The impact of microgravity and hypergravity on endothelial cells

The endothelial cells (ECs), which line the inner surface of vessels, play a fundamental role in maintaining vascular integrity and tissue homeostasis, since they regulate local blood flow and other physiological processes. ECs are highly sensitive to mechanical stress, including hypergravity and microgravity. Indeed, they undergo morphological and functional changes in response to alterations of gravity. In particular microgravity leads to changes in the production and expression of vasoactive and inflammatory mediators and adhesion molecules, which mainly result from changes in the remodelling of the cytoskeleton and the distribution of caveolae. These molecular modifications finely control cell survival, proliferation, apoptosis, migration, and angiogenesis. This review summarizes the state of the art on how microgravity and hypergravity affect cultured ECs functions and discusses some controversial issues reported in the literature

Effect of NIR laser therapy by MLS-MiS source against neuropathic pain in rats: in vivo and ex vivo analysis.

Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma

Physiological adaptations affecting drug pharmacokinetics in space: what do we really know? A critical review of the literature

As human spaceflight progresses with extended mission durations, the demand for effective and safe drugs will necessarily increase. To date, the accepted medications used during missions (for space motion sickness, sleep disturbances, allergies, pain, and sinus congestion) are administered under the assumption that they act as safely and efficaciously as on Earth. However, physiological changes have been documented in human subjects in spaceflight involving fluid shifts, muscle and bone loss, immune system dysregulation, and adjustments in the gastrointestinal tract and metabolism. These alterations may change the pharmacokinetics (PK) and pharmacodynamics of commonly used medications. Frustratingly, the information gained from bed rest studies and from in-flight observations is incomplete and also demonstrates a high variability in drug PK. Therefore, the objectives of this review are to report (i) the impact of the space environmental stressors on human physiology in relation to PK; (ii) the state-of-the-art on experimental data in space and/or in ground-based models; (iii) the validation of ground-based models for PK studies; and (iv) the identification of research gaps

Клиническое значение специальной аэрозольной формы тобрамицина в лечении хронического бронхолегочного процесса у больных муковисцидозом

The aim of this study was to evaluate clinical efficacy and safety of highly concentrated inhaled solution of tobramycin (Bramitob®, Chiesi Farmaceutici S.p.A., Italy) in patients with cystic fibrosis (CF). This was 24-wk multicenter international double-blind placebo-controlled randomized trial in parallel groups. In this study, 247 patients aged 6–45 yrs with Pseudomonas aeruginosa yielded in sputum and FEV 1 40 % to 80 % pred. were randomized in 2 groups: those inhaling aerosol tobramycin (161 patients, mean age, 14.8 ± 5.7 yrs) or placebo (84 patients, mean age, 14.7 ± 6.6 yrs). Tobramycin 300 mg b.i.d. was given at the time of basic and antipseudomonal therapy. Efficacy criteria were as follows: lung ventilation parameters, sputum culture and yielding P. aeruginosa, rate of exacerbations of pulmonary disease, rate of hospitalisations, number of workoff or school-off days, number of courses of parenteral tobramycin and other antipseudomonal antibiotics, nutritional status (weight, BMI). Safety profile included serum creatinine level, audiometric test, vital signs (heart rate, blood pressure) and adverse events. To the end of the study, FEV1  improved by 7 % in the tobramycin group and by 1 % in the placebo group (p < 0.001), FVC improved by 5.7 and 1.3 %, respectively (p = 0.002), and FEF 25–75 improved by 8.8 % and 0.7 %, respectively (p = 0.001). Frequency of P. aeruginosa eradication differed significantly between the groups to the end of 4th and 20th weeks of the study (30.8 % vs. 14.3 %; p = 0.011, and 33.3 % vs. 16.5 %; p = 0.024, respectively). Exacerbations of pulmonary disease occurred in 39.8 % of tobramycin patients and in 51.2 % of placebo patients (р = 0.09). Hospital admission was required in 18.6 % and 36.9 % of patients, respectively (p = 0.002). Parenteral tobramycin was administered to 6.2 % and 16.7 % of patients, respectively (p = 0.009), other antipseudomonals were given in 55.9 % and 70.2 % of the patients, respectively (p = 0.029). Number of patients with missing work/school days due to exacerbation of pulmonary disease was 32.3 % in tobramycin group and 57.1 % in placebo group (p < 0.001). Serious adverse events related to treatment with tobramycin were not noted. In conclusion, long-term intermittent treatment with inhaled solution of tobramycin additionally to basic and antipseudomonal therapy in CF patients significantly improved lung ventilation and eradication of P. aeruginosa, decreased the rate of exacerbations of pulmonary disease, rate of hospitalisations, and numbers of antipseudomonal courses and missing work days. The treatment was well tolerated and could be recommended for CF patients with P. aeruginosa in culture.Целью исследования явилась оценка клинической эффективности и безопасности высококонцентрированного раствора тобрамицина для ингаляций (Брамитоб®, Chiesi Farmaceutici S.p.A., Италия) у больных муковисцидозом (МВ) в 24-недельном мультицентровом, международном, двойном слепом плацебо-контролируемом рандомизированном исследовании с параллельными группами. 247 пациентов (6–45 лет), с высевом Pseudomonas aeruginosa и объемом форсированного выдоха за 1-ю с (ОФВ1) 40–80 %долж. , были разделены на 2 группы – приема аэрозольной формы тобрамицина и солевого раствора плацебо: 161 пациент (средний возраст – 14,8 ± 5,7 года) и 84 пациента (средний возраст – 14,7 ± 6,6 года) соответственно. Тобрамицин (300 мг 2 раза в день) назначали дополнительно к базовой и другой антисинегнойной терапии. Критерии эффективности: ОФВ 1 (%долж. ), форсированная жизненная емкость легких (ФЖЕЛ, %долж.), средняя объемная скорость потока на участке между 25 и 75 % ФЖЕЛ (СОС25–75 , %долж.), динамика показателей микроэкологического статуса (высев из мокроты и обсемененность P. aeruginosa), частота обострений бронхолегочного процесса, госпитализаций, количество пропущенных дней учебы / работы, парентеральных курсов тобрамицина и других антисинегнойных препаратов, динамика нутритивного статуса (вес, индекс массы тела). Профиль безопасности включал показатель сывороточного креатинина, аудиометрический тест, показатели витальных функций (частота сердечных сокращений, артериальное давление), а также побочные эффекты. К концу исследования прирост параметров функции внешнего дыхания (ФВД) в группе тобрамицина по сравнению с таковыми в группе плацебо составил: ОФВ 1 – 7 и 1 % (p < 0,001), ФЖЕЛ – 5,7 и 1,3 % (p = 0,002), СОС 25–75 – 8,8 и 0,7 % (р = 0,001). Различия в частоте эрадикации P. aeruginosa между группами тобрамицина и плацебо отмечались дважды – в конце 4-й и 20-й недель исследования: 30,8 и 14,3 % (p = 0,011), 33,3 и 16,5 % (p = 0,024). Обострения бронхолегочного процесса отмечались у 39,8 и 51,2 % пациентов в группах тобрамицина и плацебо (p = 0,09). В госпитализации нуждались 18,6 и 36,9 % пациентов (p = 0,002), в парентеральных курсах тобрамицина – 6,2 и 16,7 % пациентов (p = 0,009), других антисинегнойных антибиотиков – 55,9 и 70,2 % больных (p = 0,029). Количество пациентов, вынужденных не посещать место учебы / работы из-за обострения заболевания в группе приема тобрамицина составило 32,3 и 57,1 % (p < 0,001). Серьезные побочные эффекты, связанные с тобрамицином, не отмечались. Длительное интермиттирующее применение раствора тобрамицина для ингаляций в качестве дополнительной к базисной и другой противосинегнойной терапии у больных МВ способствует достоверному улучшению параметров ФВД, уменьшению частоты высева P. aeruginosa, снижению числа госпитализаций и курсов антисинегнойной терапии, пропущенных рабочих дней. Терапия хорошо переносится и может быть рекомендована больным МВ с высевом P. aeruginosa

Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization

The development of human liver scaffolds retaining their 3-dimensional structure and extra-cellular matrix (ECM) composition is essential for the advancement of liver tissue engineering. We report the design and validation of a new methodology for the rapid and accurate production of human acellular liver tissue cubes (ALTCs) using normal liver tissue unsuitable for transplantation. The application of high shear stress is a key methodological determinant accelerating the process of tissue decellularization while maintaining ECM protein composition, 3D-architecture and physico-chemical properties of the native tissue. ALTCs were engineered with human parenchymal and non-parenchymal liver cell lines (HepG2 and LX2 cells, respectively), human umbilical vein endothelial cells (HUVEC), as well as primary human hepatocytes and hepatic stellate cells. Both parenchymal and non-parenchymal liver cells grown in ALTCs exhibited markedly different gene expression when compared to standard 2D cell cultures. Remarkably, HUVEC cells naturally migrated in the ECM scaffold and spontaneously repopulated the lining of decellularized vessels. The metabolic function and protein synthesis of engineered liver scaffolds with human primary hepatocytes reseeded under dynamic conditions were maintained. These results provide a solid basis for the establishment of effective protocols aimed at recreating human liver tissue in vitro