Elevated creatine kinase activity in primary hepatocellular carcinoma

BACKGROUND: Inconsistent findings have been reported on the occurrence and relevance of creatine kinase (CK) isoenzymes in mammalian liver cells. Part of this confusion might be due to induction of CK expression during metabolic and energetic stress. METHODS: The specific activities and isoenzyme patterns of CK and adenylate kinase (AdK) were analysed in pathological liver tissue of patients undergoing orthotopic liver transplantation. RESULTS: The brain-type, cytosolic BB-CK isoenzyme was detected in all liver specimens analysed. Conversely, CK activity was strongly increased and a mitochondrial CK (Mi-CK) isoenzyme was detected only in tissue samples of two primary hepatocellular carcinomas (HCCs). CONCLUSION: The findings do not support significant expression of CK in normal liver and most liver pathologies. Instead, many of the previous misconceptions in this field can be explained by interference from AdK isoenzymes. Moreover, the data suggest a possible interplay between p53 mutations, HCC, CK expression, and the growth-inhibitory effects of cyclocreatine in HCC. These results, if confirmed, could provide important hints at improved therapies and cures for HCC

A cross-country review of strategies of the German development cooperation to strengthen human resources

ABSTRACT: BACKGROUND: Recent years have seen growing awareness of the importance of human resources for health in health systems and with it an intensifying of the international and national policies in place to steer a response. This paper looks at how governments and donors in five countries - Cameroon, Indonesia, Malawi, Rwanda and Tanzania - have translated such policies into action. More detailed information with regard to initiatives of German development cooperation brings additional depth to the range and entry doors of human resources for health initiatives from the perspective of donor cooperation. METHODS: This qualitative study systematically presents different approaches and stages to human resources for health development in a cross-country comparison. An important reference to capture implementation at country level was grey literature such as policy documents and programme reports. In-depth interviews along a predefined grid with national and international stakeholders in the five countries provided information on issues related to human resources for health policy processes and implementation. RESULTS: All five countries have institutional entities in place and have drawn up national policies to address human resources for health. Only some of the countries have translated policies into strategies with defined targets and national programmes with budgets and operational plans. Traditional approaches of supporting training for individual health professionals continue to dominate. In some cases partners have played an advocacy and technical role to promote human resources for health development at the highest political levels, but usually they still focus on the provision of ad hoc training within their programmes, which may not be in line with national human resources for health development efforts or may even be counterproductive to them. Countries that face an emergency, such as Malawi, have intensified their efforts within a relatively short time and by using donor funding support also through new initiatives such as the Global Fund to Fight AIDS, Tuberculosis and Malaria. CONCLUSIONS: The country case studies illustrate the range of initiatives that have surged in recent years and some main trends in terms of donor initiatives. Though attention and priority attributed to human resources for health is increasing, there is still a focus on single initiatives and programmes. This can be explained in part by the complexity of the issue, and in part by its need to be addressed through a long-term approach including public sector and salary reforms that go beyond the health secto

A time-fractional Borel-Pompeiu formula and a related hypercomplex operator calculus

In this paper we develop a time-fractional operator calculus in fractional Clifford analysis. Initially we study the $L_p$-integrability of the fundamental solutions of the multi-dimensional time-fractional diffusion operator and the associated time-fractional parabolic Dirac operator. Then we introduce the time-fractional analogues of the Teodorescu and Cauchy-Bitsadze operators in a cylindrical domain, and we investigate their main mapping properties. As a main result, we prove a time-fractional version of the Borel-Pompeiu formula based on a time-fractional Stokes' formula. This tool in hand allows us to present a Hodge-type decomposition for the forward time-fractional parabolic Dirac operator with left Caputo fractional derivative in the time coordinate. The obtained results exhibit an interesting duality relation between forward and backward parabolic Dirac operators and Caputo and Riemann-Liouville time-fractional derivatives. We round off this paper by giving a direct application of the obtained results for solving time-fractional boundary value problems.The work of M. Ferreira, M.M. Rodrigues and N. Vieira was supported by Portuguese funds through CIDMA-Center for Research and Development in Mathematics and Applications, and FCT–Fundação para a Ciência e a Tecnologia, within project UID/MAT/04106/2019. The work of the authors was supported by the project New Function Theoretical Methods in Computational Electrodynamics / Neue funktionentheoretische Methoden für instationäre PDE, funded by Programme for Cooperation in Science between Portugal and Germany (“Programa de Ações Integradas Luso-Alemãs 2017” - DAAD-CRUP - Acção No. A-15/17 / DAAD-PPP Deutschland-Portugal, Ref: 57340281). N. Vieira was also supported by FCT via the FCT Researcher Program 2014 (Ref: IF/00271/2014).publishe

Seroprevalence of Toxoplasma gondii and Neospora spp. Infections in Arab Horses, Southwest of Iran

Background: Because of the economic importance of the Arab race horses and also the role of Toxoplasma gondii and Neospora spp. in abortion and reproductive failure of these animals, we decided to perform this study. Objectives: We designed this study to investigate the seroprevalence of anti-Toxoplasma gondii and anti-Neospora spp. antibodies in Arab horses from 12 cities of Khuzestan province in southwest of Iran. Materials and Methods: From October 2009 to March 2011, a total of 235 blood samples were collected from jugular veins of Arab horses of different ages and genders from 12 cities of Khuzestan province. All the sera were tested for anti-Toxoplasma antibodies using the modified agglutination test (MAT) and the existence of anti-Neospora antibodies were tested using N-MAT for Neospora spp. Results: According to the MAT results, antibodies to T. gondii were found in 114 (48.5%) of 235 sera with titers of 1:20 in 84, 1:40 in 19, 1:80 in four, 1:160 in four, and 1:320 in three horses. According to the N-MAT results, antibodies to Neospora spp. were found in 47 (20%) of 235 sera with titers of 1:40 in 39, 1:80 in five, and 1:160 in three horses. We did not observe any statistically significant differences regarding age groups and genders between seropositive and seronegative horses for Neospora spp. using chi-square (chi(2)) test, but it seemed that anti-Toxoplasma antibodies were more prevalent in older horses ( >= 10 years old). Conclusions: The results indicated that Arab horses are exposed to these parasites in southwest of Iran. Further research is required to determine the genomic structures of these parasites in Arab horses in southwest of Iran

Infection of the Central Nervous System, Sepsis and Amyotrophic Lateral Sclerosis

Severe infections may lead to chronic inflammation in the central nervous system (CNS) which may in turn play a role in the etiopathogenesis of amyotrophic lateral sclerosis (ALS). The relentless progression and invasive supportive treatments of ALS may on the other hand induce severe infections among ALS patients.The present study included 4,004 ALS patients identified from the Swedish Patient Register during 1991-2007 and 20,020 age and sex matched general population controls. Conditional logistic regression was used to estimate the odds ratios (ORs) of ALS given a previous hospitalization for CNS infection or sepsis. Cox models were used to estimate the hazard ratios (HRs) of hospitalization for CNS infection or sepsis after ALS diagnosis. Overall, previous CNS infection (OR: 1.3, 95% confidence interval [CI]: 0.8, 2.4) or sepsis (OR: 1.2, 95% CI: 0.9, 1.6) was not associated with ALS risk. However, compared to ALS free individuals, ALS cases were more likely to be hospitalized for sepsis after diagnosis (HR: 2.6, 95% CI: 1.9, 3.5). We did not observe a higher risk of CNS infection after ALS diagnosis.Our results suggest that acute and severe infections unlikely contribute to the development of ALS; however, ALS patients are at a higher risk of sepsis after diagnosis, compared to ALS free individuals

Heat Shock Proteins and Amateur Chaperones in Amyloid-Beta Accumulation and Clearance in Alzheimer’s Disease

The pathologic lesions of Alzheimer’s disease (AD) are characterized by accumulation of protein aggregates consisting of intracellular or extracellular misfolded proteins. The amyloid-β (Aβ) protein accumulates extracellularly in senile plaques and cerebral amyloid angiopathy, whereas the hyperphosphorylated tau protein accumulates intracellularly as neurofibrillary tangles. “Professional chaperones”, such as the heat shock protein family, have a function in the prevention of protein misfolding and subsequent aggregation. “Amateur” chaperones, such as apolipoproteins and heparan sulfate proteoglycans, bind amyloidogenic proteins and may affect their aggregation process. Professional and amateur chaperones not only colocalize with the pathological lesions of AD, but may also be involved in conformational changes of Aβ, and in the clearance of Aβ from the brain via phagocytosis or active transport across the blood–brain barrier. Thus, both professional and amateur chaperones may be involved in the aggregation, accumulation, persistence, and clearance of Aβ and tau and in other Aβ-associated reactions such as inflammation associated with AD lesions, and may, therefore, serve as potential targets for therapeutic intervention

Sustained Na⁺/H⁺ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation

Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na +/H+ exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1-5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na+ and Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1-24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H + homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na+ and Ca2+ homeostasis, which reduces Na+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI. © 2014 Cengiz et al

Ulcerogenic Helicobacter pylori Strains Isolated from Children: A Contribution to Get Insight into the Virulence of the Bacteria

Infection with Helicobacter pylori is the major cause for the development of peptic ulcer disease (PUD). In children, with no other etiology for the disease, this rare event occurs shortly after infection. In these young patients, habits of smoking, diet, consumption of alcohol and non-steroid anti-inflammatory drugs and stress, in addition to the genetic susceptibility of the patient, represent a minor influence. Accordingly, the virulence of the implicated H. pylori strain should play a crucial role in the development of PUD. Corroborating this, our in vitro infection assays comparing a pool of five H. pylori strains isolated from children with PUD to a pool of five other pediatric clinical isolates associated with non-ulcer dyspepsia (NUD) showed the greater ability of PUD strains to induce a marked decrease in the viability of gastric cells and to cause severe damage in the cells cytoskeleton as well as an impairment in the production/secretion of mucins. To uncover virulence features, we compared the proteome of these two groups of H. pylori strains. Two-dimensional gel electrophoresis followed by mass-spectrometry allowed us to detect 27 differentially expressed proteins between them. In addition to the presence of genes encoding well established virulence factors, namely cagA, vacAs1, oipA “on” status, homB and jhp562 genes, the pediatric ulcerogenic strains shared a proteome profile characterized by changes in the abundance of: motility-associated proteins, accounting for higher motility; antioxidant proteins, which may confer increased resistance to inflammation; and enzymes involved in key steps in the metabolism of glucose, amino acids and urea, which may be advantageous to face fluctuations of nutrients. In conclusion, the enhanced virulence of the pediatric ulcerogenic H. pylori strains may result from a synergy between their natural ability to better adapt to the hostile human stomach and the expression of the established virulence factors

Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency

Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2–4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT−/y (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT−/y mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT−/y mice showed increased average distance from the platform site. CrT−/y mice showed reduced novel object recognition and conditioned fear memory compared to CrT+/y. CrT−/y mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder

The conserved dileucine- and tyrosine-based motifs in MLV and MPMV envelope glycoproteins are both important to regulate a common Env intracellular trafficking

BACKGROUND: Retrovirus particles emerge from the assembly of two structural protein components, Gag that is translated as a soluble protein in the cytoplasm of the host cells, and Env, a type I transmembrane protein. Because both components are translated in different intracellular compartments, elucidating the mechanisms of retrovirus assembly thus requires the study of their intracellular trafficking. RESULTS: We used a CD25 (Tac) chimera-based approach to study the trafficking of Moloney murine leukemia virus and Mason-Pfizer monkey virus Env proteins. We found that the cytoplasmic tails (CTs) of both Env conserved two major signals that control a complex intracellular trafficking. A dileucine-based motif controls the sorting of the chimeras from the trans-Golgi network (TGN) toward endosomal compartments. Env proteins then follow a retrograde transport to the TGN due to the action of a tyrosine-based motif. Mutation of either motif induces the mis-localization of the chimeric proteins and both motifs are found to mediate interactions of the viral CTs with clathrin adaptors. CONCLUSION: This data reveals the unexpected complexity of the intracellular trafficking of retrovirus Env proteins that cycle between the TGN and endosomes. Given that Gag proteins hijack endosomal host proteins, our work suggests that the endosomal pathway may be used by retroviruses to ensure proper encountering of viral structural Gag and Env proteins in cells, an essential step of virus assembly