The post-COVID stress syndrome: from the three-stage stress response of Hans Selye to COVID-19.

Stress is the nonspecific response of the body to any demand made upon it, as defined by Hans Selye more than 80 years ago, based on his animal experiments at McGill University in Montreal, Canada. By emphasizing 'nonspecificity' he tried to underline that stress response is elicited my several factors, like nowadays in COVID-19, e.g., fear of infection, social isolation, death in family, loss of employment, etc. Thus, COVID-19 has been the largest new human stressor in the twenty-first century. Selye's studies in rats also revealed 3 stages of stress response: the short initial "alarm reaction" is followed by a longer "stage of resistance", associated with increased levels of corticosterone that is often terminated by a "stage of exhaustion", referring to an exhausted adrenal cortex when the secretion of glucocorticoids drops. Fast forward, that is exactly what has been documented in severe cases of infections caused by the SARS-CoV-2 virus: in hospitalized COVID-19 patients initially the blood levels of cortisol not only have been elevated, but only those with high concentration of this natural anti-inflammatory corticosteroid survived vs. those who had low levels of cortisol, suggesting diminished adrenocortical functions. Furthermore, patients with very severe cases of COVID-19 who ended up in intensive care units had significantly low cortisol blood levels, compared to patients with equal severity of diseases due to other causes. Thus, these 'natural phenomena' in clinical medicine, unfortunately confirmed Selye's studies in experimental animals several decades ago. Still, the good news is that astute clinicians empirically recognized this and started to give potent synthetic glucocorticoids such as dexamethasone to severe COVD-19 patients and this beneficial effect of exogenous corticoids has been extensively confirmed in the scientific literature.

What is really 'Long COVID'?

The previous acute respiratory diseases caused by viruses originating from China or the middle east (e.g., SARS, MERS) remained fast developing short diseases without major sequalae or any long-lasting complications. The new COVID-19, on the other hand, not only that it rapidly spread over the world, but some patients never fully recovered or even if they did, a few weeks later started to complain not only of shortness of breath, if any, but general weakness, muscle pains and 'brain fog', i.e., fuzzy memories. Thus, these signs and symptoms were eventually labelled 'long COVID', for which the most widely used definition is 'new signs and symptoms occurring 4-8 weeks after recovering from acute stage of COVID-19'. The other most frequent manifestations associated with long COVID include headache, loss of memory, smell and of hair, nausea, and vomiting. Thus, long COVID is not a simple disease, but complex disorder of several organ systems malfunctioning; hence, it is probably more appropriate to call this a syndrome. The pathogenesis of long COVID syndrome is poorly understood, but initial and persistent vascular endothelial injury that often triggers the formation of microthrombi that if dislodged as emboli, damage several organs, especially in the brain, heart and kidney, by creating microinfarcts. The other major contributory mechanistic factor is the persistent cytokine storm that may last longer in long COVID patients than in others, probably triggered by aggregates of SARS-Co-2 discovered recently in the adrenal cortex, kidney and brain. The prevalence of long COVID is relatively high, e.g., initially varied 3-30%, and recent data indicate that 2.5% of UK population suffers from this syndrome, while in the US 14.7% of acute COVID-19 patients continued to have symptoms longer than 2 months. Thus, the long COVID syndrome deserves to be further investigated, both from clinical and basic research perspectives.

A closer look at endothelial injury-induced platelet hyperactivity and the use of aspirin in the treatment of COVID infection.

In this commentary, we make a case that the mechanism of COVID pathogenesis is related to virus-induced endothelial injury resulting in platelet activation and the formation of microthrombi both systemically and in cardiac and pulmnonary circulation which result in major causes of COVID morbidity and mortality. Aspirin by virtue of its irreversible inhibition of platelet COX-1, should reverse these platelet-induced pathogenic changes associated with COVID infection for the 6-9 day lifetime of the platelet. We also cite recent findings of a retrospective analysis that supports the use of low-dose (81 mg) aspirin to treat the symptoms associated with the early stages of COVID infection.

Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target.

Acute gastritis is often untreatable by acid secretion-inhibiting drugs. Understanding the protective mechanisms including the role of Transient Receptor Potential Ankyrin1 (TRPA1) and Vanilloid1 (TRPV1) channels localized on capsaicin-sensitive afferents and non-neuronal structures might identify novel therapeutic approaches. Therefore, we characterized a translational gastritis model using iodoacetamide (IAA) and investigated TRPA1/V1 expressions. Wistar rats and CD1, C57Bl/6J mice were exposed to IAA-containing (0.05, 0.1, 0.2, 0.3, 0.5%) drinking water for 7 or 14 days. Body weight and water consumption were recorded daily. Macroscopic lesions were scored, qualitative histopathologic investigation was performed, TRPA1/V1 immunopositivity and mRNA expressions were measured. IAA induced a concentration-dependent weight loss and reduced water intake in both species. Hyperemia, submucosal edema, inflammatory infiltration and hemorrhagic erosions developed after 7 days, while ulcers after 14 days in rats. Trpa1 mRNA/protein expressions were upregulated at both timepoints. Meanwhile, TRPV1 immunopositivity was upregulated in the gastric corpus after 0.05% IAA ingestion, but downregulated after 0.2%, whereas Trpv1 mRNA did not change. Interestingly, no macroscopic/microscopic changes were observed in mice. These are the first data for the concentration- and duration-dependent changes in the IAA-induced gastritis in rats accompanied by TRPA1 upregulation, therefore, its therapeutic potential in gastritis should further be investigated.

[The early recognition of mental morbidities during psycho-oncologic treatment]. / A pszichés morbiditások korai felismerése a pszichoonkológiai ellátás során.

Unfortunately there have been no positive changes in the main indicators of cancer incidence in Hungarian population since the turn of the millennium. The main goal of psycho-oncologic treatment is to provide the highest possible quality of life to the patient. The prevalence of mental disorders in cancer patients is high and it is accompanied by a rather small number of qualified staff. Thus, the remedy might be the identification of high-risk patients, i.e. the systematic psycho-oncologic screening. Hungary is still lacking a unified screening method that involves all oncologic treatment-providing units. Compiling the Hungarian standards for the Distress Thermometer and the Problem List is the first step of a complex program for creating a general psycho-oncologic screening. Such a comprehensive program might improve oncologic patient-care and, eventually, the quality and prospect of the lives of patients.

Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease.

BACKGROUND: VEGF-induced vascular permeability and blood vessels remodeling are key features of inflammatory bowel disease (IBD) pathogenesis. Dopamine through D2 receptor (D2R) inhibits VEGF/VPF-mediated vascular permeability and angiogenesis in tumor models. In this study, we tested the hypothesis that pathogenesis of IBD is characterized by the disturbance of dopaminergic system and D2R activity. METHODS: IL-10 knockout (KO) mice and rats with iodoacetamide-induced ulcerative colitis (UC) were treated intragastrically with D2R agonists quinpirole (1 mg/100 g) or cabergoline (1 or 5 µg/100 g). Macroscopic, histologic, and clinical features of IBD, colonic vascular permeability, and angiogenesis were examined. RESULTS: Although colonic D2R protein increased, levels of tyrosine hydroxylase and dopamine transporter DAT decreased in both models of IBD. Treatment with quinpirole decreased the size of colonic lesions in rats with iodoacetamide-induced UC (p < 0.01) and reduced colon wet weight in IL-10 KO mice (p < 0.05). Quinpirole decreased colonic vascular permeability (p < 0.001) via downregulation of c-Src and Akt phosphorylation. Cabergoline (5 µg/100 g) reduced vascular permeability but did not affect angiogenesis and improved signs of iodoacetamide-induced UC in rats (p < 0.05). CONCLUSIONS: Treatment with D2R agonists decreased the severity of UC in two animal models, in part, by attenuation of enhanced vascular permeability and prevention of excessive vascular leakage. Hence, the impairment dopaminergic system seems to be a feature of IBD pathogenesis.

[Naming and classification of steroids and human stress ulcers. Articles of historic significance published by Hans Selye 70 years ago]. / A szteroidok elnevezése, felosztása és az emberi stresszfekélyek. Selye János 70 éve megjelent történelmi jelentoségu cikkei.

The name of Hans Selye is mostly known worldwide as the discoverer of stress reaction. Yet, he made numerous other seminal and clinically relevant discoveries. Namely, since he had a focused research on steroid hormones originating from the adrenal cortex that play a crucial role in stress response, he was the first who introduced about 70 years ago the first classification of steroids that is still valid nowadays. This is based on three objective facts: (a) the names of steroid groups are identical with their organ of origin (e.g., corticoids from the adrenal cortex, testoids/androgens from the testis); (b) chemical structures of the steroids are identical within a group (e.g., all corticoids have pregnane nucleus with 21 carbon atoms); and (c) the biological effects are homogenous within a group (e.g., all glucocorticoids exert catabolic effect, while androgens are anabolic). It should be emphasized that Selye also discovered in animal models the pro-inflammmatory effect of mineralocorticoids and the anti-inflammatory properties of glucocorticoids, about 8-10 years before Nobel Prize was awarded to a physician for the first clinical use of adrenocorticotrop hormone and cortisone. Last, but not least, Selye was the first who recognized about 70 years ago the occurence of stress ulcers in humans, based on clinical reports on the huge increase in the number of perforated gastric anti-duodenal ulcers during bombings of London in World War II. The subsequent ulcer research by Selye`s former students and their contemporaries resulted in the recognition of anti-duodenal ulcer effect of dopamine, and the central gastroprotective actions of thyreotrop releasing hormone and endogenous opioids. Thus, Hans Selye made much more contributions to medical science and clinical practice than 'just' the discoverer of biologic stress response.

"Gastric cytoprotection" is still relevant.

Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant.

STAT3 and importins are novel mediators of early molecular and cellular responses in experimental duodenal ulceration.

OBJECTIVES: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers. METHODS: We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses. RESULTS: We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and ß in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or ß, and STAT3/DNA binding than wild-type mice in response to cysteamine. CONCLUSIONS: Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.

HANS SELYE 70 YEARS LATER: STEROIDS, STRESS ULCERS & H. PYLORI.

Although Hans Selye is mostly known for his discovery & development of the stress concept, he also introduced the first physiologically sound, structure-activity classification of steroids that was also based on the chemical structure of steroids in 1943. He not only introduced the names of glucocorticoids & mineralocorticoids but discovered the anti- & pro-inflammatory properties, respectively, of these steroids in animal models. Furthermore, he not only described the first stress-induced gastric ulcers in rats (1936) & characterized the first human 'stress ulcers' during the air-raids in London during World War 11 (1943). Thus, Selye was a much more productive & creative scientist than it is generally considered.

Comparative Phytotoxicity of Metallic Elements on Duckweed Lemna gibba L. Using Growth- and Chlorophyll Fluorescence Induction-Based Endpoints.

In this study, we exposed a commonly used duckweed species-Lemna gibba L.-to twelve environmentally relevant metals and metalloids under laboratory conditions. The phytotoxic effects were evaluated in a multi-well-plate-based experimental setup by means of the chlorophyll fluorescence imaging method. This technique allowed the simultaneous measuring of the growth and photosynthetic parameters in the same samples. The inhibition of relative growth rates (based on frond number and area) and photochemical efficiency (Fv/Fo and Y(II)) were both calculated from the obtained chlorophyll fluorescence images. In the applied test system, growth-inhibition-based phytotoxicity endpoints proved to be more sensitive than chlorophyll-fluorescence-based ones. Frond area growth inhibition was the most responsive parameter with a median EC50 of 1.75 mg L-1, while Fv/Fo, the more responsive chlorophyll-fluorescence-based endpoint, resulted in a 5.34 mg L-1 median EC50 for the tested metals. Ag (EC50 0.005-1.27 mg L-1), Hg (EC50 0.24-4.87 mg L-1) and Cu (EC50 0.37-1.86 mg L-1) were the most toxic elements among the tested ones, while As(V) (EC50 47.15-132.18 mg L-1), Cr(III) (EC50 6.22-19.92 mg L-1), Se(VI) (EC50 1.73-10.39 mg L-1) and Zn (EC50 3.88-350.56 mg L-1) were the least toxic ones. The results highlighted that multi-well-plate-based duckweed phytotoxicity assays may reduce space, time and sample volume requirements compared to the standard duckweed growth inhibition tests. These benefits, however, come with lowered test sensitivity. Our multi-well-plate-based test setup resulted in considerably higher median EC50 (3.21 mg L-1) for frond-number-based growth inhibition than the 0.683 mg L-1 median EC50 derived from corresponding data from the literature with standardized Lemna-tests. Under strong acute phytotoxicity, frond parts with impaired photochemical functionality may become undetectable by chlorophyll fluorometers. Consequently, the plant parts that are still detectable display a virtually higher average photosynthetic performance, leading to an underestimation of phytotoxicity. Nevertheless, multi-well-plate-based duckweed phytotoxicity assays, combined with chlorophyll fluorescence imaging, offer definite advantages in the rapid screening of large sample series or multiple species/clones. As chlorophyll fluorescence images provide information both on the photochemical performance of the test plants and their morphology, a joint analysis of the two endpoint groups is recommended in multi-well-plate-based duckweed phytotoxicity assays to maximize the information gained from the tests.

The impacts of incentive policies on improving private investment for rural electrification in Nigeria - A geospatial study.

In Nigeria, 86 million people lack electricity access, the highest number worldwide, predominantly in rural areas. Despite government efforts, constrained budgets necessitate private investors, who, without adequate incentives, are hesitant to commit capital due to perceived high risks. This study identifies three existing incentive policies-concessionary loans, capital subsidy, and financing productive use equipment-aimed at promoting rural electrification in Nigeria. Employing geospatial and regulatory analyses, we evaluate their impact on electrification planning across 22,696 population clusters. While all incentives encourage mini-grids and stand-alone systems, results show varied impacts, predominantly favouring mini-grids. Under the baseline, grid extension is optimal for 66% of clusters, followed by mini-grids (27%) and stand-alone systems (7%). Concessionary loans boost mini-grid and Stand-Alone Systems shares by 10% and 5%, respectively. Capital subsidies increase the mini-grid share to 41%, surpassing concessional loans (37%). Financing productive equipment enhances Stand-Alone Systems and mini-grid shares to 15% and 43%. Incentives impact LCOE, CAPEX, and OPEX, with average LCOE reducing to 0.31 EUR/kWh (concessionary loans), 0.30 EUR/kWh (capital subsidy), and 0.27 EUR/kWh (financing productive use). Financing productive uses proves decisively more effective in lowering costs for mini-grids and stand-alone systems than loans or capital subsidies. The important policy implications of this study reinforce the need for tailored incentives for distinct electrification options.

Rheoencephalography: A non-invasive method for neuromonitoring.

In neurocritical care, the gold standard method is intracranial pressure (ICP) monitoring for the patient's lifesaving. Since it is an invasive method, it is desirable to use an alternative, noninvasive technique. The computerized real-time invasive cerebral blood flow (CBF) autoregulation (AR) monitoring calculates the status of CBF AR, called the pressure reactivity index (PRx). Studies documented that the electrical impedance of the head (Rheoencephalography - REG) can detect the status of CBF AR (REGx) and ICP noninvasively. We aimed to test REG to reflect ICP and CBF AR. For nineteen healthy subjects we recorded bipolar bifrontal and bitemporal REG derivations and arm bioimpedance pulses with a 200 Hz sampling rate. The challenges were a 30-second breath-holding and head-down-tilt (HDT - Trendelenburg) position. Data were stored and processed offline. REG pulse wave morphology and REGx were calculated. The most relevant finding was the significant morphological change of the REG pulse waveform (2nd peak increase) during the HDT position. Breath-holding caused REG amplitude increase, but it was not significant. REGx in male and female group averages have similar trends during HDT by indicating the active status of CBF AR. The morphological change of REG pulse wave during HDT position was identical to ICP waveform change during increased ICP, reflecting decreased intracranial compliance. A correlation study between ICP and REG was initiated in neurocritical care patients. The noninvasive REG monitoring would also be useful in space research as well as in military medicine during the transport of wounded service members as well as for fighter pilots to indicate the loss of CBF and consciousness.

Physical structure of the environment contributes to the development of diversity of microalgal assemblages.

Aquatic macrophytes form a three dimensional complex structure in the littoral zones of lakes, with many physical, chemical and biological gradients and interactions. This special habitat harbours a unique microalgal assemblage called metaphyton, that differs both from the phytoplankton of the pelagial and from the benthic assemblages whose elements are tightly attached to the substrates. Since metaphytic assemblages significantly contribute to the diversity of lakes' phytoplankton, it is crucial to understand and disentangle those mechanisms that ensure their development. Therefore, we focused on the question of how a single solid physical structure contribute to maintaining metaphytic assemblages. Using a laboratory experiment we studied the floristic and functional differences of microalgal assemblages in microcosms that simulated the conditions that an open water, a complex natural macrophyte stand (Utricularia vulgaris L.), or an artificial substrate (cotton wool) provide for them. We inoculated the systems with a species rich (> 326 species) microalgal assemblage collected from a eutrophic oxbow lake, and studied the diversity, trait and functional group composition of the assemblages in a 24 day long experimental period. We found that both natural and artificial substrates ensured higher species richness than the open water environment. Functional richness in the open water environment was lower than in the aquaria containing natural macrophyte stand but higher than in which cotton wool was placed. This means that the artificial physical structure enhanced functional redundancy of the resident functional groups. Elongation measures of microalgal assemblages showed the highest variation in the microcosms that simulated the open water environment. Our results suggest that assembly of metaphytic algal communities is not a random process, instead a deterministic one driven by the niche characteristics of the complex three dimensional structure created by the stands of aquatic macrophytes.

Pediatric thyroid-like follicular renal cell carcinoma-a post-neuroblastoma case with comprehensive genomic profiling data.

Thyroid-like follicular renal cell carcinoma (TLFRCC), an emerging subtype of renal cell carcinoma, presents diagnostic challenges due to its resemblance to normal thyroid tissue. Here, we report a rare case of TLFRCC in a pediatric patient, a demographic rarely affected by this subtype. Histologically resembling a typical TLFRCC, our case exhibited unique features including post-neuroblastoma development, occurrence in a male teenager, and diffuse MelanA expression, which has not been previously reported in TLFRCC. Comprehensive genomic profiling revealed the EWSR1::PATZ1 fusion, confirming its genetic basis. Due to the advanced tumor stage, the patient received combined immunotherapy, and after a 9-month follow-up, remains tumor-free. Our case broadens the diagnostic spectrum of pediatric renal cell carcinomas, highlighting the importance of comprehensive molecular profiling in rare subtypes such as TLFRCC. Further research is needed to better understand TLFRCC's genetic landscape and optimize therapeutic strategies, especially in pediatric populations with evolving treatment protocols.

An imbalance between VEGF and endostatin underlies impaired angiogenesis in gastric mucosa of aging rats.

Gastric mucosa of aging individuals exhibits increased susceptibility to injury and delayed healing. Our previous studies in young rats showed that healing of mucosal injury depends on and is critically dependent on VEGF and angiogenesis. Since angiogenesis in aging gastric mucosa has not been examined before, in this study we examined the extent to which angiogenesis is impaired in gastric mucosa of aging vs. young rats and determined the underlying mechanisms with a focus on mucosal expression of VEGF (proangiogenic factor) and endostatin (antiangiogenic factor). Aging rats had significantly impaired gastric angiogenesis by ~12-fold, 5-fold, 4-fold, and 3-fold, respectively (vs. young rats; all P < 0.001) at 24, 48, 72, and 120 h following ethanol-induced gastric injury and reduced and delayed healing of mucosal erosions. In gastric mucosa of aging (vs. young) rats at baseline, VEGF expression was significantly reduced, whereas endostatin levels were significantly increased (P < 0.05 and P < 0.01, respectively). In contrast to young rats, gastric mucosal VEGF levels did not increase following ethanol-induced injury in aging rats. MMP-9 enzyme activity was significantly higher in gastric mucosa of aging vs. young rats both at baseline (2.7-fold) and 24 h (3.8-fold) after ethanol injury (both P < 0.001). Since endostatin is generated from collagen XVIII by MMP-9, this finding can explain the mechanism of increased endostatin expression in aging gastric mucosa. The above findings demonstrate that reduced VEGF and increased endostatin result in the impaired angiogenesis and delayed injury healing in gastric mucosa of aging rats.

Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism.

UNLABELLED: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. MATERIAL AND METHODS: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n=43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. RESULTS: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. CONCLUSIONS: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is independent of its primary function in the induction of angiogenesis.

Datasets for a multidimensional analysis connecting clean energy access and social development in sub-Saharan Africa.

In this article we present datasets used for the construction of a composite indicator, the Social Clean Energy Access (Social CEA) Index, presented in detail in [1]. This article consists of comprehensive social development data related to electricity access, collected from several sources, and processed according to the methodology described in [1]. The new composite index includs 24 indicators capturing the status of the social dimensions related to electricity access for 35 SSA countries. The development of the Social CEA Index was supported by an extensive review of the literature about electricity access and social development which led to the selection of its indicators. The structure was evaluated for its soundness using correlational assessments and principal component analyses. The raw data provided allow stakeholders to focus on specific country indicators and to observe how scores on these indicators contributed to a country overall rank. The Social CEA Index also allows to understand the number of best performing countries (out of a total of 35) for each indicator. This allows different stakeholders to identify which the weakest dimensions are of social development and thus help in addressing priorities for action for funding towards specific electrification projects. The data can be used to assign weights according to stakeholders' specific requirements. Finally, the dataset can be used for the case of Ghana to monitor the Social CEA Index progress over time through a dimension's breakdown approach.

Our Experiences with Asparaginase Activity Measurements in Children with Lymphoblastic Diseases.

BACKGROUND: Asparaginase is a key component of chemotherapy protocols for the treatment of lymphoblastic malignancies among children. Adequate asparagine depletion is an important factor to achieve optimal therapeutic outcomes. METHODS: Over a 3.5 year period, 106 patients were monitored for asparaginase activity (329 samples) in a single center of the Hungarian Pediatric Oncology-Hematology Group. In Hungary, three asparaginase products are available: native E. coli ASNase (Kidrolase), a pegylated form of this enzyme (Pegaspargase) and another native product from Erwinia chrysanthemi (Erwinase). A retrospective data analysis was performed. RESULTS: In 81% (268/329) of our patients, AEA levels were in the optimal therapeutic range of over 100 IU/L. Of 106 patients, 13 (12%) were diagnosed with 'silent inactivation'. CONCLUSIONS: Monitoring of AEA can help to identify patients with 'silent inactivation' and their asparaginase therapy can thus be optimized.