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Understanding the structural parameters of cationic amphiphiles which can influence gene transfer efficiencies of cationic amphiphiles continues to remain important for designing efficient liposomal gene delivery reagents. Previously we demonstrated the influence of structural orientation of the ester linker (widely used in covalently tethering the polar head and the non-polar tails) in modulating in vitro gene transfer efficiencies of cationic amphiphiles. However, our previously described cationic amphiphiles with ester linkers failed to deliver genes under in vivo conditions. Herein we report on the development of a highly serum compatible cationic amphiphile with circulation stable amide linker which shows remarkable selectivity in transfecting mouse lung. We also demonstrate that reversing structural orientation of the amide linker adversely affects both serum compatibility and the lung selective gene transfer property. Dynamic laser light scattering and atomic force microscopic studies revealed smaller average hydrodynamic sizes of the liposomes of transfection efficient lipid than those for the liposomes of transfection incompetent analog (148 ± 1 nm vs 214 ± 4 nm). Average surface potential of the liposomes of transfection competent amphiphiles were found to be significantly higher than that for the liposomes of transfection incompetent analog (10.7 ± 5.4 mV vs 2.8 ± 1.3 mV, respectively). Findings in fluorescence resonance energy transfer and dye entrapment experiments support lower rigidity and higher biomembrane fusogenicity of the liposomes of the transfection efficient amphiphiles. Importantly, cationic lipoplexes of the novel amide-linker based amphiphile exhibited higher mouse lung selective gene transfer properties than DOTAP, one of the widely used commercially available liposomal lung transfection kits. In summary, the present findings demonstrate for the first time that amide linker structural orientation profoundly influences the serum compatibility and lung transfection efficiencies of cationic amphiphiles.  相似文献   
2.
Toward probing an hitherto unexplored structure–activity issue namely, the relative in vitro and in vivo efficacies of cationic glycolipids with cyclic and acyclic sugar heads for targeting of genes to liver, we have designed and synthesized two novel series of cationic glycolipids with cyclic (lipids 15) and open d-galactose heads (lipids 610) containing varying spacer arm lengths in between the sugar and positively charged nitrogen atoms. Among the cyclic glycolipids, lipid 3 with six methylene units spacer in between the quaternary nitrogen atom and among the glycolipids with the open-sugar heads, lipid 6 with only two methylene units spacer were found to be the most efficacious in targeting genes to cultured HepG2 (human hepatocarcinoma cells) and primary hepatocytes. Findings in the fluorescence resonance energy transfer (FRET) studies revealed biomembrane fusibilities as important physico-chemical parameters behind the varying spacer arm dependencies in the two series. Importantly, both the serum compatible glycolipids 3 & 6 were found to be equally efficacious in selectively targeting genes to mouse livers under systemic settings. The significantly reduced efficiencies of the glycolipids 3 & 6 in transfecting primary hepatocytes as well as mice pretreated with asialofetuin (the ligands of asialoglycoprotein receptors) support the notion that the cellular uptake of the lipoplexes prepared from both the open and the cyclic sugar-head series is mediated via asialoglycoprotein receptor. In summary, our present findings demonstrate for the first time that cationic glycolipids with cyclic sugar-head require longer spacer arms than their acyclic sugar-head counterparts for efficient gene transfection and both the series hold equal promise for selective gene targeting to liver under systemic settings.  相似文献   
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4.

Objectives

To study the burden and associated risk factors for elevated blood lead levels among pre-school children (15–24 months) in urban Vellore, and to study its effects on child cognition and anemia.

Design

An investigative study through Mal-ED cohort.

Setting

Eight adjacent urban slums in Vellore, Tamil Nadu.

Participants

251 babies recruited through Mal-ED Network.

Outcome measures

Blood lead levels using Graphite Furnace Atomic Absorption Spectrophotometry method at 15 and 24 mo; hemoglobin estimation by azidemethemoglobin method; cognitive levels using Bayley Scales of Infant Development III.

Results

Around 45% of children at 15 months and 46.4% at 24 months had elevated blood lead levels (>10 μg/dL). Among children who had elevated blood lead levels at 15 months, 69.2% (45/65) continued to have elevated levels at 24 months. After adjusting for potential confounders, children from houses having a piped drinking water supply and houses with mud or clay floors were at significantly higher risk of having elevated blood lead levels at 15 months. Thirty one percent (21/67) of the children with elevated blood lead levels had poor cognitive scores. Children with elevated blood lead levels at 15 months had higher risk (Adjusted OR 1.80; 95% CI 0.80–3.99) of having poorer cognitive scores at 24 months. More than half of the children (57%) were anemic at 15 months of age, and elevated blood lead levels were not significantly associated with anemia.

Conclusions

Elevated blood lead levels are common among preschool children living in urban slums of Vellore. Poorer conditions of the living environment are associated with elevated lead levels.  相似文献   
5.
The purpose of the present study was to evaluate the effect of Telmisartan (Tel) and Losartan (Los) on nanoparticle intratumoral distribution and anticancer effects in lung cancer. A549 lung tumor cells were orthotopically and metastatically administered to Nu/nu mice. Fluorescent polystyrene nanoparticles (FPNPs, size ~ 200 nm) beads were used to study their intratumoral distribution after Tel and Los treatments. Animals were administered with FPNPs and after 2 h, FPNPs intratumoral distribution was studied by fluorescent microscopy. Tel (~ 1.12 mg/kg) and Los (~ 4.5 mg/kg) were administered by inhalation delivery at alternative days for 4 weeks to tumor bearing animals. Collagen-1, transforming growth factor beta 1 (TGF-β1), cleaved caspase-3, Vimentin and E-Cadherin expressions were studied by western blotting. To correlate the AT1 receptor blockage to anticancer effects, VEGF levels and microvessel densities (MVD) were quantified. Los and Tel treated group resulted in the 5.33 and 14.33 fold increase respectively in the FPNPs intratumoral distribution as compared to the controls. Tel treatment attenuated 2.23 and 1.70 fold Collagen 1 expression compared to untreated control and Los groups, respectively. Further, in Tel and Los treated groups, the TGF-β1 active levels were significantly (p < 0.05) decreased. Tel (at four times less dose) was 1.89 and 1.92 fold superior in anticancer activity to Los respectively in A549 orthotopic and metastatic tumor models (p < 0.05) when given by inhalation route. Tel, by virtue of its dual pharmacophoric nature could be an ideal candidate for combination therapy to improve the nanoparticle intratumoral distribution and anticancer effects.  相似文献   
6.
Aminoglycosides are potent antibacterials, but therapy is compromised by substantial toxicity causing, in particular, irreversible hearing loss. Aminoglycoside ototoxicity occurs both in a sporadic dose-dependent and in a genetically predisposed fashion. We recently have developed a mechanistic concept that postulates a key role for the mitochondrial ribosome (mitoribosome) in aminoglycoside ototoxicity. We now report on the surprising finding that apramycin, a structurally unique aminoglycoside licensed for veterinary use, shows little activity toward eukaryotic ribosomes, including hybrid ribosomes which were genetically engineered to carry the mitoribosomal aminoglycoside-susceptibility A1555G allele. In ex vivo cultures of cochlear explants and in the in vivo guinea pig model of chronic ototoxicity, apramycin causes only little hair cell damage and hearing loss but it is a potent antibacterial with good activity against a range of clinical pathogens, including multidrug-resistant Mycobacterium tuberculosis. These data provide proof of concept that antibacterial activity can be dissected from aminoglycoside ototoxicity. Together with 3D structures of apramycin-ribosome complexes at 3.5-Å resolution, our results provide a conceptual framework for further development of less toxic aminoglycosides by hypothesis-driven chemical synthesis.  相似文献   
7.
Pancreatic ductal adenocarcinoma (PDAC) represents a challenging pathology with very poor outcomes and is increasing in incidence within the general population. The majority of patients are diagnosed incidentally with insidious symptoms and hence present late in the disease process. This significantly affects patient outcomes: the only cure is surgical resection but only up to 20% of patients present with resectable disease at the time of clinical presentation. The use of “omic” technology is expanding rapidly in the field of personalised medicine - using genomic, proteomic and metabolomic approaches allows researchers and clinicians to delve deep into the core molecular processes of this difficult disease. This review gives an overview of the current findings in PDAC using these “omic” approaches and summarises useful markers in aiding clinicians treating PDAC. Future strategies incorporating these findings and potential application of these methods are presented in this review article.  相似文献   
8.
We report a case of successful reuse of a previously transplanted heart. The organ was retransplanted 16 days after the initial transplantation into a 60-year-old man who had previously received a left ventricular assist device.  相似文献   
9.

Objective(s)

We aimed at evaluating the predictive value of amniotic fluid index ≤5 on perinatal outcome in terms of effect on cardiotocography, mode of delivery, meconium in liquor, birth weight, fetal distress, APGAR score at birth and neonatal admission to ICU.

Method(s)

This is a prospective study of 308 antenatal women admitted to labor ward of MIMS during February 2014–December 2015 with gestational ages between 34 and 41 weeks. All women enrolled were subjected to history taking, examination, AFI estimation and compared between those with AFI ≤5 from rest.

Results

The non-reactive CTG, cesarean section rate due to fetal distress, low birth weight, APGAR score <7 and NICU admission were significantly high among those with oligoamnios than the control group.

Conclusion

Oligoamnios has a significant correlation with adverse perinatal outcome.
  相似文献   
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