ABSTRACT
The program code developed by others is appropriately cited in the text and listed in the references section. The raw and processed data on which study conclusions are based are not available. The statistical syntax needed to reproduce analyses in the article is available upon request. The methods section provides references for the materials described therein. We report how we determined our sample size, all data exclusions, all manipulations, and all measures in the study, and we follow APA Style Journal Article Reporting Standards. This study's design, hypotheses, and data analytic plan were not pre-registered. Prior research supports the need for elementary-aged students with reading difficulties (RD) to receive explicit systematic small group evidence-based reading instruction. Yet for many students, simply receiving an evidence-based reading instruction in a small group setting is insufficient to reach the progress milestones needed to meet grade level reading standards. The current study examined whether: (1) elementary school students with RD constitute a homogeneous or heterogeneous groups when considering their basic language and cognitive skills (using a latent profile analysis), and (2) if latent profiles are predictive of response to reading comprehension instruction (using a mixed modeling approach). The sample consisted of 335 students, including students with RD and typical students (n = 57). The results revealed heterogeneity within students with RD - there were two distinct profiles, with one having higher basic language (reading fluency and decoding) and cognitive (verbal domain productivity, cognitive flexibility, working memory) skills and lower attention skills, and the other having stronger attention skills and lower basic language and cognitive skills. The findings also suggested that latent profiles were predictive of response to reading comprehension instruction. Our results provide a convincing argument for leading the field in the direction of developing customized interventions. It is conceivable, but remains to be further examined, that researchers and educators could potentially improve reading outcomes through providing a customized reading intervention to a student based on their cognitive-language profile.
ABSTRACT
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of 15N- and 15N,13C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
Subject(s)
Aziridines , Protein Disulfide-Isomerases , Sulfonamides , Humans , Aziridines/pharmacology , Protein Disulfide-Isomerases/antagonists & inhibitors , Protein Disulfide-Isomerases/chemistry , Sulfonamides/pharmacologyABSTRACT
AIM: Monogenic diabetes (MD) represents 5-7% of antibody-negative diabetes cases and is a heterogeneous group of disorders. METHODS: We used targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay to perform genetic and clinical characteristics of a study group of 684 individuals, including 542 patients referred from 12 Polish Diabetes Centers with suspected MD diagnosed between December 2016 and December 2019 and their 142 family members (FM). RESULTS: In 198 probands (36.5%) and 66 FM (46.5%) heterozygous causative variants were confirmed in 11 different MD-related genes, including 31 novel mutations, with the highest number in the GCK gene (206/264), 22/264 in the HNF1A gene and 8/264 in the KCNJ11 gene. Of the 183 probands with MODY1-5 diabetes, 48.6% of them were diagnosed at the pre-diabetes stage and most of them (68.7%) were on diet only at the time of genetic diagnosis, while 31.3% were additionally treated with oral hypoglycaemic drugs and/or insulin. CONCLUSIONS: In summary, the results obtained confirm the efficacy of targeted NGS method in the molecular diagnosis of patients with suspected MD and broaden the spectrum of new causal variants, while updating our knowledge of the clinical features of patients defined as having MD.
Subject(s)
Diabetes Mellitus, Type 2 , High-Throughput Nucleotide Sequencing , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Genetic Testing , Health Services , Humans , MutationABSTRACT
The present study attempted to elucidate possible routes leading to the achievement of sero- positive results, among young (aged ≤1 year) wild boar population. In the years 2017-2018, the National Reference Laboratory (NRL) for African swine fever (ASF) in Poland examined nearly 27-thousand wild boar blood samples, collected during an active surveillance of ASF risk zones, for the presence of viral DNA and anti-ASFV antibodies. Out of all the examined samples, 420 were positive. However, in more than half of them (292 samples) antibodies against African swine fever virus (ASFV) were detected, while ASFV DNA was not detected in blood. Out of all 292 seropositive/PCR-negative samples, 126 belonged to young wild boars (aged ≤1 year). For this reason, the NRL in Poland has examined 10 selected seropositive wild boar carcasses to confirm or exclude post-mortem lesions for ASF as well as to investigate the presence of viral DNA in the internal organs. Neither pathological lesions for ASF nor the presence of genetic material of ASFV were found in the examined wild boars. To elucidate this outcomes, following hypotheses about possible reasons of the obtained results were drawn: the presence of convalescent animals, infection of low-virulent ASFV isolate and the vertical transmission of antibodies through the colostrum.
Subject(s)
African Swine Fever/blood , Infectious Disease Transmission, Vertical , Sus scrofa , African Swine Fever/epidemiology , African Swine Fever Virus/immunology , Animals , Antibodies, Viral/blood , Female , Male , Poland/epidemiology , Pregnancy , Seroepidemiologic Studies , SwineABSTRACT
Four commercial disinfectants were chosen for being generally accepted as effective against ASFV. Only two of them, based on sodium hypochlorite and potassium peroxymonosulfate, confirmed their effectiveness in selected concentrations. Taken together, our data supports the effectivenes of chemical disinfectants containing sodium hypochlorite (1%, 0.5% in low level soiling) and potassium peroxymonosulfate (1% in high level soiling). Furthermore, these results highlight the importance of pre-cleaning steps to remove soiling before proper disinfection which improves the effectiveness of tested disinfectants.
Subject(s)
African Swine Fever Virus/drug effects , Disinfectants/pharmacology , FomitesABSTRACT
A plethora of studies have suggested the involvement of various eicosanoids in heart failure. The aim of this study was to profile eicosanoid release from isolated murine heart at transition and end-stage phases of heart failure (HF) in Tgαq*44 mice as compared with age-matched wild-type FVB mice. Using an UPLC-MS/MS-based method, the concentration of selected eicosanoids was measured in cardiac effluents collected from isolated perfused mice hearts according to the Langendorff technique in Tgαq*44 and FVB mice (8- and 12-month-old) in basal conditions and in response to bolus injection of arachidonic acid (AA), a major substrate for eicosanoids. In basal conditions, only some eicosanoids were detected in the coronary effluents, with 6-keto-PGF1α, PGD2, 12-HETE detected at the highest concentration. In response to AA, a wide range of its metabolites was detected, including not only prostanoids and HETEs, but also EETs and DHETs. Cardiac production of 6-keto-PGF1α, PGD2, PGE2, PGF2α, TXB2 in basal conditions was unchanged at the transition phase of HF, whereas it was increased at the end-stage of disease in Tgαq*44 mice as compared with age-matched FVB mice. In response to AA, the synthesis of PGE2, 12-, 15-HETEs, 8,9-, 11,12-DHETs were also elevated at the end-stage phase of HF in Tgαq*44 mice as compared to healthy animals. AA-induced vasodilation effect was greater at the end-stage phase of HF in Tgαq*44 mice as compared with age-matched FVB mice, but it was not changed at the transition phase of the disease. In conclusion, eicosanoid profiling in isolated perfused heart pointed to PGI2, PGD2 and 12-HETE as the most abundant AA metabolites of the isolated murine heart. In Tgαq*44 mice, the end-stage phase of heart failure was accompanied by major activation of cyclooxygenase pathways (PGI2, TXA2, PGD2, PGE2, PGF2α), 8,9-, 11,12-EET/DHETs pathways and 12-, 15-HETEs pathways in the heart.
Subject(s)
Eicosanoids/metabolism , Heart Failure/metabolism , Myocardium/metabolism , Animals , Chromatography, High Pressure Liquid , Chronic Disease , Mice , Prostaglandin-Endoperoxide Synthases/metabolism , Tandem Mass SpectrometryABSTRACT
Alzheimer's Disease (AD) is the most common cause of dementia in the elderly. Centenarians - reaching the age of >100 years while maintaining good cognitive skills - seemingly have unique biological features allowing healthy aging and protection from dementia. Here, we studied the expression of SIRT1 along with miR-132 and miR-212, two microRNAs known to regulate SIRT1, in lymphoblastoid cell lines (LCLs) from 45 healthy donors aged 21 to 105 years and 24 AD patients, and in postmortem olfactory bulb and hippocampus tissues from 14 AD patients and 20 age-matched non-demented individuals. We observed 4.0-fold (P = 0.001) lower expression of SIRT1, and correspondingly higher expression of miR-132 (1.7-fold; P = 0.014) and miR-212 (2.1-fold; P = 0.036), in LCLs from AD patients compared with age-matched healthy controls. Additionally, SIRT1 expression was 2.2-fold (P = 0.001) higher in centenarian LCLs compared with LCLs from individuals aged 56-82 years; while centenarian LCLs miR-132 and miR-212 indicated 7.6-fold and 4.1-fold lower expression, respectively. Correlations of SIRT1, miR-132 and miR-212 expression with cognitive scores were observed for AD patient-derived LCLs and postmortem AD olfactory bulb and hippocampus tissues, suggesting that higher SIRT1 expression, possibly mediated by lower miR-132 and miR-212, may protect aged individuals from dementia and is reflected in their peripheral tissues.
Subject(s)
Alzheimer Disease/pathology , Longevity/genetics , MicroRNAs/metabolism , Sirtuin 1/metabolism , Adult , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , Case-Control Studies , Female , Hippocampus/metabolism , Humans , Male , Middle Aged , Olfactory Bulb/metabolism , Young AdultABSTRACT
The role of nitric oxide (NO) in tumour progression and metastasis is not clear, therefore the present work aimed to better characterise the effects of nitric oxide synthase (NOS) inhibition by L-Nω-nitroarginine methyl ester (L-NAME) on primary tumour growth, pulmonary metastasis, inflammatory state and prostacyclin (PGI2)/thromboxane A2 (TXA2) balance in a 4T1 murine model of breast cancer. To distinguish effects of NO deficiency on disease development, 4T1 cancer cells were administered orthotopically or intravenously to Balb/c mice. The systemic NO bioavailability, pulmonary inflammation and plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were assessed. The study shows that, in the orthotopic model of 4T1 breast cancer, L-NAME hampered primary tumour growth, reduced pulmonary metastases, delayed inflammatory response but did not alter biosynthesis of TXB2 and 6-keto-PGF1α as well as PGI2/TXA2 ratio in cancer-bearing mice. Interestingly, in the intravenous model of 4T1 breast cancer, NOS inhibition did not influence metastasis nor inflammation, but it increased both TXB2 and 6-keto-PGF1α biosynthesis without affecting PGI2/TXA2 ratio. In conclusion, in a 4T1 murine model of metastatic breast cancer, NO plays a major role in primary tumour development, while NO is not the key mediator of cancer cell extravasation to the lungs. Furthermore, NO-deficiency activates a PGI2-dependent compensatory mechanism only in the intravenous model of 4T1 breast cancer.
Subject(s)
Breast Neoplasms/pathology , Lung Neoplasms/pathology , Nitric Oxide Synthase/metabolism , Nitric Oxide/deficiency , Animals , Disease Models, Animal , Disease Progression , Epoprostenol/metabolism , Female , Lung Neoplasms/secondary , Mice , Mice, Inbred BALB C , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Thromboxane A2/metabolism , Thromboxane B2/bloodABSTRACT
OBJECTIVE: Targeting understanding enhanced osseointegration kinetics, the goal of this study was to characterize the surface morphology and composition of Ti and TiZr dental implant substrates subjected to one of two surface treatments developed by Straumann. These two treatments are typically known as SLA and SLActive, with the latter resulting in more rapid osseointegration. METHODS: A range of techniques was applied to characterize four different substrate/surface treatment combinations (TiSLA, TiSLActive, TiZrSLA, and TiZrSLActive). Contact angle measurements established their hydrophilic/hydrophobic nature. Surface morphology was probed with scanning electron microscopy. X-ray diffraction, Raman µ-spectroscopy, and X-ray photoelectron spectroscopy were used to elucidate the composition of the near-surface region. RESULTS: Consistent with previous work, surface morphology was found to differ only at the nanoscale, with both SLActive substrates displaying nano-protrusions. Spectroscopic data indicate that all substrates exhibit surface films of titanium oxide displaying near TiO2 stoichiometry. Raman µ-spectroscopy reveals that amorphous TiO2 is most likely the only phase present on TiSLA, whilst rutile-TiO2 is also evidenced on TiSLActive, TiZrSLA, and TiZrSLActive. For TiZr alloy substrates, there is no evidence of discrete phases of oxidized Zr. X-ray photoelectron spectra demonstrate that all samples are terminated by adventitious carbon, with it being somewhat thicker (â¼1nm) on TiSLA and TiZrSLA. SIGNIFICANCE: Given previous in vivo studies, acquired data suggest that both nanoscale protrusions, and a thinner layer of adventitious carbon contribute to the more rapid osseointegration of SLActive dental implants. Composition of the surface oxide layer is apparently less important in determining osseointegration kinetics.
Subject(s)
Dental Implants , Osseointegration , Titanium , Dental Materials , Microscopy, Electron, Scanning , Photoelectron Spectroscopy , Surface PropertiesABSTRACT
A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.
Subject(s)
Amino Alcohols/pharmacology , Anticonvulsants/chemistry , Anticonvulsants/pharmacology , Drug Design , Epilepsy/drug therapy , Amino Alcohols/administration & dosage , Amino Alcohols/chemistry , Animals , Anticonvulsants/administration & dosage , Anticonvulsants/chemical synthesis , Chemistry, Physical , Dose-Response Relationship, Drug , Epilepsy/chemically induced , Male , Mice , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , PilocarpineABSTRACT
Marine sediments from the North Pacific document two episodes of expansion and strengthening of the subsurface oxygen minimum zone (OMZ) accompanied by seafloor hypoxia during the last deglacial transition. The mechanisms driving this hypoxia remain under debate. We present a new high-resolution alkenone palaeotemperature reconstruction from the Gulf of Alaska that reveals two abrupt warming events of 4-5 degrees Celsius at the onset of the Bølling and Holocene intervals that coincide with sudden shifts to hypoxia at intermediate depths. The presence of diatomaceous laminations and hypoxia-tolerant benthic foraminiferal species, peaks in redox-sensitive trace metals, and enhanced (15)N/(14)N ratio of organic matter, collectively suggest association with high export production. A decrease in (18)O/(16)O values of benthic foraminifera accompanying the most severe deoxygenation event indicates subsurface warming of up to about 2 degrees Celsius. We infer that abrupt warming triggered expansion of the North Pacific OMZ through reduced oxygen solubility and increased marine productivity via physiological effects; following initiation of hypoxia, remobilization of iron from hypoxic sediments could have provided a positive feedback on ocean deoxygenation through increased nutrient utilization and carbon export. Such a biogeochemical amplification process implies high sensitivity of OMZ expansion to warming.
Subject(s)
Global Warming/history , Ice Cover , Oxygen/analysis , Seawater/chemistry , Alaska , Aquatic Organisms/metabolism , Carbon/metabolism , Diatoms/metabolism , Feedback , Foraminifera/metabolism , Geologic Sediments/chemistry , History, Ancient , Oxygen/chemistry , Oxygen/metabolism , Pacific Ocean , Solubility , TemperatureABSTRACT
OBJECTIVE: Widespread hypovitaminosis D and an increased incidence of metabolic syndrome (MetS) represent significant problems of contemporary medicine but link between them remain unresolved. We aimed to define relationship between vitamin D serum concentration and exponents of MetS. PATIENTS AND METHODS: The studies were conducted on 70 individuals (51 with and 19 without MetS). Concentrations of 25(OH)D (25-hydroxyergocalciferol and 25-hydroxycholecalciferol), calcium, cholesterol, HDL, cholesterol LDL, triglycerides, fasting glucose, blood pressure and anthropometric parameters were measured. RESULTS: Median concentration of vitamin D in the research population amounted to 41.46 nmol/L. Concentration of 25(OH)D in MetS group was lower than in remainder participants (38.45 nmol/L vs. 58.50 nmol/L, p = 0.0104). An inverse correlation was demonstrated between 25(OH)D level on one hand and body weight, waist and hips circumference, adipose body weight, Body Mass Index, Waist to Height Ratio (WHtR), glycaemia and number of MetS components on the other in persons free of MetS. No such relationships could be documented in MetS group. In the entire population values of Waist to Hip Ratio (WHpR) and WHtR indices manifested correlation with hyperglycaemia, hypertriglyceridaemia, low HDL concentrations. CONCLUSIONS: In persons without MetS a relationship was detected between vitamin D concentration and exponents of metabolic syndrome, although further studies on this problem are required.
Subject(s)
Metabolic Syndrome/blood , Metabolic Syndrome/diagnosis , Vitamin D Deficiency/blood , Vitamin D Deficiency/diagnosis , Vitamin D/blood , Adiposity/physiology , Adult , Blood Glucose/metabolism , Body Weight/physiology , Cholesterol, LDL/blood , Cross-Sectional Studies , Fasting/blood , Female , Humans , Male , Metabolic Syndrome/epidemiology , Middle Aged , Risk Factors , Vitamin D Deficiency/epidemiologyABSTRACT
We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34(+)-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD.
Subject(s)
Cell Cycle/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Hematopoietic Stem Cells/drug effects , Hormone Replacement Therapy , Human Growth Hormone/deficiency , Human Growth Hormone/pharmacology , Adolescent , Child , Child, Preschool , Gene Expression/drug effects , Gene Expression Profiling , Human Growth Hormone/administration & dosage , Humans , Insulin-Like Growth Factor I/drug effects , Receptors, Somatotropin/drug effectsABSTRACT
Cellular immunity against cancer can be achieved with viral vector- and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously demonstrated that the relatively low intrinsic immunogenicity of DNA vaccines could be enhanced by inclusion of endoplasmic reticulum (ER) targeting and universal helper epitopes within the vaccine. We now evaluated whether an optimal antigen format, as defined in DNA vaccines, can further enhance the effectiveness of recombinant Semliki Forest virus (rSFV) vaccines. To this purpose, we generated, characterized and evaluated the efficacy of rSFV replicon particles expressing human papillomavirus E6 and/or E7 proteins fused to several helper T-cell epitopes and an ER targeting signal. Here, we show that inclusion of a helper cassette and an ER targeting signal enhanced protein stability and markedly augmented the frequencies of human papillomavirus-specific T cells. Even at an immunization dose of as low as 10(5) replicon particles, this novel vaccine achieved tumor regression and protection. Thus, even highly effective viral vector vaccines can benefit from an improved antigen format, based on the inclusion of defined helper epitopes and ER targeting.
Subject(s)
Antigens, Viral/immunology , Cancer Vaccines/immunology , Oncogene Proteins, Viral/immunology , Papillomavirus E7 Proteins/immunology , Papillomavirus Vaccines/immunology , Animals , Antigens, Viral/administration & dosage , Antigens, Viral/genetics , Cancer Vaccines/administration & dosage , Cricetinae , Epitopes, T-Lymphocyte/chemistry , Female , Humans , Kidney/cytology , Mice, Inbred C57BL , Oncogene Proteins, Viral/administration & dosage , Oncogene Proteins, Viral/genetics , Oncogene Proteins, Viral/metabolism , Papillomavirus E7 Proteins/administration & dosage , Papillomavirus E7 Proteins/genetics , Papillomavirus E7 Proteins/metabolism , Papillomavirus Vaccines/genetics , Papillomavirus Vaccines/metabolism , Semliki forest virus/genetics , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Uterine Cervical Neoplasms/prevention & control , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunologyABSTRACT
A convenient procedure has been developed for the determination of dissociation constants (pKa) and partition (log P) and distribution (log D) coefficients of three new aminopropan-2-ol derivatives with beta-adrenolytic activity briefly called 2F109, ANBL and TWo8. The apparent acid dissociation constant (psKa) in these water-insoluble compounds was determined potentiometrically in dimethylformamide-water, dimethyl sulfoxide-water and methanol-water mixtures at a temperature of 25 degrees C. The aqueous pKa values assessed by Yasuda-Shedlovsky extrapolation were 8.64 +/- 0.06, 8.85 +/- 0.51 and 8.26 +/- 0.45 for 2F109, ANBL and TWo8, respectively. Lipophilicity expressed by chromatographic retention factor was determined by reversed phase liquid chromatography at pH 10.5 using a Zorbax Extend C18 column (log k10.5), and at pH 7.4 using an immobilized artificial membrane IAM.PC.DD2 column (log k7.4), respectively. The log k of each compound extrapolated to 100% aqueous phase (log kw10.5 and and log kw7.4) were corrected with log P and log D of acebutolol, atenolol, metoprolol,pindolol, propranolol and sotalol used as the model drugs.
Subject(s)
Adrenergic beta-Antagonists/chemistry , Adrenergic beta-Antagonists/pharmacokinetics , Propanolamines/chemistry , Propanolamines/pharmacokinetics , Adrenergic beta-Antagonists/pharmacology , Algorithms , Chromatography, High Pressure Liquid , Indicators and Reagents , Lipids/chemistry , Potentiometry , Propanolamines/pharmacology , SolventsABSTRACT
The research objective was to determine the activity of microorganisms in the soil exposed to direct influence of a landfill, as well as in the soil beyond its influence. Fluorescein diacetate (FDA) hydrolytic activity and respiration in the soil were determined. The highest number of cultivated bacteria was recorded at the site located within the zone of direct influence exerted by the landfill, whereas the least amount was found at a distance of 1000 metres from the landfill. In contrast, the largest numbers of molds were observed in the soil at a distance of 1000 m from the headquarters of the landfill. The highest FDA hydrolytic activity and biological oxygen demand (BOD5) were recorded in the soil by the headquarters of the landfill, and the least parameters were revealed at a distance of 1000 m from the landfill. It was found a high correlation between the number of bacteria and FDA hydrolytic activity of soil and BOD5 in the north-eastern of the landfill. However, in the same place, there is a low correlation between the number of molds, and FDA hydrolytic activity of soil and BOD5.
Subject(s)
Bacteria/growth & development , Fungi/physiology , Soil Microbiology , Soil/analysis , Bacterial Load , Biological Oxygen Demand Analysis , Fluoresceins , Hazardous Waste , Poland , Refuse Disposal , Spectrometry, FluorescenceABSTRACT
We examined the relationship between maternal reproductive history and the newborn's risk of isolated congenital malformations in a large case-control cohort from the Polish Registry of Congenital Malformations. Congenital malformations were classified into four categories: isolated congenital heart defects (n=1673), isolated cleft palate (n=255), cleft lip with or without cleft palate (n=448) and renal agenesis (n=103). The case groups were compared with a shared group of 2068 controls recruited in the same time period and geographic area. Multivariable logistic regression was used to assess the risk associated with maternal gravidity and of previous miscarriages after accounting for maternal age and other potential risk factors. In unadjusted analyses, maternal gravidity was significantly associated with increased risk of all four classes of congenital malformations. After adjustment, a significant association persisted for congenital heart defects [odds ratio (OR)=1.22, [95% confidence interval (CI) 1.09, 1.36], P=0.0007] and cleft lip with or without cleft palate (OR=1.21, [95% CI 1.09, 1.36], P=0.0005). A similar trend existed for isolated cleft palate (OR=1.18, [95% CI 1.02, 1.37], P=0.03). There was no appreciable increase in the risk of congenital malformations associated with a maternal history of miscarriages, but a trend for a protective effect on the occurrence of cleft lip with or without cleft palate was observed (OR=0.72, [95% CI 0.52, 0.99], P=0.045). Based on our data, maternal gravidity represents a significant risk factor for congenital heart defects and cleft lip with or without cleft palate in the newborn infant. Our data do not support an increase in risk because of past history of miscarriages.
Subject(s)
Cleft Lip/etiology , Cleft Palate/etiology , Congenital Abnormalities/etiology , Gravidity , Heart Defects, Congenital/etiology , Adult , Case-Control Studies , Cleft Lip/epidemiology , Cleft Palate/epidemiology , Cohort Studies , Congenital Abnormalities/epidemiology , Female , Heart Defects, Congenital/epidemiology , Humans , Infant , Infant, Newborn , Kidney/abnormalities , Kidney Diseases/congenital , Logistic Models , Male , Maternal Age , Odds Ratio , Poland/epidemiology , Pregnancy , Reproductive History , Risk Factors , Young AdultABSTRACT
AIM: This phase III clinical study in growth hormone deficiency (GHD) children with growth retardation was designed to compare efficacy and safety of Omnitrope((R)) with Genotropin((R)) and assess the long-term safety and efficacy of Omnitrope((R)). The results of 7 years of treatment with Omnitrope((R)) are presented. PATIENTS AND METHODS: Eighty-nine treatment-naïve, prepubertal children with GHD were randomized (part 1) to Omnitrope((R)) lyophilisate (group A, n = 44) or Genotropin((R)) (group B, n = 45) for 9 months and received a subcutaneous dose of 0.03 mg/kg/day. In part 2, patients receiving Omnitrope((R))lyophilisate continued the same treatment for a further 6 months, while patients on Genotropin((R)) were switched to Omnitrope((R)) liquid for the subsequent 6 months. In part 3, patients in both groups received Omnitrope((R))liquid for a period up to 69 months. RESULTS: The development of the 4 auxological parameters (height, height SD score, height velocity and height velocity SD score) and IGF-1 and IGFBP-3 levels were comparable between both groups of patients and confirmed the well-known growth response of GHD children to recombinant human GH treatment. Omnitrope((R)) was well tolerated and safe over 7 years of treatment. CONCLUSION: The clinical comparability between Omnitrope((R)) and Genotropin((R)) was demonstrated within 9 months of treatment. Long-term safety and efficacy of 7 years of treatment with Omnitrope((R)) was proven.
Subject(s)
Growth Disorders/drug therapy , Human Growth Hormone/deficiency , Human Growth Hormone/therapeutic use , Adolescent , Body Height/drug effects , Child , Child, Preschool , Female , Growth Disorders/blood , Growth Disorders/pathology , Human Growth Hormone/administration & dosage , Human Growth Hormone/adverse effects , Humans , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor Binding Proteins/blood , Insulin-Like Growth Factor I/metabolism , Male , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Treatment Outcome , Weight Gain/drug effectsABSTRACT
No reports are available about the course of pregnancies in women with tetrahydrobiopterin (BH(4)) deficiencies or the effects of treatment with BH(4), L-dopa/carbidopa and 5-hydroxytryptophan (5-OHTrp) on fetal development. We present for the first time the case of a mother with late-diagnosed mild form of 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the course of her two subsequent pregnancies and clinical evaluation with follow-up of two offspring. In both pregnancies neurotransmitter precursors, as well as BH(4) dosages were increased proportionally to the mother's weight gain. To prevent maternal phenylketonuria (MPKU) syndrome, special attention was paid to increasing BH(4) dosages. Both pregnancies were complicated by threatened premature labour, by the mother's nicotinism and additionally, in the first pregnancy, by gestational diabetes mellitus and vaginitis. The first child was born in the 31st week of pregnancy with the symptoms of moderate intrauterine growth retardation (IUGR) and brain malformation in the form of right sided closed-lip schizencephaly with absence of septum pellucidum. Although the girl demonstrates mild left-sided hemiparesis, her psychological development at the age of 8 years is above average. The second child was born in the 37th week of pregnancy without brain anomalies and at the age of 5 years his psychomotor development is appropriate for the age. As the cause of brain malformations resulting in physical impairment in the first child is unknown, more data are essential to verify conclusions about the influence of the mother's BH(4) deficiency and the safety of her treatment for fetal development.
Subject(s)
Phenylketonurias/complications , Phosphorus-Oxygen Lyases/deficiency , Pregnancy Complications/enzymology , Adolescent , Biopterins/analogs & derivatives , Biopterins/deficiency , Biopterins/therapeutic use , Child , Child, Preschool , Delayed Diagnosis , Female , Humans , Infant, Newborn , Male , Phenylketonurias/diagnosis , Phenylketonurias/drug therapy , Phenylketonurias/enzymology , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Outcome , Young AdultABSTRACT
Studies on mixed chimerism are currently focused primarily on obtaining less toxic conditioning protocols. With these issues in mind, we have undertaken the attempt to optimize the procedure of mixed chimerism induction in mice. In order to reduce toxicity, we used decreasing doses of total body irradiation (TBI) together with combination of blocking antibodies. We also tried to eliminate immunosuppression (cyclophosphamide - CP) treatment after bone marrow transplantation. B6.SJL-PtprcaPep3b mice were injected with 20-30 x 106 bone marrow cells from Balb C mice. Mice were treated with TBI (3 - 1.5 - 0 Gy) on "-1" day of the experiment and blocking antibodies against CD40L ("0", and "4" days) and additionally anti-CD8 ("-2" day) and/or anti-NK1.1 ("-3" day). Mice in certain groups also received CP (175 mg/kg) on "2" day. Presence of mixed chimerism was assessed in peripheral blood cells by flow cytometry on the 1st, 2nd, 3rd, 4th, 6th and 8th weeks of the experiment by detecting of CD45.1 (characteristic for B6.SJL-PtprcaPep3b strain) and CD45.2 (characteristic for Balb C strain) antigens expression. We also analyzed the percentage of peripheral blood CD8 T-cells (CD3e/CD8a) and NK cells (Ly-49D/NK1.1). We found that reduction of TBI dose and elimination of CP decrease the rate of mixed chimerism formation. The highest percentage of donor cells was obtained in the group of animals treated with 3 Gy of TBI, CP and combination of anti-CD40L, anti-CD8, and anti-NK1.1 antibodies. The 3 Gy TBI was necessary to induce stable mixed chimerism, but it could be obtained without the CP use. The percentage of CD3e/CD8a and Ly-49D/NK1.1 cells was significantly lower in the groups of mice treated by corresponding antibodies. Moreover, we observed the lowest number of peripheral blood Ly-49D/NK1.1 cells in the group of animals with highest mixed chimerism. Our experiments in mice model can help in better understanding of mixed chimerism phenomenon and in selecting the method of mixed chimerism induction with lowest possible toxicity. This also might improve the protocols of stable mixed chimerism induction in humans, and in the future, the effectiveness of vascularized organ transplantation.