Wanda Furmaga-Jabłońska

Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.

OBJECTIVE To assess the efficacy and safety of lansoprazole in treating infants with symptoms attributed to gastroesophageal reflux disease (GERD) that have persisted despite a >or= 1-week course of nonpharmacologic management. STUDY DESIGN This multicenter, double-blind, parallel-group study randomized infants with persisting symptoms attributed to GERD to treatment with lansoprazole or placebo for 4 weeks. Symptoms were tracked through daily diaries and weekly visits. Efficacy was defined primarily by a >or= 50% reduction in measures of feeding-related crying and secondarily by changes in other symptoms and global assessments. Safety was assessed based on the occurrence of adverse events (AEs) and clinical/laboratory data. RESULTS Of the 216 infants screened, 162 met the inclusion/exclusion criteria and were randomized. Of those, 44/81 infants (54%) in each group were responders--identical for lansoprazole and placebo. No significant lansoprazole-placebo differences were detected in any secondary measures or analyses of efficacy. During double-blind treatment, 62% of lansoprazole-treated subjects experienced 1 or more treatment-emergent AEs, versus 46% of placebo recipients (P= .058). Serious AEs (SAEs), particularly lower respiratory tract infections, occurred in 12 infants, significantly more frequently in the lansoprazole group compared with the placebo group (10 vs 2; P= .032). CONCLUSIONS This study detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to GERD in infants age 1 to 12 months. SAEs, particularly lower respiratory tract infections, occurred more frequently with lansoprazole than with placebo.

Sporadic Alzheimer’s Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer’s Disease Genes

The study of sporadic Alzheimer’s disease etiology, now more than ever, needs an infusion of new concepts. Despite ongoing interest in Alzheimer’s disease, the basis of this entity is not yet clear. At present, the best-established and accepted “culprit” in Alzheimer’s disease pathology by most scientists is the amyloid, as the main molecular factor responsible for neurodegeneration in this disease. Abnormal upregulation of amyloid production or a disturbed clearance mechanism may lead to pathological accumulation of amyloid in brain according to the “amyloid hypothesis.” We will critically review these observations and highlight inconsistencies between the predictions of the “amyloid hypothesis” and the published data. There is still controversy over the role of amyloid in the pathological process. A question arises whether amyloid is responsible for the neurodegeneration or if it accumulates because of the neurodegeneration. Recent evidence suggests that the pathophysiology and neuropathology of Alzheimer’s disease comprises more than amyloid accumulation, tau protein pathology and finally brain atrophy with dementia. Nowadays, a handful of researchers share a newly emerged view that the ischemic episodes of brain best describe the pathogenic cascade, which eventually leads to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible dementia of Alzheimer type. The most persuasive evidences come from investigations of ischemically damaged brains of patients and from experimental ischemic brain studies that mimic Alzheimer-type dementia. This review attempts to depict what we know and do not know about the triggering factor of the Alzheimer’s disease, focusing on the possibility that the initial pathological trigger involves ischemic episodes and ischemia-induced gene dysregulation. The resulting brain ischemia dysregulates additionally expression of amyloid precursor protein and amyloid-processing enzyme genes that, in addition, ultimately compromise brain functions, leading over time to the complex alterations that characterize advanced sporadic Alzheimer’s disease. The identification of the genes involved in Alzheimer’s disease induced by ischemia will enable to further define the events leading to sporadic Alzheimer’s disease-related abnormalities. Additionally, knowledge gained from the above investigations should facilitate the elaboration of the effective treatment and/or prevention of Alzheimer’s disease.

Brain Ischemia Activates β- and γ-Secretase Cleavage of Amyloid Precursor Protein: Significance in Sporadic Alzheimer’s Disease

Amyloid precursor protein cleavage through β- and γ-secretases produces β-amyloid peptide, which is believed to be responsible for death of neurons and dementia in Alzheimer’s disease. Levels of β- and γ-secretase are increased in sensitive areas of the Alzheimer’s disease brain, but the mechanism of this process is unknown. In this review, we prove that brain ischemia generates expression and activity of both β- and γ-secretases. These secretases are induced in association with oxidative stress following brain ischemia. Data suggest that ischemia promotes overproduction and aggregation of β-amyloid peptide in brain, which is toxic for ischemic neuronal cells. In our review, we demonstrated the role of brain ischemia as a molecular link between the β- and the γ-secretase activities and provided a molecular explanation of the possible neuropathogenesis of sporadic Alzheimer’s disease.

Neuronal Autophagy: Self-eating or Self-cannibalism in Alzheimer’s Disease

Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer’s disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, β-amyloid peptide (plaques) and τ-protein (tangles). In Alzheimer’s disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer’s disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer’s disease brains. τ-protein has been found to control the stability of microtubules, however, phosphorylation of τ-protein or an increase in the total level of τ-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer’s disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for β-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of β-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for β-amyloid peptide aggregation and accumulation in Alzheimer’s disease. However, the key role of autophagy in Alzheimer’s disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, β-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer’s disease. In this review we present the recent evidence linking autophagy to Alzheimer’s disease and the role of autophagic regulation in the development of full-blown Alzheimer’s disease.

Dysregulation of Amyloid-β Protein Precursor, β-Secretase, Presenilin 1 and 2 Genes in the Rat Selectively Vulnerable CA1 Subfield of Hippocampus Following Transient Global Brain Ischemia

Abstract The interaction between brain ischemia and Alzheimer’s disease (AD) has been intensively investigated recently. Nevertheless, we have not yet understood the nature and mechanisms of the ischemic episodes triggering the onset of AD and how they influence its slow progression. The assumed connection between brain ischemia and the accumulation of amyloid-β (Aβ) peptide awaits to be clearly explained. In our research, we employed a rat cardiac arrest model to study the changes in gene expression of amyloid-β protein precursor (AβPP) and its cleaving enzymes, β- and γ-secretases (including presenilins) in hippocampal CA1 sector, following transient 10-min global brain ischemia. The quantitative reverse-transcriptase PCR assay demonstrated that the expression of all above genes that contribute to Aβ peptide generation was dysregulated during 30 days in postischemic hippocampal CA1 area. It suggests that studied Aβ peptide generation-related genes can be involved in AβPP metabolism, following global brain ischemia and will be useful to identify the molecular mechanisms underpinning that cerebral ischemia might be an etiological cause of AD via dysregulation of AβPP and its cleaving enzymes, β- and γ-secretases genes, and subsequently, it may increase Aβ peptide production and promote the gradual and slow development of AD neuropathology. Our data demonstrate that brain ischemia activates delayed neuronal death in hippocampus in an AβPP-dependent manner, thus defining a new and important mode of ischemic cell death.

Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest

BACKGROUND Brain ischemia may be causally related with Alzheimers disease. Probably, presenilin gene dysregulation may be associated with Alzheimers disease neuropathology. Consequently, we have examined quantitative changes in both presenilin 1 and 2 genes in the medial temporal lobe cortex following 10-min global brain ischemia in rats. METHODS Global brain ischemia was induced by cardiac arrest in female rats that were allowed to survive for 2, 7 and 30 days. The expression of presenilin genes was evaluated in the rat medial temporal lobe cortex with the use of quantitative RT-PCR analysis. RESULTS Presenilin 1 gene expression tended to be downregulated from days 2 to 7 postischemia but at day 30, there was a reverse tendency. The greatest overexpression of presenilin 2 gene was noted at 2-nd day whilst on day 7, the expression of this gene was only modestly elevated. Eventually, at day 30 expression of presenilin 2 gene was modestly downregulated. Alterations of presenilin 2 gene expression between 2 and 7 days and between 2 and 30 days were statistically significant. CONCLUSIONS Thus, presented changes suggest that the significant dysregulation of presenilin 2 gene may be connected with a response of neuronal cells to transient global brain ischemia due to cardiac arrest. Finally, the ischemia-induced gene dysregulation may play a key role in the late onset of Alzheimers-type dementia.

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

Brain ischemia may be causally related with Alzheimers disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimers disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.

The Evaluation of Diagnostic Role of Cardiac Troponin T (cTnT) in Newborns with Heart Defects

Heart diseases are a significant cause of morbidity and mortality in newborns. Diagnostic methods are often not sufficient or, in many cases, cannot be used. There is a great advance in medical knowledge concerning biomarkers in the diagnosis of circulatory system in adult patients. Among them, cardiac troponins play the main role. In current literature, there is not enough data concerning the possibility of using them in neonatal cardiac diagnostics. Aim of the Study. To evaluate diagnostic usefulness of cTnT in correlation with other markers of circulatory failure and myocardial damage in newborns with heart defects. Patients and Methods. The study involved 83 newborns up to 46 weeks of postmenstrual age. The exclusion criteria were severe perinatal asphyxia and presence of severe noncardiac diseases. Patients were divided into 2 main groups: group I—54 patients with congenital heart defects (CHDs), and group II (control)—29 healthy neonates. All patients underwent detailed examination of circulatory system. Cardiac troponin T (cTnT) concentrations were evaluated by Roche CARDIAC T Quantitive test. Results. Performed studies revealed that cTnT levels in newborns with heart pathology were significantly higher than in healthy ones. However, cTnT concentrations in patients with CHD did not correlate with clinical symptoms of heart failure, nor with echocardiographic markers of LV function. Type of heart defect did not influence cTnT levels as well. Only hemodynamic significance evaluated by echocardiography influenced the cTnT levels with statistical significance. Conclusions. (1) Statistically significant differences in cTnT levels between newborns with heart defects and healthy subjects were shown. (2) CTnT levels in newborns with heart defects refer only to hemodynamic significance of the defect.

Dysregulation of Autophagy, Mitophagy, and Apoptotic Genes in the Medial Temporal Lobe Cortex in an Ischemic Model of Alzheimer’s Disease

Ischemic brain damage is a pathological incident that is often linked with medial temporal lobe cortex injury and finally its atrophy. Post-ischemic brain injury associates with poor prognosis since neurons of selectively vulnerable ischemic brain areas are disappearing by apoptotic program of neuronal death. Autophagy has been considered, after brain ischemia, as a guardian against neurodegeneration. Consequently, we have examined changes in autophagy (BECN 1), mitophagy (BNIP 3), and apoptotic (caspase 3) genes in the medial temporal lobe cortex with the use of quantitative reverse-transcriptase PCR following transient 10-min global brain ischemia in rats with survival 2, 7, and 30 days. The intense significant overexpression of BECN 1 gene was noted on the 2nd day, while on days 7–30 the expression of this gene was still upregulated. BNIP 3 gene was downregulated on the 2nd day, but on days 7–30 post-ischemia, there was a significant reverse tendency. Caspase 3 gene, associated with apoptotic neuronal death, was induced in the same way as BNIP 3 gene after brain ischemia. Thus, the demonstrated changes indicate that the considerable dysregulation of expression of BECN 1, BNIP 3, and caspase 3 genes may be connected with a response of neuronal cells in medial temporal lobe cortex to transient complete brain ischemia.

A new polemic to acrylamide toxicity

Nutrition is the most important environmental factor that plays a crucial role in shortand long-term health outcomes. Growing evidence exists that some ingredients of preserved foods can induce epigenetic phenomena in genotoxic and nongenotoxic ways, with long-term effects on human health. Conversely, the short-term effects of harmful food components can cause structural damage to various systems and organs from the direct toxic tissue effects the cause functional failure [1]. Genotoxic and non-genotoxic pathways have been suggested for the carcinogenic effect of acrylamide. Of the possible nongenotoxic mechanisms, acrylamide may influence the redox status of cells and thus gene transcription or it may interfere with DNA repair or hormonal balance [2]. According to Dybing et al. [3], 6 of 10 000 people will develop cancer as a result of ingesting acrylamide in foodstuffs. In rats, increased cases of thyroid and mammary gland tumors and scrotal mesothelioma have been noted [4]. In humans, increased risks of renal, ovarian, endometrial, and breast cancers and oral cavity cancer in non-smoking women have been reported [4]. Some cancer types have been observed in rats and humans, e.g., endometrial cancer, but there have been some inconsistencies [4]. Interestingly, in humans, some indications for inverse associations have been observed for lung and bladder cancers in women and for prostate, hypopharynx, and oropharynx cancers in men [4]. These observations indicate that genotoxicitymaynot be the only mechanism by which acrylamide causes cancer and other pathologies. The estimated risks based on the epidemiologic studies for the sites with an observed positive association were considerably higher than those based on extrapolations from the rat studies [4]. These results and the fact that acrylamide is present at high levels in different everyday foods stress the design research into a low-dose rate of exposure of dietary acrylamide and the possible risk for long-term and short-term health outcomes. In addition to essential nutrients and harmful molecules, human foodstuffs also contain substances with protective properties such as lectins, digestive enzyme inhibitors, glycoalkaloids, and fiber from fruits and vegetables. Dietary fiber is a complex of substances that are not digested and not absorbed in the digestive tract. The proven health benefits of a high-fiber diet include prevention of constipation, regulation of cholesterol and glucose levels in the blood, and anticancer activity. This idea is based on information that soluble and insoluble dietary fibers restrict absorption and help to eliminate toxins, heavy metals, and carcinogenic substances from the organism by an acceleration