Interaction of Liposomal Drug Delivery Systems with Cells and Tissues: Microscopic Studies

Liposomes , as drug carriers, can be administered into the body by several routes e.g. intravenously, intraperitoneally, intramuscularly, intratracheally and topically among others. Radiolabelled markers are suitable to monitor the distribution and elimination of liposomes, but the tissue deposition of intact liposomes, the mode and sites of drug release from the liposomes and liposome-cell interactions cannot be investigated morphologically. Microscopic techniques could provide information regarding the intact state of liposomes and possibly the dynamics of liposomes in tissues provided that they can be identified with certainty in vivo. This is a formidable problem and in spite of several attempts, there is still a lot of work and new ideas needed to overcome this problem. This paper gives a detailed review of liposome markers used in light and electron microscopy. The use of markers or the technique involved in the identification of liposomes in cells or t issues is discussed. The feasibility of using colloidal iron, a new electron dense marker, as a marker for intravenously injected liposomes was investigated in mice. Intact multilamellar vesicles containing colloidal iron were identified in the liver, spleen and lung of mice injected with liposomes. The liver and the spleen are organs for the storage of iron containing proteins (ferritin, hemosiderin), therefore studying the disposition of colloidal iron from the liposomes was not possible. However, in organs not containing iron, e.g. lung, the presence of colloidal iron can easily be recognized. The colloidal iron marker may be suitable to label liposomes targeted to the brain , heart or certain tumors

Post-Menopausal Effects of Resistance Training on Muscle Damage and Mitochondria

Manfredi, TG, Monteiro, MA, Lamont, LS, Singh, MF, Foldvari, M, White, S, Cosmas, AC, and Urso, ML. Postmenopausal effects of resistance training on muscle damage and mitochondria. J Strength Cond Res 27(2): 556–561, 2013—The purpose of this study was to measure the effects of a 12-month progressive resistance training intervention on muscle morphology and strength gains in postmenopausal women. Skeletal muscle biopsies were obtained from the vastus lateralis of 5 independent community-dwelling women (mean age: 75.6 ± 4.28 years; mean height: 163 ± 5.34 cm; mean weight: 72 ± 17.5 kg) before 6 months and 12 months after progressive resistance training. Muscle strength (1 repetition maximum) was measured at the same time points. After 6 months of training, morphological analysis revealed evidence of increased proteolysis and tissue repair, and rudimentary fiber development. The percent of Z-bands with mild Z-band disruption increased from 43.9% at baseline to 66.7% after 6 months of training (p \u3c 0.01). Mitochondrial volume also increased (percent of mitochondria = 0.86% at baseline, 1.19% at 6 months, and 1.04% at 12 months, p \u3c 0.05), and there was a shift to larger sized mitochondria. The training did not result in statistically significant increases in muscle leg strength (p \u3c 0.18). It appears that mild Z-band disruption acts as a precursor for increased protein synthesis and stimulates an increase in mitochondrial mass. Therefore, although a progressive resistance training program in this population did not increase muscle strength, it did demonstrate clinical applications that lend support to the importance of resistance training in older adults

On the role of bacterial metalloproteases in COVID-19 associated cytokine storm

The cytokine release syndrome or cytokine storm, which is the hyper-induction of inflammatory responses has a central role in the mortality rate of COVID-19 and some other viral infections. Interleukin-6 (IL-6) is a key player in the development of cytokine storms. Shedding of interleukin-6 receptor (IL-6Rα) results in the accumulation of soluble interleukin-6 receptors (sIL-6R). Only relatively few cells express membrane-bound IL-6Rα. However, sIL-6R can act on potentially all cells and organs through the ubiquitously expressed gp130, the coreceptor of IL-6Rα. Through this, so-called trans-signaling, IL-6–sIL-6R is a powerful factor in the development of cytokine storms and multiorgan involvement. Some bacteria (e.g., Serratia marcescens, Staphylococcus aureus, Pseudomonas aeruginosa, Listeria monocytogenes), commonly considered to cause co-infections during viral pneumonia, can directly induce the shedding of membrane receptors, including IL-6Rα, or enhance endogenous shedding mechanisms causing the increase of sIL-6R level. Here we hypothesise that bacteria promoting shedding and increase the sIL-6R level can be an important contributing factor for the development of cytokine storms. Therefore, inhibition of IL-6Rα shedding by drastically reducing the number of relevant bacteria may be a critical element in reducing the chance of a cytokine storm. Validation of this hypothesis can support the consideration of the prophylactic use of antibiotics more widely and at an earlier stage of infection to decrease the mortality rate of COVID-19

Optical second harmonic generation in Yttrium Aluminum Borate single crystals (theoretical simulation and experiment)

Experimental measurements of the second order susceptibilities for the second harmonic generation are reported for YAl3(BO3)4 (YAB) single crystals for the two principal tensor components xyz and yyy. First principles calculation of the linear and nonlinear optical susceptibilities for Yttrium Aluminum Borate YAl3(BO3)4 (YAB) crystal have been carried out within a framework of the full-potential linear augmented plane wave (FP-LAPW) method. Our calculations show a large anisotropy of the linear and nonlinear optical susceptibilities. The observed dependences of the second order susceptibilities for the static frequency limit and for the frequency may be a consequence of different contribution of electron-phonon interactions. The imaginary parts of the second order SHG susceptibility chi_{123}^{(2)}(omega), chi_{112}^{(2)}(omega), chi_{222}^{(2)}(omega), and chi_{213}^{(2)}(omega) are evaluated. We find that the 2(omega) inter-band and intra-band contributions to the real and imaginary parts of chi_{ijk}^{(2)}\l(omega) show opposite signs. The calculated second order susceptibilities are in reasonably good agreement with the experimental measurements.Comment: 16 pages, 11 figure

Circulation of four Anaplasma phagocytophilum ecotypes in Europe

Background: Anaplasma phagocytophilum is the etiological agent of granulocytic anaplasmosis in humans and animals. Wild animals and ticks play key roles in the enzootic cycles of the pathogen. Potential ecotypes of A. phagocytophilum have been characterized genetically, but their host range, zoonotic potential and transmission dynamics has only incompletely been resolved. Methods. The presence of A. phagocytophilum DNA was determined in more than 6000 ixodid ticks collected from the vegetation and wildlife, in 289 tissue samples from wild and domestic animals, and 69 keds collected from deer, originating from various geographic locations in The Netherlands and Belgium. From the qPCR-positive lysates, a fragment of the groEL-gene was amplified and sequenced. Additional groEL sequences from ticks and animals from Europe were obtained from GenBank, and sequences from human cases were obtained through literature searches. Statistical analyses were performed to identify A. phagocytophilum ecotypes, to assess their host range and their zoonotic potential. The population dynamics of A. phagocytophilum ecotypes was investigated using population genetic analyses. Results: DNA of A. phagocytophilum was present in all stages of questing and feeding Ixodes ricinus, feeding I. hexagonus, I. frontalis, I. trianguliceps, and deer keds, but was absent in questing I. arboricola and Dermacentor reticulatus. DNA of A. phagocytophilum was present in feeding ticks and tissues from many vertebrates, including roe deer, mouflon, red foxes, wild boar, sheep and hedgehogs but was rarely found in rodents and birds and was absent in badgers and lizards. Four geographically dispersed A. phagocytophilum ecotypes were identified, that had significantly different host ranges. All sequences from human cases belonged to only one of these ecotypes. Based on population genetic parameters, the potentially zoonotic ecotype showed significant expansion. Conclusion: Four ecotypes of A. phagocytophilum with differential enzootic cycles were identified. So far, all human cases clustered in only one of these ecotypes. The zoonotic ecotype has the broadest range of wildlife hosts. The expansion of the zoonotic A. phagocytophilum ecotype indicates a recent increase of the acarological risk of exposure of humans and animals

Comparative Genomic Hybridization (CGH) Reveals a Neo-X Chromosome and Biased Gene Movement in Stalk-Eyed Flies (Genus Teleopsis)

Chromosomal location has a significant effect on the evolutionary dynamics of genes involved in sexual dimorphism, impacting both the pattern of sex-specific gene expression and the rate of duplication and protein evolution for these genes. For nearly all non-model organisms, however, knowledge of chromosomal gene content is minimal and difficult to obtain on a genomic scale. In this study, we utilized Comparative Genomic Hybridization (CGH), using probes designed from EST sequence, to identify genes located on the X chromosome of four species in the stalk-eyed fly genus Teleopsis. Analysis of log2 ratio values of female-to-male hybridization intensities from the CGH microarrays for over 3,400 genes reveals a strongly bimodal distribution that clearly differentiates autosomal from X-linked genes for all four species. Genotyping of 33 and linkage mapping of 28 of these genes in Teleopsis dalmanni indicate the CGH results correctly identified chromosomal location in all cases. Syntenic comparison with Drosophila indicates that 90% of the X-linked genes in Teleopsis are homologous to genes located on chromosome 2L in Drosophila melanogaster, suggesting the formation of a nearly complete neo-X chromosome from Muller element B in the dipteran lineage leading to Teleopsis. Analysis of gene movement both relative to Drosophila and within Teleopsis indicates that gene movement is significantly associated with 1) rates of protein evolution, 2) the pattern of gene duplication, and 3) the evolution of eyespan sexual dimorphism. Overall, this study reveals that diopsids are a critical group for understanding the evolution of sex chromosomes within Diptera. In addition, we demonstrate that CGH is a useful technique for identifying chromosomal sex-linkage and should be applicable to other organisms with EST or partial genomic information

Ageing, Muscle Power and Physical Function: A Systematic Review and Implications for Pragmatic Training Interventions.

BACKGROUND: The physiological impairments most strongly associated with functional performance in older people are logically the most efficient therapeutic targets for exercise training interventions aimed at improving function and maintaining independence in later life. OBJECTIVES: The objectives of this review were to (1) systematically review the relationship between muscle power and functional performance in older people; (2) systematically review the effect of power training (PT) interventions on functional performance in older people; and (3) identify components of successful PT interventions relevant to pragmatic trials by scoping the literature. METHODS: Our approach involved three stages. First, we systematically reviewed evidence on the relationship between muscle power, muscle strength and functional performance and, second, we systematically reviewed PT intervention studies that included both muscle power and at least one index of functional performance as outcome measures. Finally, taking a strong pragmatic perspective, we conducted a scoping review of the PT evidence to identify the successful components of training interventions needed to provide a minimally effective training dose to improve physical function. RESULTS: Evidence from 44 studies revealed a positive association between muscle power and indices of physical function, and that muscle power is a marginally superior predictor of functional performance than muscle strength. Nine studies revealed maximal angular velocity of movement, an important component of muscle power, to be positively associated with functional performance and a better predictor of functional performance than muscle strength. We identified 31 PT studies, characterised by small sample sizes and incomplete reporting of interventions, resulting in less than one-in-five studies judged as having a low risk of bias. Thirteen studies compared traditional resistance training with PT, with ten studies reporting the superiority of PT for either muscle power or functional performance. Further studies demonstrated the efficacy of various methods of resistance and functional task PT on muscle power and functional performance, including low-load PT and low-volume interventions. CONCLUSIONS: Maximal intended movement velocity, low training load, simple training methods, low-volume training and low-frequency training were revealed as components offering potential for the development of a pragmatic intervention. Additionally, the research area is dominated by short-term interventions producing short-term gains with little consideration of the long-term maintenance of functional performance. We believe the area would benefit from larger and higher-quality studies and consideration of optimal long-term strategies to develop and maintain muscle power and physical function over years rather than weeks

Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency

BACKGROUND: While autoimmunity and hyperinflammation secondary to recombinase activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. The majority of patients (55.6%) presented with more than one autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AN), respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in the majority of cases (64.7%, 73.7%, and 71.4% for AIHA, ITP, and AN, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multi-lineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management