Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial

Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.<p></p> Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial.<p></p> Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.<p></p> Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings

Патогенетические механизмы гипотензивного действия α2-адреномиметиков

PURPOSE: To determine pathogenic mechanism of alfaadrenergic agonists’ hypotensive action by brimonidine 0.2% administration in patients with open-angle glaucoma.METHODS: 88 patients (age 69.1±7.25) diagnosed with mild open-angle glaucoma and with disease history of less than 1 year were included in the study. Patients were divided into two groups according to their drug regimen. Group 1 consisted of 12 patients (24 eyes) with brimonidine 0.2% instillations. Group 2 consisted of 76 patients (133 eyes) and was further divided into four subgroups. The 1st subgroup included 36 patients (66 eyes) with brimonidine 0.2% monotherapy; the 2nd subgroup included 18 patients (29 eyes) with a combined treatment with brimonidine 0.2% and prostaglandin analogues; the 3rd subgroup included 13 patients (20 eyes) with brimonidine 0.2% added to timololum 0.5%; the 4th subgroup included 9 patients (18 eyes) with brimonidine 0.2% added to dorzolamidum 2%. Patients of Group 1 underwent uveoscleral outflow examination and had the following coefficients calculated: general outflow facility coefficient (Cgen), uveoscleral outflow facility coefficient (Cuveo), aqueous humor minute volume (F). Hypotensive regimen efficiency action in Group 2 was measured by means of dynamic contour tonometry (Pascal tonometer, «SMT Swiss Microtechnology AG»).RESULTS: In Group 1 intraocular pressure (Po) decreased to 17.5±4.01 mmHg (р=0.04) (by 28% from the initial level), Cgen increased up to 0.23±0.06 mm3 /min/mmHg (р=0.01) (by 35% from the initial level), Cuveo increased up to 0.12±0.02 mm3 /min/mmHg (р=0.01) (by 71% from the initial level), F decreased to 1.5±0.6 mm3 /min (р=0.04) (by 48% from the initial level). Only one patient on the group had intolerance to the drug. In Group 2 after 3 months of follow-up Po decreased from 23.2±4.92 to 16.3±4.64 mmHg in the 1st subgroup (by 29.7% from the initial level); from 23.4±3.84 to 18.2±4.83 mmHg (р=0.04) in the 2nd subgroup (by 22.2% from the initial level); from 23.3±3.19 to 17.2±4.53 mmHg in the 3rd subgroup (by 26.2% from the initial level); from 22.0±2.85 to 17.4±2.82 mmHg in the 4th subgroup (by 21.9% from the initial level). Brimonidine 0.2% was discontinued in 14 patients (15.9% of the total number of patients) due to various reasons (intolerance to the drug or insufficient hypotensive action).CONCLUSION: Pathogenesis of α2-adrenergic agonists’ hypotensive action involves aqueous humor outflow increase by uveoscleral pathway and significant aqueous humor minute volume reduction. Hypotensive efficiency with IOP decrease by 24.6% was revealed in case of brimonidine 0.2% monotherapy. Additional reduction of intraocular pressure by 21.1% from the initial level was revealed in case of brimonidine 0.2% prescription in combination with other drugs. A more prominent hypotensive effect was revealed after 3 months of treatment compared to a 1 month treatment course. In most cases patients showed a high tolerability to brimonidine 0.2%. ЦЕЛЬ. Определить патогенетические механизмы гипотензивного действия α2-адреномиметиков на примере использования 0,2% раствора бримонидина у больных открытоугольной глаукомой.МЕТОДЫ. Проведено обследование 88 больных в возрасте 69,1±7,25 года с начальной открытоугольной глаукомой со стажем заболевания менее 1 года. Больные были разделены на группы в зависимости от проводимой медикаментозной терапии: 1-я группа — 12 человек (24 глаза), которым проводились инстилляции 0,2% раствора бримонидина; 2-я группа — 76 человек (133 глаза) — была разделена на подгруппы. В 1-й подгруппе 36 человек (66 глаз) получали монотерапию 0,2% раствором бримонидина; во 2-й подгруппе у 18 больных (29 глаз) оценивали эффект бримонидина 0,2% на фоне терапии простагландинами; у 13 человек (20 глаз) 3-й подгруппы бримонидин 0,2% был добавлен к терапии тимололом 0,5%; в 4-й под- группе 9 больным (18 глаз) бримонидин 0,2% был добавлен к терапии дорзоламидом 2%. Пациентам 1-й группы проводили исследование увеосклерального оттока с вычислением коэффициента легкости оттока по общему пути (Собщ), коэффициента легкости оттока по увеосклеральному пути (Сувео), минутного объема камерной влаги (F). У пациентов 2-й группы гипотензивный эффект оценивали с помощью динамической контурной тонометрии тонометром Pascal, SMT «Swiss Microtechnology AG».РЕЗУЛЬТАТЫ. В группе 1 выявлено снижение истинного внутриглазного давления (Ро) до 17,5±4,01 мм рт.ст. (р=0,04) (на 28% от исходного уровня); увеличение Собщ до 0,23±0,06 мм3 /мин/мм рт.ст. (р=0,01) (на 35% от величины исходного оттока); увеличение Сувео до 0,12±0,02 мм3 /мин/мм рт.ст. (р=0,01) (на 71% от исходной величины); уменьшение F до 1,5±0,6 мм3 /мин (р=0,04) (на 48% от исходного уровня). Непереносимость препарата в этой группе была только у одного пациента. Во 2-й группе через 3 месяца наблюдения Ро в 1-й подгруппе снизилось с 23,2±4,92 до 16,3±4,64 мм рт.ст. (на 29,7% от исходного уровня); во 2-й подгруппе с 23,4±3,84 до 18,2±4,83 мм рт.ст. (р=0,04) (на 22,2% от исходного уровня); в 3-й подгруппе с 23,3±3,19 до 17,2±4,53 мм рт.ст. (на 26,2% от исходного уровня); в 4-й подгруппе с 22,0±2,85 до 17,4±2,82 мм рт.ст. (на 21,9% от исходного уровня). По разным причинам (непереносимость препарата и недостаточный гипотензивный эффект) лечение 0,2% раствором бримонидина было отменено у 14 пациентов (15,9% от общего числа больных).ЗАКЛЮЧЕНИЕ. Патогенез гипотензивного эффекта α2-адреномиметиков заключается в усилении оттока внутриглазной жидкости по увеосклеральному пути и значимом снижении минутного объема камерной влаги. В условиях монотерапии 0,2% раствором бримонидина гипотензивная эффективность составила 24,6%, в случаях его назначения на фоне лечения другими препаратами отмечено дополнительное снижение внутриглазного давления на 21,1% от исходного уровня. Выявлено усиление гипотензивного эффекта 0,2% раствора бримонидина через три месяца применения по сравнению с одномесячным сроком терапии. У большинства пациентов 0,2% раствору бримонидина свойственна хорошая переносимость.

Вторичная неоваскулярная глаукома как первое проявление ВИЧ-инфекции: клинический случай

Secondary neovascular glaucoma can be the first sign of HIV infection. The main pathogenesis of proliferative processes in the iris and anterior chamber angle are HIVassociated angiopathy, which initiates hypoxia, and an imbalance of endothelial factors. Secondary neovascular glaucoma often occurs as a complication of central retinal vein thrombosis in the older age group or a consequence of previous uveitis. Neovascular glaucoma occurring in a young patient may indicate HIV infection. The publication describes a clinical case of secondary neovascular glaucoma in a young patient as the first sign of manifestation of the HIV infection. A 40-year-old patient with laboratory-confirmed HIV infection complained of decreased vision, pain, redness and lacrimation in the left eye. No other systemic signs of HIV infection were detected. Ophthalmological examination revealed a weak uveal reaction and single vessels along the pupillary edge of the iris. The reason of vision decrease was glaucomatous atrophy of the optic nerve due to neovascular glaucoma. One of the methods of surgical treatment of patients with neovascular glaucoma is modified direct cyclocryopexy, its advantage is a low risk of hemorrhagic complications, suppression of neovascularization, adequate hypotensive and analgesic effects. This clinical case illustrates a good hypotensive result in a 4-year follow-up.Вторичная неоваскулярная глаукома может быть первым признаком ВИЧ-инфицирования. ВИЧ-ассоциированная ангиопатия, инициирующая гипоксию, в сочетании с дисбалансом эндотелиальных факторов являются основными патогенетическими звеньями развития пролиферативных процессов радужки и угла передней камеры. Вторичная неоваскулярная глаукома часто возникает как осложнение тромбоза центральной вены сетчатки в старшей возрастной группе или как следствие перенесенного увеита. Возникновение неоваскулярной глаукомы у молодого пациента может свидетельствовать о ВИЧ-инфицировании. Публикация описывает клинический случай вторичной неоваскулярной глаукомы у молодого пациента как первого признака манифестации ВИЧ-инфекции. Пациент 40 лет обратился с жалобами на снижение зрения, боль, покраснение и слезотечение на левом глазу на фоне лабораторно подтвержденной ВИЧ-инфекции. Системно других признаков ВИЧ-инфекции выявлено не было. По данным офтальмологического обследования выявлена слабая увеальная реакция и единичные сосуды по зрачковому краю радужки. Установлено, что причиной снижения зрения являлась глаукоматозная атрофия зрительного нерва вследствие неоваскулярной глаукомы. Одним из методов хирургического лечения пациентов с неоваскулярной глаукомой является прямая циклокриопексия (ПЦКП) в модификации, преимуществом которой является низкий риск геморрагических осложнений, подавление неоваскуляризации, адекватные гипотензивный и болеутоляющий эффекты. Клинический случай иллюстрирует хороший гипотензивный результат за 4 года наблюдения

New Synthetic Thrombin Inhibitors: Molecular Design and Experimental Verification

BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications

Novel sulI binary vectors enable an inexpensive foliar selection method in Arabidopsis

<p>Abstract</p> <p>Background</p> <p>Sulfonamide resistance is conferred by the <it>sul</it>I gene found on many <it>Enterobacteriaceae </it>R plasmids and Tn21 type transposons. The <it>sul</it>I gene encodes a sulfonamide insensitive dihydropteroate synthase enzyme required for folate biosynthesis. Transformation of tobacco, potato or <it>Arabidopsis </it>using <it>sul</it>I as a selectable marker generates sulfadiazine-resistant plants. Typically <it>sul</it>I-based selection of transgenic plants is performed on tissue culture media under sterile conditions.</p> <p>Findings</p> <p>A set of novel binary vectors containing a <it>sul</it>I selectable marker expression cassette were constructed and used to generate transgenic <it>Arabidopsis</it>. We demonstrate that the <it>sul</it>I selectable marker can be utilized for direct selection of plants grown in soil with a simple foliar spray application procedure. A highly effective and inexpensive high throughput screening strategy to identify transgenic <it>Arabidopsis </it>without use of tissue culture was developed.</p> <p>Conclusion</p> <p>Novel <it>sul</it>I-containing <it>Agrobacterium </it>binary vectors designed to over-express a gene of interest or to characterize a test promoter in transgenic plants have been constructed. These new vector tools combined with the various beneficial attributes of sulfonamide selection and the simple foliar screening strategy provide an advantageous alternative for plant biotechnology researchers. The set of binary vectors is freely available upon request.</p

Typology and distribution of small farms in Europe: Towards a better picture

The contribution of small farms to local food supply, food security and food sovereignty is widely acknowledged at a global level. In the particular case of Europe, they often are seen as an alternative to large and specialised farms. Assessing the real role of small farms has been limited by a lack of information, as small farms are frequently omitted from agricultural censuses and national statistics. It is also well acknowledged that small farms differ widely, and are distributed according to different spatial patterns across Europe, fulfilling different roles according to the agriculture and territorial characteristics of each region. This paper presents the result of a novel classification of small farms at NUTS-3 level in Europe, according to the relevance of small farms in the agricultural and territorial context of each region, and based on a typology of small farms considering different dimensions of farm size. The maps presented result from an extensive data collection and variables selected according to European wide expert judgement, analysed with advanced cluster procedures. The results provide a fine grained picture of the role of small farms at the regional level in Europe today, and are expected to support further data analysis and targeted policy intervention