Chitosan Versus Dapagliflozin in a Diabetic Cardiomyopathy Mouse Model.

Diabetes mellitus is a metabolic disorder with global economic implications that can lead to complications such as diabetic cardiomyopathy. The aim of this study was to compare the effects of chitosan versus dapagliflozin in mouse diabetic cardiomyopathy. We used 32 C57Bl/6 male mice aged between 8 and 10 weeks, which were randomly divided into Control-without diabetes mellitus (DM), type 1 DM (T1DM), T1DM + Chitosan, and T1DM + Dapapgliflozin groups. We induced diabetes with streptozotocin and treated the animals for 12 weeks. The analysis showed a reduction in intramyocardial fibrosis in the T1DM + Dapapgliflozin compared to T1DM animals. In T1DM + CHIT, a reduction in intramyocardial fibrosis was observed although, accordingly, there was also no significant decrease in blood glucose. The level of oxidative stress was reduced in the groups of treated animals compared to T1DM. All these observed changes in the structure and function of hearts were highlighted in the echocardiographic examination. In the treated groups, there was delayed appearance of left ventricular (LV) hypertrophy, a slight decrease in the ejection fraction of the LV, and an improved diastolic profile. The results demonstrate that chitosan has promising effects on diabetic cardiomyopathy that are comparable to the beneficial effects of dapagliflozin.

An Overview of EGFR Mechanisms and Their Implications in Targeted Therapies for Glioblastoma.

Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood-brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.

Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy.

Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways.

Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma.

The aim of our study was to assess the sympathetic nervous system's involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system's activity predicts increased gastric carcinoma severity.

Platelet-Derived Growth Factor Receptor and Ionizing Radiation in High Grade Glioma Cell Lines.

Treatment of high grade gliomas (HGGs) has remained elusive due to their high heterogeneity and aggressiveness. Surgery followed by radiotherapy represents the mainstay of treatment for HGG. However, the unfavorable location of the tumor that usually limits total resection and the resistance to radiation therapy are the major therapeutic problems. Chemotherapy with DNA alkylating agent temozolomide is also used to treat HGG, despite modest effects on survival. Disregulation of several growth factor receptors (GFRs) were detected in HGG and receptor amplification in glioblastoma has been suggested to be responsible for heterogeneity propagation through clonal evolution. Molecularly targeted agents inhibiting these membrane proteins have demonstrated significant cytotoxicity in several types of cancer cells when tested in preclinical models. Platelet-derived growth factor receptors (PDGFRs) and associated signaling were found to be implicated in gliomagenesis, moreover, HGG commonly display a Platelet-derived growth factor (PDGF) autocrine pathway that is not present in normal brain tissues. We have previously shown that both the susceptibility towards PDGFR and the impact of the PDGFR inactivation on the radiation response were different in different HGG cell lines. Therefore, we decided to extend our investigation, using two other HGG cell lines that express PDGFR at the cell surface. Here, we investigated the effect of PDGFR inhibition alone or in combination with gamma radiation in 11 and 15 HGG cell lines. Our results showed that while targeting the PDGFR represents a good means of treatment in HGG, the combination of receptor inhibition with gamma radiation did not result in any discernable difference compared to the single treatment. The PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways are the major signaling pathways emerging from the GFRs, including PDGFR. Decreased sensitivity to radiation-induced cell death are often associated with redundancy in these pro-survival signaling pathways. Here we found that Phosphoinositide 3-kinases (PI3K), Extracellular-signal-regulated kinase 1/2 (ERK1/2), or c-Jun N-terminal kinase 1/2 (JNK1/2) inactivation induced radiosensitivity in HGG cells.

Silencing of epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) via siRNA-induced cell death in glioblastoma.

The failure of therapies targeting tumor angiogenesis may be caused by anti-angiogenic resistance mechanisms induced by VEGF and non-VEGF pathways alterations. Anti-angiogenic therapy failure is also attributed to immune system, acting by tumor-associated macrophages that release pro-angiogenic factors and a consequent increase of blood vessels. Recently, in a study by Rheal et al., a new angiogenic receptor, epidermal growth factor, latrophilin, and 7 trans-membrane domain-containing protein 1 on chromosome 1(ELTD1) has been identified as a promising glioma biomarker. In this study we aim to analyse whether this receptor may be used as a target molecule in glioblastoma therapy. Our results showed that small interfering RNA silencing ELTD1 caused cytotoxicity in glioblastoma cells. We also found that PDGFR, VEGFR, and their common PI3K/mTOR intracellular pathway inactivation-induced cytotoxicity in glioblastoma cells. Further, we found high percent of cytotoxicity in a low passage glioblastoma cell line after BEZ235 (a dual inhibitor of PI3K/mTOR pathway) treatment at nanomolar concentrations, compared to AG1433 (a PDGFR inhibitor) and SU1498 (a VEGFR inhibitor) that were only cytotoxic at micromolar ranges. In the future, these could prove as attractive therapeutic targets in single therapy or coupled with classic therapeutic approaches such as chemotherapy of radiotherapy.

Correlations between Retinal Microvascular Parameters and Clinical Parameters in Young Patients with Type 1 Diabetes Mellitus: An Optical Coherence Tomography Angiography Study.

OBJECTIVES: In the current study, we investigated the correlations between retinal microvascular parameters using optical coherence tomography angiography (OCTA) and clinical parameters for a group of 69 young patients with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This retrospective, exploratory study enrolled 69 patients between 5 years old and 30 years old who met the inclusion criteria. All the study participants underwent a comprehensive ophthalmic examination and OCTA scans for the evaluation of the retinal microcirculation. The retinal OCTA parameters were correlated with the following clinical parameters: the patient's age at the onset of the disease, the duration of T1DM, the BMI at the time of enrollment in the study, the HbA1C values at onset, the mean values of HbA1C over the period of monitoring the disease and the degree of DKA at onset. RESULTS: For the study group, the foveal avascular zone (FAZ) area and perimeter correlated positively with the mean value of HbA1C (Pearson correlation, Sig.2-Tailed Area: 0.044; perimeter: 0.049). The total vessel density in the superficial capillary plexus (SCP) correlated negatively with the duration of T1DM, based on the superior and inferior analyzed areas (Spearman correlation, Sig.2-Tailed SCP in total region: 0.002; SCP in the superior region: 0.024; SCP in the inferior region: 0.050). The foveal thickness also correlated negatively with the levels of diabetic ketoacidosis (DKA) at onset (Spearman correlation, Sig.2-Tailed: 0.034) and the levels of HbA1C at onset (Spearman correlation, Sig.2-Tailed: 0.047). Further on, the study patients were distributed into two groups according to the duration of the disease: group 1 included 32 patients with a duration of T1DM of less than 5 years, and group 2 included 37 patients with a duration of T1DM of more than 5 years. Independent t-tests were used to compare the OCTA retinal parameters for the two subgroups. While the FAZ-related parameters did not show significant statistical differences between the two groups, the vessel densities in both the SCP and DCP were significantly lower in group 2. CONCLUSIONS: Our data suggest that specific alterations in OCTA imaging biomarkers correlate with various clinical parameters: the FAZ area and perimeter increase with higher mean values of HbA1C, leading to poor metabolic control. Moreover, the SCP total vessel density decreases as the duration of T1DM increases. Regarding the vessel densities in the SCP and the DCP, they decrease with a duration of the disease of more than 5 years.

Retinal Microvascular Alterations in a Patient with Type 1 Diabetes Mellitus, Hemoglobin D Hemoglobinopathy, and High Myopia-Case Report and Review of the Literature.

Type 1 diabetes mellitus (type 1 DM) is one of the most prevalent endocrinological diseases among children and young adults, with a growing incidence rate reaching up to 2.9 new cases per year per 100,000 persons below 15 years of age. We report a rare case of a 20-year-old female patient with type 1 DM, hemoglobin D (HbD) heterozygote variant and high myopia of -10.00 spheric diopters, and describe the retinal microvascular alterations visible on OCT angiography (angio-OCT). The patient also presented with a severe stature deficit (less than three standard deviations) and delayed puberty, which could not be explained only by suboptimal glycemic control and indicated possible hypopituitarism. HbA1c level evaluated with the high-performance liquid chromatography (HPLC) method was 6.5%, a falsely low value due to HbD hemoglobinopathy. On ophthalmic evaluation, the angio-OCT scan showed the following retinal microvascular alterations in the right eye (RE): the FAZ (Foveal Avascular Zone) area was 0.39 mm2, the FAZ perimeter was 2.88 mm, and the circularity index was 0.58. The following alterations were shown in the left eye (LE): the FAZ area was 0.34 mm2, the FAZ perimeter was 3.21 mm, and the circularity index was 0.41. Clinicians should consider high-performance retinal screening methods such as angio-OCT evaluation for young type 1 DM patients, especially for those with associated pathologies like high myopia and hemoglobinopathies. Moreover, multiple evaluation methods of HbA1c values are mandatory as hemoglobinopathies can interfere with the accuracy of HbA1c assay methods.

Dapagliflozin Ameliorates Neural Damage in the Heart and Kidney of Diabetic Mice.

(1) Background: Measures for the control of diabetes mellitus (DM) and, especially, for the control of its complications represent a main objective of the research carried out on this disease, since both mortality and morbidity relating to DM represent real problems for the health system worldwide. The aim of our study was to evaluate nervous tissue from the heart and kidneys of mice with diabetes induced by streptozotocin (STZ) in the presence or absence of dapagliflozin (DAPA) treatment. (2) Methods: For this purpose, we used 24 C 57Bl/6 male mice, aged between 8 and 10 weeks. The mice were divided into three groups: sham (DM-), control (DM+), and treated (DM+). Diabetes mellitus was induced by injecting a single intraperitoneal dose of STZ. The duration of diabetes in the mice included in our study was 12 weeks after STZ administration; then, the heart and kidneys were sampled, and nervous tissue (using the primary antibody PGP 9.5) from the whole heart, from the atrioventricular node, and from the kidneys was analyzed. (3) Results: The density of nerve tissue registered a significant decrease in animals from the control group (DM+), to a value of 0.0122 ± 0.005 mm2 nerve tissue/mm2 cardiac tissue, compared with the sham group (DM-), wherein the value was 0.022 ± 0.006 mm2 nervous tissue/mm2 cardiac tissue (p = 0.004). Treatment with dapagliflozin reduced the nerve tissue damage in the treated (DM+DAPA) group of animals, resulting in a nerve tissue density of 0.019 ± 0.004 mm2 nerve tissue/mm2 cardiac tissue; a statistically significant difference was noted between the control (DM+) and treated (DM+DAPA) groups (p = 0.046). The same trends of improvement in nerve fiber damage in DM after treatment with DAPA were observed both in the atrioventricular node and in the kidneys. (4) Conclusions. These data suggest that dapagliflozin, when used in streptozotocin-induced diabetes in mice, reduces the alteration of the nervous system in the kidneys and in the heart, thus highlighting better preservation of cardiac and renal homeostasis, independent of any reduction in the effects of hyperglycemia produced in this disease.

Early Retinal Microvascular Alterations in Young Type 1 Diabetic Patients without Clinical Retinopathy.

The purpose of this study is to identify and quantify preclinical changes with the help of optical coherence tomography angiography (OCTA) within the retinal microcirculation of young type 1 diabetes (T1D) patients without clinical signs of diabetic retinopathy (DR) and to compare these results with those obtained from healthy age-matched subjects. OCTA is currently used for monitoring diabetic retinopathy; however, there is no current consensus on which OCTA parameter alterations predict the first clinical signs of diabetic retinopathy. The main challenge that young patients with T1D face during the course of the disease is that they can rapidly progress to the development of DR, especially during adolescence. Moreover, they also present an increased risk of rapid progression toward advanced stages of DR and vision loss compared to type 2 diabetes patients, indicating the importance of early diagnosis and intervention. The limitations of the currently used screening procedures that led to the conceptualization of our study are the difficulties in performing fluorescein angiography tests for diagnosing the clinical signs of DR on young patients, namely the invasive procedure of dye injection, the risk of allergic reactions and the long duration of the examination. Moreover, given the long life expectancy of young T1D patients, it is essential to identify the preclinical changes in retinal microvasculature before reaching the first clinical signs quantifiable by FFA. The clinical study enrolled 119 subjects aged between 4 and 30 years old with a mean age of 13 years old, comprising 61 T1D patients with a mean duration of the disease of 4 years and 8 months and 58 healthy age-matched subjects for the control group. OCTA scans were performed using the RevoNX 130 OCTA device (Optopol) to evaluate the following retinal parameters: foveal avascular zone (FAZ) area, perimeter and circularity, overall foveal thickness, and superficial and deep vessel densities. Statistically significant differences between the two groups were identified for the following parameters: the FAZ area in the T1D group (0.42 ± 0.17) was larger than the control group (0.26 ± 0.080), the FAZ circularity (0.41 ± 0.11) was decreased compared to the control group (0.61 ± 0.08) and the FAZ perimeter was larger (3.63 ± 0.97) compared to the control group (2.30 ± 0.50). The overall foveal thickness was decreased in the T1D group (222.98 ± 17.33) compared to the control group (230.64 ± 20.82). The total vessel density of the superficial capillary plexus (SCP) on an investigated area of 6 X 6 mm centered around the fovea was decreased in the T1D group (37.4164 ± 2.14) compared to the control group (38.0241 ± 2.44). Our data suggest that specific imaging biomarkers such as FAZ perimeter, area and circularity, decreased overall foveal thickness and decreased vessel density in the SCP precede the clinical diagnosis of DR in young T1D patients and represent useful parameters in quantifying capillary nonperfusion in T1D patients without clinical signs of DR.

Retinal Functional Impairment in Diabetic Retinopathy.

BACKGROUND: Diabetic retinopathy (DR) is a neurodegenerative disease of the retina. The aim of our study was to analyze latency changes in a full-field electroretinogram (ERG) in patients with type 2 diabetes. MATERIAL: This prospective study included 15 diabetic patients without DR, 16 diabetic patients with non-proliferative DR, 14 patients with pre-proliferative DR, 15 patients with proliferative DR, and 14 age-matched controls. All the participants underwent ophthalmologic examination and full-field ERGs. The ERGs were recorded with the Metrovision MonPackOne system. The latencies were analyzed for "a"- and "b"-waves in the dark-adapted (DA) 0.01 ERG, DA 3.0 ERG, DA oscillatory potentials, light-adapted (LA) 3.0 ERG, and 30 Hz flicker ERG. RESULTS: The delayed responses of healthy subjects compared to diabetic patients without DR were the DA oscillatory potentials (25.45 ± 1.04 ms vs. 26.15 ± 0.96 ms, p = 0.027). When comparing diabetic patients without DR and with non-proliferative DR, we did not obtain statistically significant delays. Significant delays in the DA 0.01 "b"-wave (61.91 ± 5.52 ms vs. 66.36 ± 8.12 ms, p = 0.029), DA 3.0 "b"-wave (41.01 ± 2.50 ms vs. 44.16 ± 3.78 ms, p = 0.035), and LA 3.0 "a"-wave (16.21 ± 0.91 ms vs. 16.99 ± 1.16 ms, p = 0.045) were found between non-proliferative DR and pre-proliferative DR. When comparing the groups of patients with pre-proliferative DR and proliferative DR, the LA 3.0 ERG "b"-wave (32. 63 ± 2.53 ms vs. 36.19 ± 3.21 ms, p < 0.0001), LA 30 Hz flicker ERG "a"-wave (19.56 ± 3.59 vs. 21.75 ± 4.74 ms, p= 0.025), and "b"-wave (32.23 ± 4.02 vs. 36.68 ± 3.48 ms, p = 0.017) were delayed. CONCLUSIONS: the electrophysiological findings from our study indicate that there is a substantial dysfunction of the neural retina in all stages of DR.

Optic neuropathies post-Covid 19 - review.

The Corona virus infection started at the end of 2019 in Wuhan - China and spread rapidly throughout the world, generating the Covid 19 pandemic. The manifestations of the Covid disease were extremely varied, from a simple flu, with fever, cough, weakness, headache, joint pain, up to severe pneumonia, with severe acute respiratory syndrome (SARS-Cov2) and even death. The symptomatology of the disease, the evolution and the complications that appeared varied, depending on the associated pathology - diabetes mellitus (DM), hypertension (HT), the age and the immune status of the patient. Aim: The ocular manifestations related to Covid 19 were mostly represented by conjunctivitis, but the neurotropic character of Corona virus could justify the appearance of certain neuro-ophthalmological manifestations, such as: optic neuritis (ON), cranial nerve palsies, visual field (VF) anomalies. The aim of this paper was to research the cases of optic neuropathy post-Covid 19, published in the specialty literature between 2020 and 2022. The following were evaluated: risk factors, distribution by age group and gender, evolution and complications, as well as the clinical forms of optic neuropathies. Materials and methods: We used Google Scholar and PubMed databases to find articles on optic neuropathies related to the Covid-19 infection. We followed the articles published during the pandemic and selected 21 cases, belonging to 17 authors, irrespective of their origin and the language in which they were written. Results: 21 patients affected by ON in the Covid-19 disease, 11 women and 10 men, were mentioned. The optic neuropathies described by the authors were: retrobulbar optic neuropathy, only one associated with myelin oligodendrocyte glycoprotein (MOG), papillitis, neuroretinitis, anterior ischemic optic neuropathy (AION), out of which one arteritic anterior ischemic optic neuropathy (AAION) and the others non-arteritic anterior ischemic optic neuropathy (NAAION), one being related to pronation in an oro-tracheal intubated (OTI) patient with acute respiratory distress syndrome (ARDS). Discussions: The neuro-ophthalmological complications associated with Covid 19 disease can be severe, so the patients should be monitored continuously. Many investigations (serological, immunological and imaging exams) are necessary to exclude other etiologies of ON. Conclusions: A complete ophthalmological exam is mandatory for each patient diagnosed with Covid 19 disease, even if they have ocular manifestations or not. Abbreviations: SARS-Cov2 = severe acute respiratory syndrome; DM = Diabetes mellitus; HT = Hypertension; ON = Optic neuritis; VF = Visual field ; NS = Nervous system; CRP = C-reactive Protein; CL = cytokines; IL = interleukins; TNFɑ = tumor necrosis factor; CNS = central nervous system; ACE = angiotensin-converting enzyme; CRVO = central retinal vein occlusion; MOG = myelin oligodendrocyte glycoprotein; MOG-AD = myelin oligodendrocyte glycoprotein antibody disease; BBB = blood-brain barrier; ARDS = acute respiratory distress syndrome; IOP = intraocular pressure; CVP = central venous pressure; MSOF = multiple systems organ failure; AAION = arteritic anterior ischemic optic neuropathy; NAION = non-arteritic anterior ischemic optic neuropathy; AION = anterior ischemic optic neuropathy; OCT = optical coherence tomography; CT = computer tomography; AFG = angiofluorography; MRI = magnetic resonance imaging; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; AQP4 = anti aquaporin 4; NMO = neuromyelitis optica; CSF = cerebrospinal fluid; OTI = oro-tracheal intubated; VA = visual acuity; ONTT = optic neuritis treatment trial; RNFL = retinal nerve fiber layer; ICU = intensive care unit; LE = left eye; RE = right eye; MS = multiple sclerosis; ICH = intracranial hypertension; BCVA = best correction visual acuity; LP = light perception; APD = afferent pupillary defect; BM = biomicroscopy; PDN = prednisone; MTX = methotrexate; MTPN = methylprednisolone; NSAID = non-steroidal anti-inflammatory drugs; CGL = cells ganglion layer; VEP = visual evoked potential; CF = counting fingers.

Glioblastoma pharmacotherapy: A multifaceted perspective of conventional and emerging treatments (Review).

Due to its localisation, rapid onset, high relapse rate and resistance to most currently available treatment methods, glioblastoma multiforme (GBM) is considered to be the deadliest type of all gliomas. Although surgical resection, chemotherapy and radiotherapy are among the therapeutic strategies used for the treatment of GBM, the survival rates achieved are not satisfactory, and there is an urgent need for novel effective therapeutic options. In addition to single-target therapy, multi-target therapies are currently under development. Furthermore, drugs are being optimised to improve their ability to cross the blood-brain barrier. In the present review, the main strategies applied for GBM treatment in terms of the most recent therapeutic agents and approaches that are currently under pre-clinical and clinical testing were discussed. In addition, the most recently reported experimental data following the testing of novel therapies, including stem cell therapy, immunotherapy, gene therapy, genomic correction and precision medicine, were reviewed, and their advantages and drawbacks were also summarised.

Cellular and molecular events underlying the dysregulated response of the aged brain to stroke: a mini-review.

BACKGROUND: Age-related brain injuries, including stroke, are a major cause of physical and mental disabilities. OBJECTIVE: Therefore, studying the basic mechanism underlying functional recovery after brain stroke in aged subjects is of considerable clinical interest. METHODS: This review summarizes the effects of age on recovery after stroke in an animal model, with emphasis on the underlying cellular mechanisms. RESULTS: Data from our laboratory and elsewhere indicate that, behaviorally, aged rats were more severely impaired by stroke than young rats, and they also showed diminished functional recovery. Infarct volume did not differ significantly between young and aged animals, but critical differences were apparent in the cytological response to stroke, most notably an age-related acceleration in the development of the glial scar. Early infarct in older rats is associated with premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration and accelerated apoptosis. In aged rats, neuroepithelial-positive cells were rapidly incorporated into the glial scar, but these neuroepithelial-like cells did not make a significant contribution to neurogenesis in the infarcted cortex in young or aged animals. The response of plasticity-associated proteins like MAP1B, was delayed in aged rats. Tissue recovery was further delayed by an age-related increase in the amount of the neurotoxic C-terminal fragment of the beta-amyloid precursor protein (A-beta) at 2 weeks poststroke. CONCLUSION: The available evidence indicates that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis for this phenomenon in the aging brain could yield novel approaches to neurorestoration in the elderly.

Implications of inflammation and remodeling of the enteric glial cells in colorectal adenocarcinoma.

AIM: The aim of our study was to assess glial fibrillary acidic protein (GFAP) glial cell phenotype in the enteric nervous system (ENS) in colorectal adenocarcinoma of different tumor grading and, also, to establish correlations between these changes and the tumor proliferative activity and the tumor-infiltrating leukocytes. PATIENTS, MATERIALS AND METHODS: We ran an observational, prospective study on a group of 52 patients diagnosed with colorectal adenocarcinoma. They were surgically treated in the 1st Surgery Clinic of the Emergency County Hospital of Craiova, Romania. From the surgically resected pieces, after pathological confirmation and tumor grading, 3-µm thick seriate sections were cut and processed for immunohistochemistry for detecting GFAP, S100, CD45 and Ki-67. RESULTS: Evaluation of GFAP glial cell type in the ENS of colorectal cancer with different stages of differentiation showed that the density of these nervous elements is higher in well-differentiated (G1) colorectal tumors compared to moderately differentiated (G2) and poorly differentiated (G3) colorectal tumors. For well-differentiated colorectal adenocarcinoma, we did not find any correlations between GFAP glial cell type in the ENS and the tumor proliferative activity or with tumor-infiltrating leukocytes. In what the moderately and poorly differentiated adenocarcinoma are concerned, we found a high inverse variation between GFAP glial cell type in the ENS and the proliferative activity, on one hand, and, between GFAP glial cell type in the ENS and the tumor-infiltrating leukocytes, on the other hand. CONCLUSIONS: The decrease in the density of GFAP glial cell type in the ENS with tumor grading of colorectal cancer and the inverse variation with the tumor proliferative activity and with the tumor-infiltrating leukocytes might serve as putative prognostic factors in colorectal cancer.

Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer.

INTRODUCTION: Intratumoral heterogeneity implies the existence of differences between tumor cells, which can best be shown by histochemical and immunohistochemical techniques. The histological study is a mandatory step in any research aimed at characterizing tumor heterogeneity. Immunohistochemistry (IHC) also plays an important role in the differentiation of tumor types, assessing aggressiveness. MATERIALS AND METHODS: Investigated group consisted of 50 patients with colorectal adenocarcinoma, for each were recorded clinicopathological data and harvested samples intraoperatively, which were included in paraffin blocks. We perform Hematoxylin-Eosin staining for histological grade and other indices. IHC study used Avidin-Biotin-Peroxidase (ABC), with the markers: CK7, CK20, MUC1, MUC2, Ki-67, PCNA, p53, KRAS, BCL2, PTEN, EGFR. The resulting data were analyzed by statistical methods. RESULTS: Most of colorectal adenocarcinoma studied had no special histological features and had G2 grade. IHC detected in most cases the CK20+÷CK7- phenotype (78%) and MUC1 (74%) protein expression. The proliferation markers (Ki-67 and PCNA) were present in all tumor mass with a variable index, which shows high intratumoral heterogeneity, but p53 and KRAS were distributed more uniformly, showing low intratumoral heterogeneity. PTEN was expressed nuclearly in 86% of the cases and EGFR in 42%. CONCLUSIONS: The expression profiles of cytokeratins and mucins in the colorectal adenocarcinomas are useful in defining tumor phenotypes with different prognosis and therapy. We found a significant positive correlation between KRAS protein expression and BCL2 and TP53 expression. The study demonstrated the intratumoral and intertumoral heterogeneity, expressed at phenotypic level.

Microglial voltage-gated sodium channels modulate cellular response in Alzheimer's disease--a new perspective on an old problem.

Alzheimer's disease (AD) determines gradual loss of cognition and memory function, eventually leading to clinical manifest dementia. The pathogenic mechanisms of AD remain elusive and treatment options unsatisfactory, targeting only symptoms like memory loss, behavior changes, sleep disorders and seizures. These therapies are not stopping the disease's progression, at their best they can only delay it. Accumulating evidence suggests that AD is associated with a microglial dysfunction. Microglia are resident immune cells that provide continuous surveillance within the brain. When excessively activated, microglial response can also have detrimental effects via the exacerbation of inflammatory processes and release of neurotoxic substances. Recently, it was recognized that microglia express voltage-gated ion channels, in particularly voltage-gated sodium channels (VGSC). Pharmacological block of VGSC has been attempted symptomatically in AD to control the epileptic features often associated with AD, as well as to relieve detrimental behavioral and psychological symptoms of dementia. The success of VGSC treatment in AD was unexpectedly variable, ranging from very beneficial to plain detrimental. This variability could not be satisfactorily explained solely by the neuronal effects. This article will try to discuss possible implication of microglial VGSC dysfunction in AD according to available data, own personal experience of the authors and propose a new way to investigate its possible implications.

Motor unit changes in normal aging: a brief review.

Aging is explored by multiple lines of research, in a pursuit of understanding this natural process. The motor response is usually the main dependent variable in studies regarding physical or cognitive decline in aging. It is therefore critical to understand how the motor function changes with age. The present review, aims at presenting briefly some of the most recently published works in the field, focusing on the three key components of the motor unit. The changes that the skeletal muscle undergoes aging sarcopenia, alteration of fiber type distribution and also intimate metabolic transformations. The neuromuscular junction suffers at cellular and molecular level, with possible implications of various cell components, mediators and oxidative stress. Motoneuron loss and change in their physiological properties accompany remodeling in the motor units. The applicability of knowledge in this field lies in possible interventions intended to counteract these age-related losses.

Optical coherence tomography investigation of ischemic stroke inside a rodent model.

Although already in use in several medical domains, only recently optical coherence tomography (OCT) has been applied in the study of ischemic events. In this paper, we will focus on characterizing ischemic stroke, in a rat model, by OCT. Investigations were carried on a set of 25 rats, on which ischemic stroke was inflicted by a transient occlusion of the middle cerebral artery (tMCAO). Animals were sacrificed 1, 3, 7 and 28 days after occlusion. We tested the OCT's power of detection and discrimination of stroke area compared to both normal, contralateral hemisphere and non-affected brain tissue, together with the aid of histochemical and pathological examination. Our results show a great potential of OCT to be used as a detection tool in acute and chronic phases of stroke.

Optical coherence tomography as a promising imaging tool for brain investigations.

This paper will review the newest results and directions for the usage of optical coherence tomography as an imaging tool for brain studies, focusing mostly on a rodent model. Together with state of the art in the field, based on some of the most recent work, this paper will include a brief look on some results obtained by our group. Brain injuries and stroke data obtained by optical coherence tomography analyzing will be presented as a possibility of detection and evaluation for affected tissue, using this imaging system.