Late diagnosis of cerebral palsy in a 16-year-old girl – a case report

Cerebral palsy is the most common cause of motor disability in children. Cerebral palsy is a static encephalopathy with a variable clinical picture and multifactorial aetiology. Disorders arise from disturbances in the early development of the brain in the foetal, perinatal or postnatal period. The disease affects around 17 million people worldwide; its incidence is estimated to be 1.5–3 per 1,000 live births. A slight male predominance is observed. The disease has a multifactorial aetiology, with prematurity being the most important risk factor. There are four types of cerebral palsy: spastic (the most common – (70%), dystonic (10%), mixed (15%) and ataxic (5%). In addition to motor disability of varying severity, the majority of patients present with other accompanying deficits, such as mental retardation, epilepsy, dysphagia, impaired hearing and vision. The diagnosis of cerebral palsy should be based on detailed medical history, including pregnancy and childbirth as well as a regular assessment of the child’s development from the first months of life. In the case of clinical doubts, the diagnosis is extended to include magnetic resonance imaging, electroencephalography, metabolic and genetic tests. Children with cerebral palsy require a comprehensive, multidisciplinary care, including physical therapy and rehabilitation. Bobath and Vojta concepts are the most common rehabilitation approaches. Early diagnosis and regular rehabilitation are crucial to ensure adequate quality of life for a child with cerebral palsy. The paper presents a case of a 16-year-old girl with a long history of pain in the lower limbs, spine and temporomandibular joints. The symptoms were accompanied by chest pain as well as numbness and weakness of the left upper limb.W krajach wysokorozwiniętych mózgowe porażenie dziecięce stanowi najczęstszą przyczynę niepełnosprawności ruchowej występującej w dzieciństwie. Jest to stałe, choć zmieniające się w czasie zaburzenie ruchu i postawy, wynikające z trwałego i niepostępującego uszkodzenia mózgu w stadium jego niezakończonego rozwoju. Choroba dotyczy około 17 milionów ludzi na całym świecie, a zapadalność wynosi 1,5–3 na 1000 żywych urodzeń. Obserwuje się niewielką przewagę zachorowań wśród chłopców. Etiologia choroby jest zróżnicowana, jednak najważniejszy czynnik ryzyka stanowi wcześniactwo. Wyróżnia się cztery postaci mózgowego porażenia dziecięcego: spastyczną (70%), dystoniczną (10%), ataktyczną (5%) i mieszaną (15%). Towarzyszą mu również inne zaburzenia, w tym upośledzenie umysłowe, padaczka oraz zaburzenia wzroku, słuchu i połykania. Podstawą diagnozy są szczegółowy wywiad lekarski, uwzględniający przebieg ciąży i porodu, oraz regularna ocena rozwoju dziecka od pierwszych miesięcy życia. W przypadku wątpliwości klinicznych diagnostykę uzupełnia się o badanie rezonansu magnetycznego głowy, elektroencefalografię, testy metaboliczne i genetyczne. Dzieci z mózgowym porażeniem dziecięcym wymagają kompleksowej, wielodyscyplinarnej opieki. Najczęściej są rehabilitowane według metody Bobath lub Vojty. Wczesna i systematyczna rehabilitacja jest niezbędna do tego, by zmniejszyć trwałe następstwa choroby i poprawić jakość życia pacjenta. W pracy przedstawiono opis przypadku 16-letniej dziewczynki z obciążonym wywiadem okołoporodowym, konsultowanej przez licznych specjalistów z powodu długotrwałego bólu kończyn dolnych, kręgosłupa i stawów skroniowo-żuchwowych. Objawom towarzyszyły ból w klatce piersiowej oraz drętwienie i osłabienie lewej kończyny górnej

Therapeutic Perspectives of Adenosine Deaminase Inhibition in Cardiovascular Diseases

Adenosine deaminase (ADA) is an enzyme of purine metabolism that irreversibly converts adenosine to inosine or 2′deoxyadenosine to 2′deoxyinosine. ADA is active both inside the cell and on the cell surface where it was found to interact with membrane proteins, such as CD26 and adenosine receptors, forming ecto-ADA (eADA). In addition to adenosine uptake, the activity of eADA is an essential mechanism that terminates adenosine signaling. This is particularly important in cardiovascular system, where adenosine protects against endothelial dysfunction, vascular inflammation, or thrombosis. Besides enzymatic function, ADA protein mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. Furthermore, alteration in ADA activity was demonstrated in many cardiovascular pathologies such as atherosclerosis, myocardial ischemia-reperfusion injury, hypertension, thrombosis, or diabetes. Modulation of ADA activity could be an important therapeutic target. This work provides a systematic review of ADA activity and anchoring inhibitors as well as summarizes the perspectives of their therapeutic use in cardiovascular pathologies associated with increased activity of ADA

The Effect of a High-Fat Diet on the Fatty Acid Composition in the Hearts of Mice

The Western diet can lead to alterations in cardiac function and increase cardiovascular risk, which can be reproduced in animal models by implementing a high-fat diet (HFD). However, the mechanism of these alterations is not fully understood and may be dependent on alterations in heart lipid composition. The aim of this study was to evaluate the effect of an HFD on the fatty acid (FA) composition of total lipids, as well as of various lipid fractions in the heart, and on heart function. C57BL/6 mice were fed an HFD or standard laboratory diet. The FA composition of chow, serum, heart and skeletal muscle tissues was measured by gas chromatography–mass spectrometry. Cardiac function was evaluated by ultrasonography. Our results showed an unexpected increase in polyunsaturated FAs (PUFAs) and a significant decrease in monounsaturated FAs (MUFAs) in the heart tissue of mice fed the HFD. For comparison, no such effects were observed in skeletal muscle or serum samples. Furthermore, we found that the largest increase in PUFAs was in the sphingolipid fraction, whereas the largest decrease in MUFAs was in the phospholipid and sphingomyelin fractions. The hearts of mice fed an HFD had an increased content of triacylglycerols. Moreover, the HFD treatment altered aortic flow pattern. We did not find significant changes in heart mass or oxidative stress markers between mice fed the HFD and standard diet. The above results suggest that alterations in FA composition in the heart may contribute to deterioration of heart function. A possible mechanism of this phenomenon is the alteration of sphingolipids and phospholipids in the fatty acid profile, which may change the physical properties of these lipids. Since phospho- and sphingolipids are the major components of cell membranes, alterations in their structures in heart cells can result in changes in cell membrane properties

The new insight into extracellular NAD+NAD^{+} degradation : the contribution of CD38 and CD73 in calcific aortic valve disease

Nicotinamide adenine dinucleotide (NAD(+)) is crucial for cell energy metabolism and many signalling processes. Recently, we proved the role of ecto‐enzymes in controlling adenine nucleotide–dependent pathways during calcific aortic valve disease (CAVD). This study aimed to investigate extracellular hydrolysis of NAD(+) and mononucleotide nicotinamide (NMN) in aortic valves and aorta fragments of CAVD patients and on the inner aortic surface of ecto‐5′‐nucleotidase knockout mice (CD73−/−). Human non‐stenotic valves (n = 10) actively converted NAD(+) and NMN via both CD73 and NAD(+)‐glycohydrolase (CD38) according to our analysis with RP‐HPLC and immunofluorescence. In stenotic valves (n = 50), due to reduced CD73 activity, NAD(+) was degraded predominantly by CD38 and additionally by ALP and eNPP1. CAVD patients had significantly higher hydrolytic rates of NAD(+) (0.81 ± 0.07 vs 0.56 ± 0.10) and NMN (1.12 ± 0.10 vs 0.71 ± 0.08 nmol/min/cm(2)) compared with controls. CD38 was also primarily engaged in human vascular NAD(+) metabolism. Studies using specific ecto‐enzyme inhibitors and CD73−/− mice confirmed that CD73 is not the only enzyme involved in NAD(+) and NMN hydrolysis and that CD38 had a significant contribution to these pathways. Modifications of extracellular NAD(+) and NMN metabolism in aortic valve cells may be particularly important in valve pathology and could be a potential therapeutic target

Elevated Plasma Concentration of 4-Pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) Highlights Malignancy of Renal Cell Carcinoma

Nicotinamide (NA) derivatives play crucial roles in various biological processes, such as inflammation, regulation of the cell cycle, and DNA repair. Recently, we proposed that 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR), an unusual derivative of NA, could be classified as an oncometabolite in bladder, breast, and lung cancer. In this study, we investigated the relations between NA metabolism and the progression, recurrence, metastasis, and survival of patients diagnosed with different histological subtypes of renal cell carcinoma (RCC). We identified alterations in plasma NA metabolism, particularly in the clear cell RCC (ccRCC) subtype, compared to papillary RCC, chromophobe RCC, and oncocytoma. Patients with ccRCC also exhibited larger tumor sizes and elevated levels of diagnostic serum biomarkers, such as hsCRP concentration and ALP activity, which were positively correlated with the plasma 4PYR. Notably, 4PYR levels were elevated in advanced stages of ccRCC cancer and were associated with a highly aggressive phenotype of ccRCC. Additionally, elevated concentrations of 4PYR were related to a higher likelihood of mortality, recurrence, and particularly metastasis in ccRCC. These findings are consistent with other studies, suggesting that NA metabolism is accelerated in RCC, leading to abnormal concentrations of 4PYR. This supports the concept of 4PYR as an oncometabolite and a potential prognostic factor in the ccRCC subtype

Cardiac Mitochondria Dysfunction in Dyslipidemic Mice

Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr−/−) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates’ pool in the hearts of 6-month Ldlr−/− mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr−/− vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr−/− mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations

4-Pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR)—A Novel Oncometabolite Modulating Cancer-Endothelial Interactions in Breast Cancer Metastasis

The accumulation of specific metabolic intermediates is known to promote cancer progression. We analyzed the role of 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR), a nucleotide metabolite that accumulates in the blood of cancer patients, using the 4T1 murine in vivo breast cancer model, and cultured cancer (4T1) and endothelial cells (ECs) for in vitro studies. In vivo studies demonstrated that 4PYR facilitated lung metastasis without affecting primary tumor growth. In vitro studies demonstrated that 4PYR affected extracellular adenine nucleotide metabolism and the intracellular energy status in ECs, shifting catabolite patterns toward the accumulation of extracellular inosine, and leading to the increased permeability of lung ECs. These changes prevailed over the direct effect of 4PYR on 4T1 cells that reduced their invasive potential through 4PYR-induced modulation of the CD73-adenosine axis. We conclude that 4PYR is an oncometabolite that affects later stages of the metastatic cascade by acting specifically through the regulation of EC permeability and metabolic controls of inflammation