ABSTRACT
With the introduction of the latest class of biologic drugs targeting interleukin (IL)-23p19, three new, highly effective drugs can be used for the treatment of chronic plaque psoriasis. However, poorer skin improvement as well as higher rates of serious adverse events have been reported for patients under real-world conditions (outside clinical trials). This accounts especially for patients who have already been treated with biologic drugs. We therefore aimed to determine effectiveness and safety of IL-23p19 inhibitors in real-world patients by analysing data from the Psoriasis Registry Austria (PsoRA) in this observational, retrospective, multicentre cohort study. Data for 197 patients (52.3% biologic-non-naïve), who were treated with anti-IL-23p19 antibodies (127 guselkumab, 55 risankizumab and 15 tildrakizumab) for at least 3 months, were eligible for analysis. In general, biologic-non-naïve patients displayed a less favourable response to anti-IL-23 treatment as compared to biologic-naïve patients. However, after correction for previous biologic exposure, few differences in PASI improvement were detected among biologic-naïve and -non-naïve patients treated with different IL-23p19 inhibitors. This indicates that treatment effectiveness is not related to the class of the previously administered therapy in biologic-non-naïve patients. Therefore, IL-23p19 inhibitors represent a promising treatment alternative for patients who have not responded to previous biologics. However, as with other biologic agents (including IL-17 inhibitors), we did not observe an entirely satisfactory treatment response (i.e. PASI < 3 and/or PASI 75) to anti-IL-23 treatment in one out of four to five patients. Adverse events (mainly non-severe infections) were observed in 23 (11.7%) patients with no major differences regarding the administered IL-23 inhibitor or previous biologic exposure.
Subject(s)
Biological Products , Graft vs Host Disease , Psoriasis , Austria/epidemiology , Biological Products/therapeutic use , Cohort Studies , Graft vs Host Disease/drug therapy , Humans , Interleukin-23 , Psoriasis/drug therapy , Registries , Retrospective Studies , Severity of Illness Index , Treatment OutcomeABSTRACT
BACKGROUND: The ongoing global SARS-CoV-2 pandemic has caused over 4.7 million infections greatly challenging healthcare workers (HCW) and medical institutions worldwide. The SARS-CoV-2 pandemic has shown to significantly impact mental and physical health of HCW. Thus, implementation of testing facilities supporting HCW are urgently needed. METHODS: A low-threshold SARS-CoV-2 testing facility was introduced at the University Hospital Bonn, Germany, in March 2020. Irrespective of clinical symptoms employees were offered a voluntary and free SARS-CoV-2 test. Furthermore, employees returning from SARS-CoV-2 risk regions and employees after risk contact with SARS-CoV-2 infected patients or employees were tested for SARS-CoV-2 infection. Pharyngeal swabs were taken and reverse transcription polymerase chain reaction for detection of SARS-CoV-2 was performed, test results being available within 24 h. Profession, symptoms and reason for SARS-CoV-2 testing of employees were recorded. RESULTS: Between 9th March and April 30, 2020, a total of 1510 employees were tested for SARS-CoV-2 infection. 1185 employees took advantage of the low-threshold testing facility. One percent (n = 11) were tested positive for SARS-CoV-2 infection, 18% being asymptomatic, 36% showing mild and 36% moderate/severe symptoms (missing 10%). Furthermore, of 56 employees returning from SARS-CoV-2 risk regions, 18% (10/56) were tested SARS-CoV-2 positive. After risk contact tracking by the hospital hygiene 6 patient-to-employee transmissions were identified in 163 employees with contact to 55 SARS-CoV-2 positive patients. CONCLUSION: In the absence of easily accessible public SARS-CoV-2 testing facilities low-threshold SARS-CoV-2 testing facilities in hospitals with rapid testing resources help to identify SARS-CoV-2 infected employees with absent or mild symptoms, thus stopping the spread of infection in vulnerable hospital environments. High levels of professional infection prevention training and implementation of specialized wards as well as a perfectly working hospital hygiene network identifying and tracking risk contacts are of great importance in a pandemic setting.
Subject(s)
COVID-19 Testing , COVID-19/diagnosis , COVID-19/epidemiology , Disease Outbreaks/prevention & control , Hospitals, University , Personnel, Hospital , SARS-CoV-2 , Adult , Female , Germany , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Drug survival rates reflect efficacy and safety and may be influenced by the availability of alternative treatment options. Little is known about time-dependent drug survival in psoriasis and the effect of increasing numbers of biologic treatment options. OBJECTIVES: To determine whether drug survival is influenced by the availability of treatment options and by factors such as gender, psoriatic arthritis or previous biologic treatment. METHODS: This observational, retrospective, multicentre cohort study analysed data from patients registered in the Austrian Psoriasis Registry (PsoRA) who were treated with biologics between 1 January 2015 and 30 November 2019. RESULTS: A total of 1572 patients who received 1848 treatment cycles were included in this analysis. The highest long-term Psoriasis Area and Severity Index improvement was observed after treatment with ixekizumab, followed by ustekinumab and secukinumab, adalimumab and etanercept. Overall, ustekinumab surpassed all other biologics in drug survival up to 48 months. However, when adjusted for biologic naïvety, its superiority vanished and drug survival rates were similar for ixekizumab (91·6%), secukinumab (90·2%) and ustekinumab (92·8%), all of them superior to adalimumab (76·5%) and etanercept (71·9%) at 12 months and beyond. Besides biologic non-naïvety (2·10, P < 0·001), the introduction of a new drug such as secukinumab or ixekizumab (relative hazard ratio 1·6, P = 0·001) and female gender (1·50, P = 0·019) increased the risk of treatment discontinuation overall, whereas psoriatic arthritis did not (1·12, P = 0·21). CONCLUSIONS: The time-dependent availability of drugs should be considered when analysing and comparing drug survival. Previous biologic exposure significantly influences drug survival. Women are more likely to stop treatment.
Subject(s)
Biological Products , Psoriasis , Adalimumab , Austria , Cohort Studies , Etanercept , Female , Humans , Psoriasis/drug therapy , Registries , Retrospective Studies , Survival Rate , Treatment Outcome , UstekinumabABSTRACT
Persistence rates over 36 months with denosumab in patients diagnosed with osteoporosis in a real-world setting were examined, along with baseline patient characteristics predictive of persistence. This study represents the longest observational period with denosumab persistence and shows higher persistence rates when compared to bisphosphonates. INTRODUCTION: The study objective was to describe long-term persistence with denosumab among patients treated for osteoporosis in a real-world setting. We also sought to examine patient characteristics predictive of persistence. Lastly, this study attempted to place the results in context by conducting a literature review of published persistence data for denosumab. METHODS: This retrospective, non-interventional study analyzed 1158 patients from a specialty community private practice to assess patient persistence with denosumab in routine care. Persistence was defined as receiving seven denosumab injections, using an 8-week permissible gap, over 36 months. Non-persistent patients were further investigated retrospectively to identify reasons for discontinuation, when available. RESULTS: Demographic analysis showed a population of 1158 patients with mean age 68.4 years old and baseline T-score - 2.7; nearly half of which experienced a prior osteoporosis-related fracture. In a Kaplan-Meier survival analysis, 36-month persistence overall was 50.7%. Net persistence, as defined by receiving seven injections in the allowable time frame, was 64.2% of the cohort. In a multivariate analysis, prior vertebral fractures and recent osteoporosis therapy were associated with higher persistence; age greater than 75 years was associated with non-persistence. Reasons for discontinuation were available in 91.6% of non-persistent patients and categorized to include the ten most common explanations. CONCLUSION: This study to our knowledge represents the longest continuous observational period providing data on denosumab persistence in a real-world setting. The total persistence noted is quite robust when compared to bisphosphonates and is within the upper range of prior published studies of denosumab with shorter observation periods.
Subject(s)
Bone Density Conservation Agents/administration & dosage , Denosumab/administration & dosage , Medication Adherence/statistics & numerical data , Osteoporosis/drug therapy , Aged , Bone Density Conservation Agents/therapeutic use , Denosumab/therapeutic use , Drug Administration Schedule , Female , Humans , Injections, Subcutaneous , Kaplan-Meier Estimate , Male , Middle Aged , Osteoporosis, Postmenopausal/drug therapy , Osteoporotic Fractures/prevention & control , Retrospective Studies , United StatesABSTRACT
SUMMARY: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months. INTRODUCTION: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period). METHODS: We performed a post hoc analysis to assess the effect of teriparatide 20 µg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period. RESULTS: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events. CONCLUSION: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Osteoporosis/drug therapy , Osteoporotic Fractures/prevention & control , Teriparatide/therapeutic use , Bone Density Conservation Agents/adverse effects , Female , Hip Fractures/epidemiology , Hip Fractures/prevention & control , Humans , Incidence , Male , Osteoporosis/epidemiology , Osteoporotic Fractures/epidemiology , Recurrence , Spinal Fractures/epidemiology , Spinal Fractures/prevention & control , Teriparatide/adverse effects , United States/epidemiologyABSTRACT
BACKGROUND: Several static Bethesda-type assays are routinely used to determine ADAMTS-13-neutralizing autoantibodies in acquired thrombotic thrombocytopenic purpura (TTP), but the inhibitory activity of these antibodies has not been thoroughly evaluated under the more physiologic condition of flow. OBJECTIVES: We investigated whether ADAMTS-13 inhibitor assessment with the FRETS-VWF73 assay is predictive for evaluation under flow. METHODS: Anti-ADAMTS-13 autoantibodies were purified from patients with acquired TTP by chromatography involving an ADAMTS-13 affinity matrix and/or protein G. ADAMTS-13 activity was measured with the FRETS-VWF73 assay and a novel flow assay determining the ADAMTS-13-mediated decrease in platelet aggregate surface coverage, caused by perfusion of a suspension containing platelets, erythrocytes and von Willebrand factor (VWF) over a surface coated with extracellular matrix components. The neutralizing activities of ADAMTS-13 inhibitors were compared under static conditions and under flow by use of the two assays. RESULTS: The suitability of the flow-based ADAMTS-13 activity assay for quantification of ADAMTS-13 inhibitors could be demonstrated by reversibility of the ADAMTS-13-dependent decrease in surface coverage upon addition of goat ADAMTS-13 antiserum. Testing the neutralizing activity of purified autoantibodies from six patients in the flow assay according to their FRETS-VWF73-based inhibitor titers gave rise to vastly different inhibitory effects, indicating a discrepancy in inhibitor assessment between static and flow conditions. CONCLUSIONS: Anti-ADAMTS-13 autoantibodies may show inhibitory properties in vivo that are not consistent with the ADAMTS-13 inhibitor levels determined in routine static assays, possibly because certain epitopes are selectively exposed under shear. Consequently, the course of disease and treatment efficacy may vary among TTP patients, despite common inhibitor titers.
Subject(s)
ADAM Proteins/chemistry , ADAM Proteins/immunology , Autoantibodies/chemistry , Blood Coagulation Tests/instrumentation , Hematologic Tests/methods , Purpura, Thrombotic Thrombocytopenic/blood , ADAMTS13 Protein , Blood Coagulation Tests/methods , Cytoskeletal Proteins/chemistry , Fluorescence Resonance Energy Transfer , Humans , Immunoglobulin G/chemistry , LIM Domain Proteins/chemistry , Platelet Aggregation , Protein Binding , Purpura, Thrombotic Thrombocytopenic/diagnosis , RNA-Binding Proteins , Shear Strength , Stress, Mechanical , von Willebrand Factor/chemistryABSTRACT
AIMS: To test if multi-surface models can provide a soil-specific prediction of metal mobilization by phytosiderophores (PS) based on the characteristics of individual soils. METHODS: Mechanistic multi-surface chemical equilibrium modeling was applied for obtaining soil-specific predictions of metal and PS speciation upon interaction of the PS 2'-deoxymugineic acid (DMA) with 6 soils differing in availability of Fe and other metals. Results from multi-surface modeling were compared with empirical data from soil interaction experiments. RESULTS: For soils in which equilibrium was reached during the interaction experiment, multi-surface models could well predict PS equilibrium speciation. However, in uncontaminated calcareous soils, equilibrium was not reached within a week, and experimental and modeled DMA speciation differed considerably. In soils with circum-neutral pH, on which Fe deficiency is likely to occur, no substantial Fe mobilization by DMA was predicted. However, in all but the contaminated soils, Fe mobilization by DMA was observed experimentally. Cu and Ni were the quantitatively most important metals competing with Fe for complexation and mobilization by DMA. CONCLUSION: Thermodynamics are unable to explain the role of PS as Fe carrier in calcareous soils, and the kinetic aspects of metal mobilization by PS need to be closer examined in order to understand the mechanisms underlying strategy II Fe acquisition.
ABSTRACT
Evolutionary transitions between sex-determining mechanisms (SDMs) are an enigma. Among vertebrates, individual sex (male or female) is primarily determined by either genes (genotypic sex determination, GSD) or embryonic incubation temperature (temperature-dependent sex determination, TSD), and these mechanisms have undergone repeated evolutionary transitions. Despite this evolutionary lability, transitions from GSD (i.e. from male heterogamety, XX/XY, or female heterogamety, ZZ/ZW) to TSD are an evolutionary conundrum, as they appear to require crossing a fitness valley arising from the production of genotypes with reduced viability owing to being homogametic for degenerated sex chromosomes (YY or WW individuals). Moreover, it is unclear whether alternative (e.g. mixed) forms of sex determination can persist across evolutionary time. It has previously been suggested that transitions would be easy if temperature-dependent sex reversal (e.g. XX male or XY female) was asymmetrical, occurring only in the homogametic sex. However, only recently has a mechanistic model of sex determination emerged that may allow such asymmetrical sex reversal. We demonstrate that selection for TSD in a realistic sex-determining system can readily drive evolutionary transitions from GSD to TSD that do not require the production of YY or WW individuals. In XX/XY systems, sex reversal (female to male) occurs in a portion of the XX individuals only, leading to the loss of the Y allele (or chromosome) from the population as XX individuals mate with each other. The outcome is a population of XX individuals whose sex is determined by incubation temperature (TSD). Moreover, our model reveals a novel evolutionarily stable state representing a mixed-mechanism system that has not been revealed by previous approaches. This study solves two long-standing puzzles of the evolution of sex-determining mechanisms by illuminating the evolutionary pathways and endpoints.
Subject(s)
Evolution, Molecular , Sex Determination Processes , Animals , Female , Male , Models, Genetic , Selection, Genetic , TemperatureABSTRACT
Results described here span a total of three field seasons and quantitatively depict the effects of an economically important fungal pathogen (Blumeriella jaapii) on tart cherry (Prunus cerasus 'Montmorency') leaf physiology. For the first time, leaf photosynthesis, stomatal conductance (g(s)), maximum ribulose-1,5-bisphosphate carboxylation rate (V(cmax)), and maximum electron transport (J(max)) were measured as functions of visible cherry leaf spot disease (CLS) severity. Defined as the proportion of chlorotic and necrotic tissue per leaf, CLS severity was estimated from leaves of mature 'Montmorency' trees in 2007, 2008, and 2009. Briefly, as visible disease severity increased, all of the leaf-level physiological parameters decreased significantly (P < 0.01) and disproportionately. Thus, the effects of visible symptoms on leaf photosynthetic metabolic function encroached upon asymptomatic tissue as well. Impairment of photosynthetic metabolism in 'Montmorency' tart cherry leaves due to CLS appears to be mediated through disproportionately large perturbations in g(s), V(cmax), and J(max). These findings offer a new perspective on the amount of damage that this serious disease can inflict.
Subject(s)
Ascomycota/physiology , Host-Pathogen Interactions , Photosynthesis , Plant Diseases , Prunus/microbiology , Carbon Dioxide/metabolism , Fungicides, Industrial , Plant Leaves/metabolism , Plant Transpiration , Prunus/metabolismABSTRACT
INTRODUCTION: Uremic toxins play a pivotal role in the development of systemic complications of chronic kidney disease (CKD), which are largely mediated by the activation of the immune system. Triggers of inflammation in CKD are largely unknown and strategies aiming to reduce circulating ligands that could start the inflammatory response are potentially important. In the present study, we investigated the impact of sevelamer hydrochloride treatment in reducing endotoxemia and inflammation in a group of hemodialysis (HD) patients. MATERIAL AND METHODS: HD patients, who were converted from calcium carbonate treatment to sevelamer according to KDOQI guidelines, were included and prospectively followed for 6 months. Systemic inflammation was evaluated by serum ultra-high-sensitivity C-reactive protein (hsCRP) using an automated immunoturbidimetric assay. Endotoxin was measured using Limulus amebocyte lysate chromogenic endpoint assay. All the analyses were performed immediately before conversion and after 6 months of treatment. RESULTS: After the exclusion of patients discontinuing the treatment, 20 patients (mean dialysis time 12 +/- 4 months on HD, age 52 +/- 2 years, 38% males, 11% diabetics) were included in the analysis. No significant changes were observed in Ca, P and PTH levels, while a reduction in cholesterol levels was seen. Plasma concentration of hsCRP and endotoxin significantly decreased after 6 months of conversion to sevelamer compared with baseline. CONCLUSION: We conclude that sevelamer treatment leads to a decrease in hsCRP levels, which was accompanied by a parallel decrease in endotoxemia, suggesting that endotoxemia may contribute to the systemic inflammation in HD patients, which was partially reduced by the use of sevelamer.
Subject(s)
Endotoxemia/drug therapy , Inflammation/drug therapy , Polyamines/administration & dosage , Renal Insufficiency, Chronic/complications , C-Reactive Protein/analysis , Chelating Agents , Endotoxins/blood , Female , Follow-Up Studies , Humans , Male , Middle Aged , Polyamines/therapeutic use , Prospective Studies , Renal Dialysis , Renal Insufficiency, Chronic/drug therapy , Sevelamer , Treatment OutcomeABSTRACT
SUMMARY: Fractures have a significant impact on the quality of life for the patient in addition to an enormous indirect cost in lost productivity for our economy. While majority of fractures heal uneventfully, some fail to heal even after many months resulting in nonunion. INTRODUCTION: Sternal nonunions, although rare, are particularly onerous for the patient given the magnitude of impact on quality of life. METHODS: Current treatment for fracture nonunions emphasizes various approaches to surgical fixation in addition to bone grafting. These treatments are aggressive and have a variety of drawbacks, rendering them suboptimal as a therapeutic approach. CONCLUSION: Based on the success of teriparatide in animal studies to accelerate fracture healing, there is growing interest in using this drug in humans for the same purpose. We report a case of what we believe to be the first successful use of teriparatide in the healing of a sternal nonunion fracture.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Fractures, Ununited/drug therapy , Sternum/injuries , Teriparatide/therapeutic use , Aged , Fracture Healing/drug effects , Fractures, Ununited/diagnostic imaging , Humans , Male , Sternum/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
The problem of a representative body of a three-dimensional lattice is considered. The cell fulfilling a + b + c = min is clearly not unique: even five mutually non-congruent such cells can exist in some lattices [Gruber (1973). Acta Cryst. A29, 433-440]. The idea that this number could be reduced by replacing the cell (i.e. a parallelepiped) by another, possibly more suitable, geometrical object is considered. For this object a lattice tetrahedron fulfilling the condition a + b + c + d + e + f = min is chosen, a to f being the lengths of its edges. It is called the minitetrahedron of the lattice. In this article, the problem is solved in detail for lattices that can be generated by a basis a, b, c fulfilling |a| + |b| + |c| = min, b x c > or = 0, a x c > or = 0, a x b > or = 0. It turns out that in this case not more than two mutually non-congruent minitetrahedra can exist. Necessary and sufficient conditions for the uniqueness are found. They have the form of inequalities between the lengths of the edges and diagonals of the parallelepiped formed by the vectors a, b, c. A procedure for determining all minitetrahedra of a given lattice is shown. Some results are illustrated graphically and all assertions are proved mathematically.
ABSTRACT
In the Great Lakes region of the United States, cherry growers are poised to re-adopt copper-based fungicides to manage cherry leaf spot disease (CLS), caused by Blumeriella jaapii. However, application of copper is often associated with leaf bronzing. In growth chamber experiments, bronzing was observed on foliage of tart cherry (Prunus cerasus 'Montmorency') seedlings 1 week following application of a copper-based fungicide, only when leaves were also exposed to nightly dew. In potted, 1-year-old trees outdoors, light-saturated rates of net CO2 assimilation (A) and stomatal conductance (gs) were not affected by treatment with copper sulfate, chlorothalonil, tebuconazole, or trifloxystrobin compared to a nonsprayed control. In 2005 and 2006, A and gs were measured during late summer on leaves of mature trees in an orchard subjected to the following fungicide programs: synthetic fungicides only; synthetic fungicides integrated with copper-based fungicides; or not sprayed. Bronzing symptoms were observed on trees sprayed with copper. Regression analysis revealed that neither A nor gs decreased as leaf surface area affected by bronzing increased (R2 = 0.004, P = 0.80 and R2 = 0.006, P = 0.74, respectively). Leaf bronzing associated with application of copper-based fungicides may therefore be inconsequential to foliar gas exchange in tart cherry during late summer.
ABSTRACT
Feather pecking and cannibalism are still major problems in alternative systems for laying hens. Literature and practical experience indicate that unfavourable rearing conditions might be important risk factors for the occurrence of these behavioural disturbances during the laying period. Typical rearing conditions of laying hens from 50 rearing units in Germany and Austria are presented. Obvious risk factors during rearing for feather pecking and cannibalism during the laying period were found. Most flocks were kept under high stocking density (mean: 15 pullets per m' useable area) and some flocks had access to litter only after the second week of life or access to raised perches after the fourth week of life. Plumage condition of pullets and laying hens varied widely in non-beak-trimmed as well as in beak-trimmed flocks. The percentage of pullets with damaged plumage was higher in beak-trimmed than in non-beak-trimmed flocks (medians: 53 % versus 30 %, p = 0,022). In laying hens there was a higher percentage of hens with plumage damage in non-beak-trimmed flocks compared to beak-trimmed flocks (medians: 23 % versus 50 %, p = 0,007). Data analysis will be continued, especially with regard to particular risk factors.
Subject(s)
Agonistic Behavior/physiology , Animal Husbandry/methods , Poultry/physiology , Animal Husbandry/standards , Animals , Beak/physiology , Cannibalism , Female , Housing, Animal , Population Density , Poultry/growth & development , Risk Factors , Time FactorsABSTRACT
Inflammation and immune system activation seem to play an important role in the development and progression of dementia. Hyperhomocysteinemia is common in various forms of dementia, and a significant relationship was found between concentrations of homocysteine and immune activation marker neopterin. B vitamin supplementation is able to slow-down homocysteine formation in patients. In an open-label study, effects of B vitamin supplementation (Beneuran compositum ) on concentrations of homocysteine and neopterin were investigated in 58 patients with Alzheimer's disease (n=30), vascular dementia (n=12) and mild cognitive impairment (n=16). In all groups of patients, a significant percentage of patients presented with homocysteine concentrations >15 micromol/L and with elevated concentrations of immune activation marker neopterin. Decline of homocysteine concentrations was observed after one month of B vitamin supplementation (all p<0.01; paired Kruskal-Wallisn-test). By contrast, neopterin concentrations remained unchanged (all p>0.05). B vitamin supplementation in patients with various forms of dementia did not influence neopterin concentrations, which indicates that the degree of immune activation and inflammation remained unchanged. The question remains, if lowering of homocysteine by folate supplementation alone could have any beneficial effect to modulate the course of dementia development and if longer period of supplementation would also ameliorate immune system activation status.
Subject(s)
Dementia/drug therapy , Dietary Supplements , Homocysteine/drug effects , Neopterin/blood , Vitamins/therapeutic use , Female , Folic Acid/therapeutic use , Homocysteine/blood , Humans , Male , Thiamine/therapeutic use , Vitamin B 12/therapeutic use , Vitamin B 6/therapeutic useABSTRACT
The common features of biological activity displayed by vitamin D family members and adriamycin suggest the possibility of synergistic effects of the combination of these compounds. Until now, the mechanisms responsible mainly for adriamycin cytotoxic action have not been indicated. Therefore, observation of the possible common cell targets for adriamycin and vitamin D metabolites could shed more light on the mechanisms of cytotoxic activity of adriamycin. In the present study, the influence of calcidiol (25-hydroxyvitamin D(3)) and calcitriol (1alpha,25-dihydroxyvitamin D(3)) on the proliferation and cytotoxicity of adriamycin was studied. The following cell lines were tested: normal human fibroblasts-CRL 1502, human melanoma cells-ME18 and its subline-ME18/R, resistant to adriamycin. As was shown, 72 h of incubation with calcidiol or calcitriol, both at 10 microM, inhibited growth (to approx. 60%) only of the ME18 cells. Dose and time dependence of this effect has been confirmed. Antiproliferative events did not correlate with an increase of adriamycin cytotoxicity. It was noted that calcidiol and calcitriol had no significant influence on the adriamycin IC(50) values in any cell lines tested. These results point to the divergent mechanisms of action of adriamycin and vitamin D(3) metabolites.
Subject(s)
Antineoplastic Agents/pharmacology , Calcifediol/pharmacology , Calcitriol/pharmacology , Cell Division/drug effects , Doxorubicin/pharmacology , Antineoplastic Agents/toxicity , Cell Line , Dose-Response Relationship, Drug , Doxorubicin/toxicity , Drug Interactions , Drug Resistance, Neoplasm , Fibroblasts , Humans , Lethal Dose 50 , Melanoma/pathology , Tumor Cells, CulturedABSTRACT
We have studied the occurrence of the apoptosis phenomenon in the action of adriamycin (ADR) on human melanoma cells sensitive (ME18) and resistant (ME18/R) to ADR. The study has shown that the intensity of apoptotic morphological changes noted in melanoma cells depended on the duration of the ADR treatment. We have not observed any positive correlation between the induction of apoptosis and sensitivity to ADR. We have used a fluorescence microscope and flow cytometer to evaluate apoptotic events in cells treated with ADR.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Doxorubicin/pharmacology , Melanoma/drug therapy , Melanoma/pathology , Drug Resistance, Neoplasm , Flow Cytometry , Fluorescent Dyes , Humans , Indoles , Microscopy, Fluorescence , Rhodamines , Tumor Cells, CulturedABSTRACT
Myofibroblasts are fibroblasts that express certain features of smooth muscle differentiation. Increased numbers of myofibroblasts and mast cells are frequently found together in a wide variety of settings, such as normal wound repair and scleroderma skin, which suggests that mediators produced by the mast cells could play a role in the regulation of myofibroblast differentiation and function. We used a human mast cell line, HMC-1, to determine if mast cells can induce normal human dermal fibroblasts to differentiate into functional myofibroblasts in vitro. We monitored the differentiation process by assaying two properties of the myofibroblast phenotype: expression of alpha-smooth muscle actin and functional capacity to contract a collagen matrix. In both a simple coculture system and in a skin-equivalent culture system, HMC-1 cells induced alpha-smooth muscle actin expression by fibroblasts. HMC-1 cells also stimulated fibroblast contraction of collagen gels, and the relative amount of contraction was dependent upon the number of HMC-1 cells present. To characterize the individual contributions made by specific mast cell products, we examined the effects of histamine, tumor necrosis factor alpha, and tryptase. Histamine induced a clear increase in alpha-smooth muscle actin expression, but it did not appear to stimulate fibroblast contraction. Tumor necrosis factor alpha had no effect in either assay. Purified human tryptase induced alpha-smooth muscle actin expression, and blocking the proteolytic activity of tryptase with specific inhibitors reduced that response. Tryptase inhibitors also eliminated the ability of HMC-1 cells to stimulate fibroblast contraction, suggesting that tryptase secreted by the HMC-1 cells may be one of the active mast cell mediators.