Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86R and FusΔNLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93A and FusΔNLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury.

Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.

The effect of pH-compatible cleansing cloths on skin pH and the development of pressure ulcers.

AIM: Skin care plays an important role in the prevention of the development of pressure ulcers. The aim of this study was to determine the effect of skincare with a body pH-compatible cleansing cloth on the development time of pressure ulcers and on skin pH. METHODS: This experimental research was conducted with 156 patients hospitalized in intensive care clinics of a state hospital between September 2019 and 2020. The sample was calculated with a power of 80% and a significance level of 0.05 (α error) and as a result, 78 elderly patients formed the intervention group and another 78 elderly patients made up the control group. Data were collected using the Elderly Information Form, Braden Risk Assessment Scale, Pressure Ulcer Staging Tool and Skin pH Measurement Form. The pre- and post-care skin pH of both groups was measured with a skin pH meter. P < 0.05 was considered statistically significant. RESULTS: The average development time for pressure ulcers was 14.9 days in the control group, 18.9 days in the intervention group and the difference was not statistically significant (p > 0.05). Skin pH decreased in the intervention group after the skin care routine was applied, whereas it increased in the control group. CONCLUSION: It can be said that care of one's skin with a body pH-compatible cleansing cloth has a positive effect on the development time of pressure ulcers and also positively changes the skin pH to acidic.

Impact of tomato pomace powder added to extruded snacks on the in vitro gastrointestinal behaviour and stability of bioactive compounds.

In this study, extruded snacks enriched with tomato pomace powder (TPP) at ratios of 5, 10, 15, and 20% (w/w) were prepared based on some preliminary experiments. The effect of tomato pomace addition to extruded snacks on the total phenolic content, total antioxidant capacity, contents of lycopene and phenolics, as well as their in vitro bioaccessibility; and additionally, physical, textural and sensory properties of the samples were investigated. According to the results, increasing levels of TPP in snacks significantly increased the content of individual phenolics including gallic acid, protocatechuic acid, 2,5-dihydroxybenzoic acid, chlorogenic acid, rutin and quercetin. Similarly, increased amount of TPP in snacks enhanced the bioaccessible protocatechuic acid, chlorogenic acid, rutin and quercetin as well as lycopene (p < 0.05). TPP incorporated snacks displayed lower expansion indices, water absorption index (WAI) and water solubility index (WSI) and lightness; but had higher hardness, redness and yellowness values than the control. However, snacks had acceptable physical and sensory properties when enriched with 10% of TPP. The results suggest that tomato pomace can be added as a functional ingredient to improve the nutritional value of snack products.

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology.

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a much-improved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell type-specific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area- and disease stage- specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

Aneuploidy and recombination in the human preimplantation embryo. Copy number variation analysis and genome-wide polymorphism genotyping.

RESEARCH QUESTION: What are the incidence and patterns of meiotic trisomies and recombination separately and in relation to each other at the blastocyst stage via single nucleotide polymorphism genotyping combined with array comparative genomic hybridization. DESIGN: Single nucleotide polymorphism microarrays were carried out on a total of 1442 blastocyst stage embryos derived from 268 fertile couples undergoing preimplantation genetic diagnosis for the purposes of avoiding transmittance of known single gene disorders to their offspring; 24-chromosome aneuploidy screening via array comparative genomic hybridization was carried out in parallel. RESULTS: One hundred per cent of meiotic trisomies identified in these embryos were of maternal origin and their incidence increased significantly with advancing maternal age (P < 0.0001). A total of 55.8% of meiotic trisomies were meiosis I-type and 44.2% were meiosis II-type. Certain chromosomes were affected more by meiosis I-type errors, whereas others experienced more meiosis II-type errors. A detailed recombination analysis was carried out for 11,476 chromosomes and 17,763 recombination events were recorded. The average number of recombination sites was 24.0 ± 0.3 for male meiosis and 41.2 ± 0.6 for female meiosis (autosomes only). Sex-specific differences were observed in the locations of recombination sites. Comparative analysis conducted between 190 euploid embryos and 69 embryos presenting maternal meiotic trisomies showed similar recombination rates (P = 0.425) and non-recombinant chromatid rates (P = 0.435) between the two categories; differences, however, were observed when analysing embryos affected with specific maternal meiotic trisomies. CONCLUSIONS: This study yielded unique data concerning recombination and the origin of aneuploidies observed during the first few days of life and provides a novel insight into these important biological processes.

Insomnia in nursing students and related factors: A cross-sectional study.

AIM: The aim of this study is to determine the factors affecting insomnia in nursing students. METHODS: This study was conducted with 379 nursing students, studying at a university in western Anatolia/Turkey between 2014 and 2015 as a descriptive and cross-sectional analytic study. Data of the survey were collected using the Personal Inquiry Form, Pittsburgh Sleep Quality Index, Insomnia Severity Index, Trait Anxiety Inventory and the Beck Depression Inventory, and a self-administered questionnaire. RESULTS: The Insomnia Severity Index score for the students is 11.51 ± 5.04 on average. It was found that as anxiety and depression increased, the Insomnia Severity Index score for the students also increased and there was a weak positive correlation. Also, a moderate positive correlation between sleep quality and insomnia severity was found. Significant correlations were found between some of the socio-demographic characteristics (lower socio-economic situation, irregular bedtime, and smoking) and insomnia, sleep quality, anxiety, and depression. CONCLUSION: Anxiety, depression, irregular bedtime, and lower socio-economic situation are factors that make falling asleep difficult.

Prevalence and risk factors for excessive daytime of sleepiness in rural western Anotolia (Turkey): the role of obesity and metabolic syndrome.

The purpose of the present study was to identify risk factors for and prevalence of excessive daytime sleepiness and associations between demographic factors, obesity and metabolic syndrome criteria and excessive daytime somnolence (EDS). A descriptive and analytical study was conducted among 508 volunteers in primary health care centers in western Anatolia, Turkey. The data were obtained using a questionnaire and the Epworth Sleepiness Scale. Metabolic syndrome components were defined according to the criteria of the Internetional Diabetes Federation. A logistic regression model was used for statistical analysis. The mean +/- SD age was 46.3 +/- 17.3 years, body mass index was 27.0 +/- 5.4 kg/m2 and Epworth Sleepiness Scale (ESS) score was 5.0 +/- 4.4. The prevalence of EDS was 14.6% (n=74). Older age (OR 1.033; 95% CI 1.03-1.26) and high body mass index (OR 1.143; 95% CI 1.01-1.04) were associated with increased incidence of EDS. In backward logistic regression analysis, non-tea and coffee drinking (OR 6.189; 95% CI 2.10-18.2) were significantly asociated with EDS. According to our study, age, body mass index and non-tea and non-coffee drinking were associated with EDS.

Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors.

The role of the ErbB3 receptor in signal transduction is to augment the signaling repertoire of active heterodimeric ErbB receptor complexes through activating the PI3K/AKT pathway, which in turn promotes survival and proliferation. ErbB3 has recently been proposed to be involved in acquired resistance to tyrosine kinase inhibitors (TKIs), and is therefore a promising new drug cancer target. Since ErbB3 is a kinase defective receptor, it cannot be targeted by small molecule inhibitors, whereas monoclonal antibodies may offer a viable strategy for pharmacological intervention. In this study, we have utilized DNA electroporation (DNA-EP) to generate a set of novel hybridomas directed against human ErbB3, which have been characterized for their biochemical and functional properties and selected for their ability to negatively regulate the ErbB3-mediated signaling pathway. In vitro, the anti-ErbB3 antibodies modulate the growth rate of cancer cells of different origins. In vivo they show antitumoral properties in a xenograft model of human pancreatic tumor and in the ErbB2-driven carcinogenesis genetically engineered mouse model (GEMM) for mammary tumor, the BALB/neuT. Our data confirm that downregulating the ErbB3-mediated signals with the use of anti-ErbB3 monoclonal antibodies is both feasible and relevant for therapeutic purposes and provides new opportunities for novel anti-ErbB3 combinatory strategies for cancer treatment.

The risk factors effecting the dry mouth in inpatients in Hospital in west Anatolia.

AIM: The aim of the present study was to evaluate the inpatients with dry mouth and the associated risk factors. BACKGROUND: Dry mouth is defined as the excessive decrease in the amount of saliva. Hyposalivation may lead to rapid deterioration in oral health and may facilitate the development of opportunistic oral infections. Oral hygiene and evaluation of oral health are basic nursing activities. DESIGN: Cross-sectional. PARTICIPANTS: The sample size was determined to be 90 inpatients according to the power analysis calculated for the patients with dry mouth who were able or unable to take oral liquids. The study was completed with 247 inpatients in the Internal Medicine Clinic. METHODS: A patient information form was used to collect the data for the present study. Saliva samples taken for analyses of flow rates. RESULTS: The amount of saliva of patients who were unable to take oral liquid was 10·7 times lower than those taking >1500 ml of liquids daily. The amount of saliva of patients receiving humidified oxygen was 2·3 times lower than those not receiving humidified oxygen. The amount of saliva of those receiving anticholinergic drugs was 3·64 times lower than those not receiving anticholinergic drugs. CONCLUSIONS: Inability to take oral liquids and receiving humidified oxygen and anticholinergic drug therapy were significant factors for the development of dry mouth. RELEVANCE TO CLINICAL PRACTICE: The results are important for determining the risk factors for dry mouth. Being aware of dry mouth and knowing the associated risk factors are valuable information for nurses to initiate required procedures, as well as to prevent the development of oral health problems.

Isolation of Fully Human Antagonistic RON Antibodies Showing Efficient Block of Downstream Signaling and Cell Migration.

RON belongs to the c-MET family of receptor tyrosine kinases. As its well-known family member MET, RON and its ligand macrophage-stimulating protein have been implicated in the progression and metastasis of tumors and have been shown to be overexpressed in cancer. We generated and tested a large number of human monoclonal antibodies (mAbs) against human RON. Our screening yielded three high-affinity antibodies that efficiently block ligand-dependent intracellular AKT and MAPK signaling. This effect correlates with the strong reduction of ligand-activated migration of T47D breast cancer cell line. By cross-competition experiments, we showed that the antagonistic antibodies fall into three distinct epitope regions of the RON extracellular Sema domain. Notably, no inhibition of tumor growth was observed in different epithelial tumor xenografts in nude mice with any of the antibodies. These results suggest that distinct properties beside ligand antagonism are required for anti-RON mAbs to exert antitumor effects in vivo.

The effect of Turkish bath on QT dispersion.

OBJECTIVE: It is known that QT intervals might differ from each other on electrocardiogram (ECG). It is also known that diversity of QT interval between derivations is an indicator of heterogeneity of repolarization and it is a leading electrophysiological cause of ventricular arrhythmias and sudden heart death. In this study, we evaluated the effects of the Turkish bath on QT dispersion. METHODS: A total of 47 healthy volunteers were enrolled in the prospective study. The 12-lead ECG recordings were taken in all subjects before and after bath and QT dispersions were calculated. Blood pressure and the heart rate of each patient were recorded. QT dispersion was defined as the difference between the maximum and minimum QT intervals occurring in any of the 12 leads. Statistical analysis were performed using Wilcoxon rank test and paired t test. RESULTS: The mean age was 49.47+/-11.64 years; range was between 23-70 years. The mean temperature of the bath was 39.72+/-1.75 degrees C, mean humidity percent was 84.42+/-4.74%. QTc dispersion were respectively determined as 0.047+/-0.025 sec and 0.047+/-0.019 sec (p=0.981) before and after bath. We determined no correlation between duration time at bath and QTc dispersion (r=-0.069 p=0.646). CONCLUSION: In our study we found no meaningful difference in QTc dispersion in individuals who take bath. Our study is the first study in which we evaluated QTc dispersion in high temperature and humidity environment of the bath and we did not determine any effect on QTc dispersion.

Anti-EphA2 Antibodies with Distinct In Vitro Properties Have Equal In Vivo Efficacy in Pancreatic Cancer.

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human epithelial cancers and is a determinant of malignant cellular behavior in pancreatic adenocarcinoma cells. Moreover, it is expressed in tumor endothelium and its activation promotes angiogenesis. To better clarify the therapeutic potential of monoclonal antibodies (mAbs) directed to the EphA2 receptor, we generated a large number of mAbs by differential screening of phage-Ab libraries by oligonucleotide microarray technology and implemented a strategy for the rapid identification of antibodies with the desired properties. We selected two high-affinity and highly specific EphA2 monoclonal antibodies with different in vitro properties on the human pancreatic tumor cell line MiaPaCa2. One is a potent EphA2-agonistic antibody, IgG25, that promotes receptor endocytosis and subsequent degradation, and the second is a ligand antagonist, IgG28, that blocks the binding to ephrin A1 and is cross-reactive with the mouse EphA2 receptor. We measured the effect of antibody treatment on the growth of MiaPaCa2 cells orthotopically transplanted in nude mice. Both IgG25 and IgG28 had strong antitumor and antimetastatic efficacy. In vivo treatment with IgG25 determined the reduction of the EphA2 protein levels in the tumor and the phosphorylation of FAK on Tyr576 while administration of IgG28 caused a decrease in tumor vascularization as measured by immunohistochemical analysis of CD31 in tumor sections. These data show that in a pancreatic cancer model comparable therapeutic efficacy is obtained either by promoting receptor degradation or by blocking receptor activation.