PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

• MeSH
• Child MeSH
• Adult MeSH
• Immunoglobulin G therapeutic use   MeSH
• Immunologic Factors therapeutic use   MeSH
• Immunoglobulins, Intravenous MeSH
• Humans MeSH
• Adolescent MeSH
• Infusions, Subcutaneous MeSH
• Immunologic Deficiency Syndromes * diagnosis   drug therapy   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

Parasitic nematodes transition between dramatically different free-living and parasitic stages, with correctly timed development and migration crucial to successful completion of their lifecycle. However little is known of the mechanisms controlling these transitions. microRNAs (miRNAs) negatively regulate gene expression post-transcriptionally and regulate development of diverse organisms. Here we used microarrays to determine the expression profile of miRNAs through development and in gut tissue of the pathogenic nematode Haemonchus contortus. Two miRNAs, mir-228 and mir-235, were enriched in infective L3 larvae, an arrested stage analogous to Caenorhabditis elegans dauer larvae. We hypothesized that these miRNAs may suppress development and maintain arrest. Consistent with this, inhibitors of these miRNAs promoted H. contortus development from L3 to L4 stage, while genetic deletion of C. elegans homologous miRNAs reduced dauer arrest. Epistasis studies with C. elegans daf-2 mutants showed that mir-228 and mir-235 synergise with FOXO transcription factor DAF-16 in the insulin signaling pathway. Target prediction suggests that these miRNAs suppress metabolic and transcription factor activity required for development. Our results provide novel insight into the expression and functions of specific miRNAs in regulating nematode development and identify miRNAs and their target genes as potential therapeutic targets to limit parasite survival within the host.

• MeSH
• Caenorhabditis elegans genetics   MeSH
• Cholestenes pharmacology   MeSH
• Gene Deletion MeSH
• Species Specificity MeSH
• Gene Ontology MeSH
• Haemonchus drug effects   genetics   growth & development   MeSH
• Larva MeSH
• RNA, Messenger genetics   metabolism   MeSH
• MicroRNAs biosynthesis   genetics   MeSH
• Caenorhabditis elegans Proteins genetics   MeSH
• Receptor, Insulin genetics   MeSH
• RNA, Helminth biosynthesis   genetics   MeSH
• Gene Expression Regulation, Developmental drug effects   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Cytokinins are phytohormones that are involved in many processes in plants, including growth, differentiation and leaf senescence. However, they also have various activities in animals. For example, kinetin and trans-zeatin can reduce levels of several aging markers in human fibroblasts. Kinetin can also protect mice against oxidative and glyoxidative stress, and prolong fruit flies' lifespan. Additionally, several cytokinins are currently used in cosmetics. To extend knowledge of the breadth of cytokinins' activities, we examined effects of natural cytokinin bases on the model nematode Caenorhabditis elegans. We found that kinetin, para-topolin and meta-topolin prolonged the lifespan of C. elegans. Kinetin also protected the organism against oxidative and heat stress. Furthermore, our results suggest that presence of reactive oxygen species, but not DAF-16 (the main effector of the insulin/insulin-like growth factor signaling pathway), is required for the beneficial effects of kinetin. Ultra-high performance liquid chromatography-tandem mass spectrometric analysis showed that kinetin is unlikely to occur naturally in C. elegans, but the worm efficiently absorbs and metabolizes it into kinetin riboside and kinetin riboside-5'-monophosphate.

• MeSH
• Caenorhabditis elegans drug effects   genetics   physiology   MeSH
• Cytokinins pharmacokinetics   pharmacology   MeSH
• Longevity drug effects   physiology   MeSH
• Forkhead Transcription Factors genetics   metabolism   MeSH
• Insulin metabolism   MeSH
• Kinetin pharmacokinetics   pharmacology   MeSH
• Mutation MeSH
• Oxidative Stress drug effects   MeSH
• Caenorhabditis elegans Proteins genetics   metabolism   MeSH
• Heat-Shock Response drug effects   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Plant Growth Regulators pharmacokinetics   pharmacology   MeSH
• Signal Transduction drug effects   MeSH
• Thermotolerance drug effects   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Aging is an unavoidable process characterized by gradual failure of homeostasis that constitutes a critical risk factor for several age-related disorders. It has been unveiled that manipulation of various key pathways may decelerate the aging progression and the triggering of age-related diseases. As a consequence, the identification of compounds, preferably natural-occurring, administered through diet, with lifespan-extending, anti-aggregation and anti-oxidation properties that in parallel exhibit negligible side-effects is the main goal in the battle against aging. Here we analyze the role of 2,3-dehydrosilybin A/B (DHS A/B), a minor component of silymarin used in a plethora of dietary supplements. This flavonolignan is well-known for its anti-oxidative and neuroprotective properties, among others. We demonstrate that DHS A/B confers oxidative stress resistance not only in human primary cells but also in the context of a multi-cellular aging model, namely Caenorhabditis elegans (C. elegans) where it also promotes lifespan extension. We reveal that these DHS A/B outcomes are FGT-1 and DAF-16 dependent. We additionally demonstrate the anti-aggregation properties of DHS A/B in human cells of nervous origin but also in nematode models of Alzheimer's disease (AD), eventually leading to decelerated progression of AD phenotype. Our results identify DHS A/B as the active component of silymarin extract and propose DHS A/B as a candidate anti-aging and anti-aggregation compound.

• MeSH
• Cell Line MeSH
• Caenorhabditis elegans MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Longevity drug effects   MeSH
• Cricetinae MeSH
• Humans MeSH
• Protective Agents pharmacology   MeSH
• Oxidative Stress MeSH
• Protein Aggregation, Pathological prevention & control   MeSH
• Drug Evaluation, Preclinical MeSH
• Caenorhabditis elegans Proteins metabolism   MeSH
• Glucose Transport Proteins, Facilitative metabolism   MeSH
• Silymarin pharmacology   MeSH
• Cell Survival drug effects   MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Německo-české jazykové srovnání stojí v centru zájmu různých akademických pracovišť v České republice i zahraničí. Z toho pramení mj. i potřeba platformy, jež by přispěla k výměně zkušeností a poznatků mezi jednotlivými badateli v této oblasti výzkumu. Cílem nové bibliografie je proto dokumentace kontrastivních analýz výše zmíněného jazykového páru, a to z perspektivy různých lingvistických disciplín, resp. z hlediska různých rovin popisu jazyka.; Německo-české jazykové srovnání stojí v centru zájmu různých akademických pracovišť v České republice i zahraničí.

The FOXO forkhead transcription factors are potent transcriptional activators involved in a wide range of key biological processes. In this work, the real-time kinetics of the interaction between the FOXO4-DNA binding domain (FOXO4-DBD) and the DNA was studied by using surface plasmon resonance (SPR). SPR analysis revealed that the interaction between FOXO4-DBD and the double stranded DNA containing either the insulin-responsive or the Daf-16 family member-binding element is preferably described by using a conformational change model which suggests a structural change of FOXO4-DBD upon binding to the DNA. This was further confirmed by using the time-resolved tryptophan fluorescence anisotropy decay measurements which revealed profound reduction of segmental dynamics of FOXO4-DBD upon the complex formation. Alanine scanning of amino acid residues engaged in polar contacts with the DNA showed that certain non-specific contacts with the DNA backbone are very important for both the binding affinity and the binding specificity of FOXO4-DBD.

• MeSH
• DNA chemistry   MeSH
• Kinetics MeSH
• Humans MeSH
• Models, Molecular MeSH
• Surface Plasmon Resonance MeSH
• Protein Structure, Tertiary MeSH
• Transcription Factors chemistry   MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Transcriptional Activation genetics   MeSH
• Caenorhabditis elegans chemistry   metabolism   MeSH
• Forkhead Transcription Factors genetics   metabolism   MeSH
• Caenorhabditis elegans Proteins genetics   metabolism   MeSH
• Receptors, Cytoplasmic and Nuclear physiology   genetics   MeSH
• Gene Expression Regulation genetics   MeSH
• Repressor Proteins physiology   genetics   MeSH

The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of α-tocopheryl succinate (α-TOS) on cancer cells identified a mechanism whereby α-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of α-TOS-treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by α-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to α-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by α-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments.

• MeSH
• alpha-Tocopherol pharmacology   MeSH
• Apoptosis physiology   MeSH
• Forkhead Transcription Factors genetics   metabolism   MeSH
• Transcription, Genetic MeSH
• Jurkat Cells MeSH
• Humans MeSH
• Lymphoma, T-Cell genetics   metabolism   pathology   therapy   MeSH
• RNA, Small Interfering administration & dosage   genetics   MeSH
• Cell Line, Tumor MeSH
• Lung Neoplasms genetics   metabolism   pathology   therapy   MeSH
• Carcinoma, Non-Small-Cell Lung genetics   metabolism   pathology   therapy   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Promoter Regions, Genetic MeSH
• Protein Serine-Threonine Kinases antagonists & inhibitors   genetics   metabolism   MeSH
• Proto-Oncogene Proteins c-bcl-2 biosynthesis   genetics   metabolism   MeSH
• Signal Transduction MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Pozitivní vliv zpožděné zpětné sluchové vazby na řeč koktavých je znám od roku 1951 (tzv. Lee-efekt podle jména objevitele, či DAF z anglického Delayed Auditory Feedback). Předpokládá se nesoulad mezi zpětnou proprioceptivní a sluchovou vazbou, který se právě vlivem zpožděné akustické aferentace vyrovnává. Jako optimální délka zpoždění se udává délka 55 ms, v naší studii jsme použili i zpoždění kratší (dříve totiž nebylo možné z technických důvodů tato zpoždění vyšetřovat). Náš soubor obsahoval 41 pacientů. Zjistili jsme, že u 16 pacientů (39 %) došlo ke zlepšení plynulosti řeči při délce zpoždění 55 ms, což je ve shodě s předchozími studiemi. U osmi pacientů (19 %) však došlo k výraznému zlepšení plynulosti řeči i pod vlivem délky zpoždění 40 ms, zejména pak ve skupině balbutiků do 15 let. Plynulost řeči tedy lze zlepšit i při užití zpoždění kratších než 55 ms. U 13 pacientů (32 %) byl zaznamenán pozitivní vliv až do délky zpoždění 110 ms a u čtyř pacientů jsme nezaznamenali zlepšení plynulosti řeči pod vlivem DAF. Zajímavé je, že ne vždy dochází ke shodě mezi subjektivním hodnocením samotného pacienta a hodnocením objektivním. Lee-efekt se využívá nejen k diagnostickým, ale i terapeutickým účelům.

Stuttering is a serious health and social problem, which is reflected in socialising processes and job opportunities. It is a generalised discoordinative disorder of muscle groups, that take part in motor realisation of speech. The prevalence in population differs according to various authors from 1 % to 3%, of which men prevail. The opinions on etiology and therapy differ a lot, causes can be either somatic, functional or psychogenic. A positive effect of delayed auditory feedback (DAF) on speech in stutterers has been known since 1951 (so called Lee effect, named after its discoverer). There is supposed to be a disharmony between proprioceptive and auditory feedback, which is corrected by delayed auditory feedback. The optimal interval of DAF should be 55 ms. Considering that the former technologies were not able to study shorter intervals, we focused our study on intervals shorter than 55 ms and we tried to find an optimal interval of DAF. Most of previous research studied the influence of DAF on reading. Considering that severity of fluency disorder is usually smaller when reading than in spontaneous speech, we decided to study the influence of DAF using description of standard pictures. Our group of patients consisted of 41 stutterers (35 women and 6 men), aged from 8 to 35, the mean age was 15 years. We found out that 16 patients (39%) improved in speech fluency under the influence of DAF with delay speed 55 ms, which is in good accord with previous studies. However, in 8 patients (19%) speech fluency was improved using delay speed 40 ms especially in patients aged up to 15 years.We proved then that speech fluency in stutterers can be improved by using intervals shorter than 55 ms. In 13 patients (32%) we observed positive effect from delay 110 ms, mostly in patients with severe form of stuttering. Four patients (10%) did not improve at all. Normal fluency under the influence of DAF was reached by 10 patients (24%) who had mild or medium stuttering. We also observed self evaluation of patients which is not always in accordance with objective evaluation. From the group of 23 patients the accordance was reached in 7 patients, another delay interval was subjectively more pleasant in 10 patients, for 5 patients DAF was not pleasant at all and one patient was not able to assess subjectively improving or worsening. We can use the positive effect of DAF in treatment. At present there exist not only large- sized devices using DAF but also miniature devices that look like behind the ear hearing aids.We usually use table devices as an aid during speech therapy.

• MeSH
• Acoustic Stimulation MeSH
• Stuttering classification   therapy   MeSH
• Humans MeSH
• Prospective Studies MeSH
• Feedback MeSH
• Check Tag
• Humans MeSH