Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine,aggravated by L-NAME

AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NOsystem. In the 4 d after esophagogastric anastomosis creation, rats received medication(/kg intraperitoneallyonce daily: BPC 157(10 μg, 10 ng), L-NAME(5 mg), or L-arginine(100 mg) alone and/or combined or BPC 157(10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage(sum of the longest diameters, mm), esophagitis(scored 0-5), weak anastomosis(m L H2 O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter(cm H2O), progressive weight loss(g) and mortality. Immediate effect assessed blood vessels disappearance(scored 0-5) at the stomach surface immediately after anastomosis creation. RESULTS BPC 157(all regimens) fully counteracted the perilous disease course from the very beginning(i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening(with L-NAME administration) and amelioration(with L-arginine), either L-arginine amelioration prevails(attenuated esophageal and gastric lesions) or they counteract each other(L-NAME + L-arginine); with the addition of BPC 157(L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability(as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening(obtained with L-NAME administration that was counteracted); or amelioration(L-arginine + BPC 157-rats correspond to BPC 157-rats).CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.     

Radiobiological analysis of human melanoma cells on the 62 MeV CATANA proton beam

PURPOSE: To measure the ability of protons and gamma-rays to effect cell viability and cell survival of human HTB140 melanoma cells. MATERIALS AND METHODS: Exponentially growing HTB140 cells were irradiated close to the Bragg peak maximum of the 62 MeV protons or with 60Co gamma-rays with single doses, ranging from 8 - 24 Gy. Cell viability using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay was evaluated at 6 h, 24 h, 48 h or 7 days after irradiation and clonogenic survival was assessed at 7 days after irradiation. Cell cycle phase redistribution and the level of apoptosis were evaluated at 6 h and 48 h after irradiation. RESULTS: The study of cell viability as a function of time (cell survival progression) and cell survival, using a clonal assay, demonstrated the considerably stronger inactivation effect of protons compared to gamma-rays with a relative biological effectiveness (RBE) of approximately 1.64. Cell cycle phase distribution and apoptosis levels with time enabled us to investigate the development and the character of the damage induced by irradiation. Due to the high radio-resistance of HTB140 cells, cell cycle phase redistribution exhibited only a modest cell accumulation in G2/M phase. Protons but not gamma-rays induced apoptosis. CONCLUSIONS: It appears that protons reduce the number of HTB140 cells by apoptosis as well as by severe DNA damage, while gamma-rays eliminate viable cells primarily by the production of irreparable DNA damage. Protons have an increased RBE relative to gamma-rays.     

Granular-cell tumor: a rare variant of mammary tumor

BACKGROUND: Granular cell tumor (GCT) is a rare variant of mammary tumor beset with diagnostic dilemmas that may be resolved by using numerous, very complex, enzymohistochemical and immunohistochemical methods. CASE REPORTS: We reported three female patients 16, 21 and 65 years old, operated on for mammary tumor at the Surgical Clinic of the School of Medicine in Nis, over the period of thirty years, 1977 to 2007. During this period 14.022 mammary tumors were diagnosed, including these three cases. These tumors had benign characteristics, without associated tumors in other localizations. A typical histological feature of GCT was a granular cytoplasm in large ovoid cells, organized like nests or like a trabecular arrangement. The tumors were analyzed by sets of histochemical, enzymohistochemical, immunohistochemical methods as well as ultrastructural examination. Protein, S-100 neuron-specific enolase and vimentin expressed a diffuse and intensive immunohistochemical activity, while expression of estrogen and progesterone receptors, as well as HER-2 oncoprotein was negative. The ultrastructural analysis confirmed that the tumor cells were enriched by lysosomes and consequential disorganization of cytoplasm. CONCLUSION: The reported enzymo- and immunohistochemical combined methods provide a precise diagnosis and confirm the GCT's neural origin, which has been disputed for years.     

Intercrypt sentinel macrophages tune antibacterial NF-κB responses in gut epithelial cells via TNF

Intestinal epithelial cell (IEC) NF-κB signaling regulates the balance between mucosal homeostasis and inflammation. It is not fully understood which signals tune this balance and how bacterial exposure elicits the process. Pure LPS induces epithelial NF-κB activation in vivo. However, we found that in mice, IECs do not respond directly to LPS. Instead, tissue-resident lamina propria intercrypt macrophages sense LPS via TLR4 and rapidly secrete TNF to elicit epithelial NF-κB signaling in their immediate neighborhood. This response pattern is relevant also during oral enteropathogen infection. The macrophage–TNF–IEC axis avoids responses to luminal microbiota LPS but enables crypt- or tissue-scale epithelial NF-κB responses in proportion to the microbial threat. Thereby, intercrypt macrophages fulfill important sentinel functions as first responders to Gram-negative microbes breaching the epithelial barrier. The tunability of this crypt response allows the induction of defense mechanisms at an appropriate scale according to the localization and intensity of microbial triggers.     

Liver disease and COVID-19: The link with oxidative stress,antioxidants and nutrition

Varying degrees of liver injuries have been reported in patients infected with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). In general, oxidative stress is actively involved in initiation and progression of liver damage. The liver metabolizes various compounds that produce free radicals. Maintaining the oxidative/antioxidative balance is important in coronavirus disease 2019 (COVID-19) patients. Antioxidant vitamins, essential trace elements and food compounds, such as polyphenols, appear to be promising agents, with effects in oxidative burst. Deficiency of these nutrients suppresses immune function and increases susceptibility to COVID-19. Daily micronutrient intake is necessary to support anti-inflammatory and antioxidative effects but for immune function may be higher than current recommended dietary intake. Antioxidant supplements (β-carotene, vitamin A, vitamin C, vitamin E, and selenium) could have a potential role in patients with liver damage. Available evidence suggests that supplementing the diet with a combination of micronutrients may help to optimize immune function and reduce the risk of infection. Clinical trials based on the associations of diet and SARS-CoV-2 infection are lacking. Unfortunately, it is not possible to definitively determine the dose, route of administration and best timing to intervene with antioxidants in COVID-19 patients because clinical trials are still ongoing. Until then, hopefully, this review will enable clinicians to understand the impact of micronutrient dietary intake and liver status assessment in COVID-19 patients.     

Hypermagnesemia disturbances in rats,NO-related: pentadecapeptide BPC 157 abrogates, <Emphasis Type="SmallCaps">l</Emphasis>-NAME and <Emphasis Type="SmallCaps">l</Emphasis>-arginine worsen

Aim

Stable gastric pentadecapeptide BPC 157, administered before a high-dose magnesium injection in rats, might be a useful peptide therapy against magnesium toxicity and the magnesium-induced effect on cell depolarization. Moreover, this might be an NO-system-related effect. Previously, BPC 157 counteracts paralysis, arrhythmias and hyperkalaemia, extreme muscle weakness; parasympathetic and neuromuscular blockade; injured muscle healing and interacts with the NOS-blocker and NOS-substrate effects.

Main methods

Assessment included magnesium sulfate (560 mg/kg intraperitoneally)-induced muscle weakness, muscle and brain lesions, hypermagnesemia, hyperkalaemia, increased serum enzyme values assessed in rats during and at the end of a 30-min period and medication (given intraperitoneally/kg at 15 min before magnesium) [BPC 157 (10 µg, 10 ng), l-NAME (5 mg), l-arginine (100 mg), alone and/or together]. In HEK293 cells, the increasing magnesium concentration from 1 to 5 mM could depolarize the cells at 1.75 ± 0.44 mV.

Key findings

l-NAME + magnesium-rats and l-arginine + magnesium-rats exhibited worsened severe muscle weakness and lesions, brain lesions, hypermagnesemia and serum enzymes values, with emerging hyperkalaemia. However, l-NAME + l-arginine + magnesium-rats exhibited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggravated by l-NAME or l-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 µM) in vitro.

Significance

BPC 157 likely counteracts the initial event leading to hypermagnesemia and the life-threatening actions after a magnesium overdose. In contrast, a worsened clinical course, higher hypermagnesemia, and emerging hyperkalaemia might cause both l-NAME and l-arginine to affect the same events adversely. These events were also opposed by BPC 157.

     

Atrial fibrillation in immigrant groups: a cohort study of all adults 45 years of age and older in Sweden

To study the association between country of birth and incident atrial fibrillation (AF) in several immigrant groups in Sweden. The study population included all adults (n = 3,226,752) aged 45 years and older in Sweden. AF was defined as having at least one registered diagnosis of AF in the National Patient Register. The incidence of AF in different immigrant groups, using Swedish-born as referents, was assessed by Cox regression, expressed in hazard ratios (HRs) and 95% confidence intervals (CI). All models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, and neighbourhood socioeconomic status. Compared to their Swedish-born counterparts, higher incidence of AF [HR (95% CI)] was observed among men from Bosnia 1.74 (1.56–1.94) and Latvia 1.29 (1.09–1.54), and among women from Iraq 1.96 (1.67–2.31), Bosnia 1.88 (1.61–1.94), Finland 1.14 (1.11–1.17), Estonia 1.14 (1.05–1.24) and Germany 1.08 (1.03–1.14). Lower incidence of AF was noted among men (HRs ≤ 0.60) from Iceland, Southern Europe (especially Greece, Italy and Spain), Latin America (especially Chile), Africa, Asia (including Iraq, Turkey, Lebanon and Iran), and among women from Nordic countries (except Finland), Southern Europe, Western Europe (except Germany), Africa, North America, Latin America, Iran, Lebanon and other Asian countries (except Turkey and Iraq). In conclusion, we observed substantial differences in incidence of AF between immigrant groups and the Swedish-born population. A greater awareness of the increased risk of AF development in some immigrant groups may enable for a timely diagnosis, treatment and prevention of its debilitating complications, such as stroke.     

Fructose Consumption Affects Glucocorticoid Signaling in the Liver of Young Female Rats

The effects of early-life fructose consumption on hepatic signaling pathways and their relation to the development of metabolic disorders in later life are not fully understood. To investigate whether fructose overconsumption at a young age induces alterations in glucocorticoid signaling that might contribute to development of metabolic disturbances, we analysed glucocorticoid receptor hormone-binding parameters and expression of its target genes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase and glucose-6-phosphatase) and lipid metabolism (lipin-1), as well as redox and inflammatory status in the liver of female rats subjected to a fructose-rich diet immediately after weaning. The fructose diet increased hepatic corticosterone concentration, 11β-hydroxysteroid dehydrogenase type 1 level, glucocorticoid receptor protein level and hormone-binding activity, as well as lipin-1 level. The expression of glucose-6-phosphatase was reduced in fructose-fed rats, while phosphoenolpyruvate carboxykinase remained unaltered. The fructose-rich diet increased the level of fructose transporter GLUT2, while the expression of fructolytic enzymes fructokinase and aldolase B remained unaltered. The diet also affected pro-inflammatory pathways, but had no effect on the antioxidant defence system. In conclusion, a fructose-rich diet applied immediately after weaning promoted lipogenesis and enhanced hepatic glucocorticoid signaling, possibly to protect against inflammatory damage, but without an effect on gluconeogenesis and antioxidant enzymes. Yet, prolonged treatment might ultimately lead to more pronounced metabolic disturbances.     

Detecting sarcasm from paralinguistic cues: Anatomic and cognitive correlates in neurodegenerative disease

While sarcasm can be conveyed solely through contextual cues such as counterfactual or echoic statements, face-to-face sarcastic speech may be characterized by specific paralinguistic features that alert the listener to interpret the utterance as ironic or critical, even in the absence of contextual information. We investigated the neuroanatomy underlying failure to understand sarcasm from dynamic vocal and facial paralinguistic cues. Ninety subjects (20 frontotemporal dementia, 11 semantic dementia [SemD], 4 progressive non-fluent aphasia, 27 Alzheimer's disease, 6 corticobasal degeneration, 9 progressive supranuclear palsy, 13 healthy older controls) were tested using the Social Inference — Minimal subtest of The Awareness of Social Inference Test (TASIT). Subjects watched brief videos depicting sincere or sarcastic communication and answered yes–no questions about the speaker's intended meaning. All groups interpreted Sincere (SIN) items normally, and only the SemD group was impaired on the Simple Sarcasm (SSR) condition. Patients failing the SSR performed more poorly on dynamic emotion recognition tasks and had more neuropsychiatric disturbances, but had better verbal and visuospatial working memory than patients who comprehended sarcasm. Voxel-based morphometry analysis of SSR scores in SPM5 demonstrated that poorer sarcasm comprehension was predicted by smaller volume in bilateral posterior parahippocampi (PHc), temporal poles, and R medial frontal pole (pFWE < 0.05). This study provides lesion data suggesting that the PHc may be involved in recognizing a paralinguistic speech profile as abnormal, leading to interpretive processing by the temporal poles and right medial frontal pole that identifies the social context as sarcastic, and recognizes the speaker's paradoxical intentions.