract information thought to underlie cognitive, emotional, and behavioral flexibility. Here we show that the amygdala, a brain area traditionally thought to mediate emotions, also encodes abstract information that could underlie this flexibility. Monkeys performed a task in which stimulus-reinforcement contingencies varied between two sets of associations, each defining a context. Reinforcement prediction required identifying a stimulus and knowing the current context. Behavioral evidence indicated that monkeys utilized this information to perform inference and adjust their behavior. Neural representations in both amygdala and PFC reflected the linked sets of associations implicitly defining each context, a process requiring a level of abstraction characteristic of cognitive operations. Surprisingly, when errors were made, the context signal weakened substantially in the amygdala. These data emphasize the importance of maintaining abstract cognitive information in the amygdala to support flexible behavior.

A critical update on endothelial nitric oxide synthase gene variations in women with idiopathic recurrent spontaneous abortion: genetic association study, systematic review and meta-analyses.

A number of case-control studies investigated the association between idiopathic recurrent spontaneous abortion (IRSA) and variations in the gene encoding endothelial nitric oxide synthase (NOS3), but yielded contradictory results. Our aim was to test the association of the NOS3 variable number of tandem repeats (VNTR) in intron 4 and +894 G/T single-nucleotide polymorphism (SNP) with IRSA in Slovenian women (148 IRSA and 149 control women), conduct a systematic review of literature on the association between NOS3 gene variations and IRSA, and perform meta-analyses of studies that met the inclusion criteria, defined by virtue of the European Society for Human Reproduction and Embryology evidence-based guidelines for recurrent spontaneous abortion. Genotyping was performed using PCR and restriction fragment length polymorphism methods. The systematic review of literature (English language) was conducted using PubMed and Scopus databases, to 1 November 2014. We determined no association of IRSA with the VNTR in intron 4 and +894 G/T SNP in Slovenian women. Furthermore, 16 case-control studies were identified on the association between 15 NOS3 gene variations and IRSA. However, significant inconsistencies exist in the selection criteria of patients and controls between studies. The meta-analysis of VNTR in intron 4 was performed on five studies (894 patients, 944 controls), whereas the meta-analysis of +894 G/T SNP included six studies (1111 patients, 1121 controls). The association with IRSA was significant for the +894 G/T SNP under the dominant genetic model (GT+TT versus GG) based on fixed (odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.28-1.86, P = <0.01) and random effects models (OR = 1.54, 95% CI = 1.03-2.31, P = 0.03). In conclusion, the GT and TT genotypes of the +894 G/T SNP in women might contribute to a predisposition to IRSA. Additional genetic association and functional studies in different populations with larger numbers of participants and a uniformly defined IRSA are needed to clarify the contribution of NOS3 +894 G/T gene variation to IRSA.

Molecular hydrogen in sports medicine: new therapeutic perspectives.

In the past 2 decades, molecular hydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. Beneficial effects of molecular hydrogen in clinical environment are observed especially in oxidative stress-mediated diseases, such as diabetes mellitus, brain stem infarction, rheumatoid arthritis, or neurodegenerative diseases. A number of more recent studies have reported that molecular hydrogen affects cell signal transduction and acts as an alkalizing agent, with these newly identified mechanisms of action having the potential to widen its application in clinical medicine even further. In particular, hydrogen therapy may be an effective and specific innovative treatment for exercise-induced oxidative stress and sports injury, with potential for the improvement of exercise performance. This review will summarize recent research findings regarding the clinical aspects of molecular hydrogen use, emphasizing its application in the field of sports medicine.

Age at implantation and auditory memory in cochlear implanted children.

Early cochlear implantation, before the age of 3 years, provides the best outcome regarding listening, speech, cognition an memory due to maximal central nervous system plasticity. Intensive postoperative training improves not only auditory performance and language, but affects auditory memory as well. The aim of this study was to discover if the age at implantation affects auditory memory function in cochlear implanted children. A total of 50 cochlear implanted children aged 4 to 8 years were enrolled in this study: early implanted (1-3y) n = 27 and late implanted (4-6y) n = 23. Two types of memory tests were used: Immediate Verbal Memory Test and Forward and Backward Digit Span Test. Early implanted children performed better on both verbal and numeric tasks of auditory memory. The difference was statistically significant, especially on the complex tasks. Early cochlear implantation, before the age of 3 years, significantly improve auditory memory and contribute to better cognitive and education outcomes.

Prediction of adult height by Tanner-Whitehouse method in young Caucasian male athletes.

BACKGROUND: Although the accuracy of final height prediction using skeletal age development has been confirmed in many studies for children treated for congenital primary hypothyroidism, short normal children, constitutionally tall children, no studies compared the predicted adult height at young age with final stature in athletic population. AIM: In this study, the intention was to investigate to what extent the Tanner-Whitehouse (TW) method is adequate for prediction of final stature in young Caucasian male athletes. DESIGN: Prospective observational study. METHODS: Plain radiographs of the left hand and wrist were obtained from 477 athletic children (ranging in age from 8.0 to 17.9 years) who came to the outpatient clinic between 2000 and 2011 for adult height estimation, with no orthopedic trauma suspected. Adult height was estimated using bone age rates according to TW method. Height was measured both at baseline and follow-up (at the age of 19 years). RESULTS: No significant difference was found between the estimated adult height (184.9 ± 9.7 cm) and final stature (185.6 ± 9.6 cm) [95% confidence interval (CI) 1.61-3.01, P = 0.55]. The relationship between estimated and final adult height was high (r = 0.96). Bland-Altman analysis confirmed that the 95% of differences between estimated adult height and final stature lie between limits of agreement (mean ± 2 SD) (-5.84 and 4.52 cm). CONCLUSION: TW method is an accurate method of predicting adult height in male normal-growing athletic boys.

Correlation between explosive strength, aerobic power and repeated sprint ability in elite basketball players.

AIM: The aim of this study was to examine the relationship between explosive strength and aerobic power with basketball-specific repeated sprint ability in elite male basketball players. METHODS: Twenty-four elite basketball players (age 22.2±3.4 years, height 197.1±6.2 cm, weight 95.7±8.8 kg; training experience 11.0±3.1 years; mean±SD), participated in the study. Subjects performed countermovement jump (CMJ) test and incremental pseudo-ramp test protocol with measured CMJ height and VO2max, respectively. Specific repeated sprint ability (RSA) test was conducted, with total sprinting time (summation of 10 sprint times - RSAtot) and sprint decrement (fatigue index - RSAFI) calculated. RESULTS: Significant decrements in sprint performance from the eight 30-m sprint (P<0.05) were observed. Strong inverse correlation was found between CMJ and RSAtot (r=-0.74, P<0.01). No significant correlation was found between VO2max and RSA outcomes neither between CMJ and RSAFI. CONCLUSION: CMJ is a predictor of RSA in elite basketball players. It seems that coaches and strength and conditioning professionals should devote additional time for explosive strength development in elite basketball players during preparatory period to enhance RSA performance.

Systolic right ventricular adaptive changes in athletes as predictors of the maximal functional capacity: a pulsed tissue Doppler study.

AIM: The aim of this study was to extend the analysis of the systolic right ventricular (RV) adaptation to combined endurance and strength training, to assess the utility of tissue Doppler imaging in detecting the degree of these changes and to find independent RV predictors of the maximal functional capacity. METHODS: Standard Doppler and TDI were used to assess cardiac parameters at rest in 37 elite male athletes (16 wrestlers, 21 water polo players) and 20 sedentary subjects of similar age. Progressive maximal test on treadmill was used to assess VO2max. The obtained parameters were adjusted for HR, FFM, and BSA. RESULTS: Wrestlers showed higher VO2max than controls, but lesser than water polo players. RV diameter was larger in athletes. Right atrial pressure (RVE/e) was higher in water polo players than in other groups. Systolic function assessed by tricuspid annular plane systolic excursion (TAPSE) and RVs' was the highest in wrestlers. Global RV systolic parameters myocardial performance index (MPI) and preejection time/ejection time index (PET/ET) were similar. On multivariate analysis systolic parameters were independent predictors of VO2max only in wrestlers: RVs' (beta=3.18, P=0.001) and RV ET (beta=2.32, P=0.001). RVE/e` correlated with RVs' (r=-0.57, P=0.000). TAPSE correlated with RV ET (r=0.32, P=0.015) and RVs` (beta=0.28, P=0.033). CONCLUSION: Systolic function assessed by TAPSE and RVs` has more improved in less endurance athletes. RVs`and TDI ejection time predict VO2max in wrestlers, and possibly in other athletes with lesser right atrial pressure. TDI enables quantifying RV adaptation degree in athletes, but complementary to M-mode technique.

Daily timing of salivary cortisol responses and aerobic performance in lean and obese active females.

The main aim of the present study was to study the effects of morning and afternoon physical activities on cortisol responses in obese and lean women. Twenty women volunteered to participate in this study. Subjects were divided into an obese group (BMI =29.1 kg/m2) and a lean group (BMI =19 kg/m2). All subjects participated in an exercise program consisting of treadmill running at 65+/-2 % VO2max until exhaustion. In order to study effects of circadian rhythm, exercise was performed at a similar intensity and in similar environmental conditions at both 8:00 AM and 4:00 PM. Saliva specimens were collected at rest 20 minutes before activity and then immediately after the exercise in both morning and afternoon sessions. Morning and afternoon exercise resulted in a significant increase in salivary cortisol concentrations compared to basal levels in both lean and obese women (p<0.05), though the change in cortisol concentrations were higher in lean. The aerobic function of lean and obese women in the morning and afternoon showed a significant increase of 13.8 % and 5.9 %; respectively, with lean being consistently higher than obese. In conclusion, the stress response to exercise is related to circadian rhythm and individual's body weight. Based on the results of this study, it is suggested that overweight women perform exercises in the afternoon to minimize the stress response for the exercise volume performed (Tab. 1, Fig. 3, Ref. 39). Full Text in free PDF www.bmj.sk.