Development of PLGA micro- and nanorods with high capacity of surface ligand conjugation for enhanced targeted delivery

 Particle shape has been recognized as one of the key properties of nanoparticles in biomedical applications including targeted drug delivery. Targeting ability of shape-engineered particles depends largely on targeting ligands conjugated on the particle surface. However, poor capacity for surface ligand conjugation remains a problem in anisotropic nanoparticles made with biodegradable polymers such as PLGA. In this study, we prepared anisotropic PLGA nanoparticles with abundant conjugatable surface functional groups by a film stretching-based fabrication method with poly (ethylene-alt-maleic acid) (PEMA). Scanning electron microscopy images showed that microrods and nanorods were successfully fabricated by the PEMA-based film stretching method. The presence of surface carboxylic acid groups was confirmed by confocal microscopy and zeta potential measurements. Using the improved film-stretching method, the amount of protein conjugated to the surface of nanorods was increased three-fold. Transferrin-conjugated, nanorods fabricated by the improved method exhibited higher binding and internalization than unmodified counterparts. Therefore, the PEMA-based film-stretching system presented in this study would be a promising fabrication method for non-spherical biodegradable polymeric micro- and nanoparticles with high capacity of surface modifications for enhanced targeted delivery     

Arterial embolization and prophylactic catheterization for the treatment for severe obstetric hemorrhage*

BACKGROUND. To evaluate indications, efficacy, and complications associated with arterial embolization and prophylactic balloon catheterization in the management of obstetric hemorrhage at a university hospital. METHODS. Twenty-two women underwent arterial embolization between February 2001 and November 2003 for the treatment for primary postpartum hemorrhage resulting from abnormal placentation (n=11), uterine atony (n=7), paravaginal laceration (n=3), and disseminated intravascular coagulopathy (n=1). Blood loss was between 3.2 and 15 l. In seven patients, abnormal placentation was diagnosed prenatally and in these patients balloon catheterization was performed prophylactically before elective cesarean section. RESULTS. Of the seven patients, who underwent prophylactic catheterization, embolization was successful in five resulting in adequate hemostasis. Hysterectomy was performed in three, in two patients for uncontrolled hemorrhage and in one patient for placental invasion to bladder. There were no complications associated with prophylactic catheterization and embolization. The other 15 patients were treated in an emergency setting. In eight patients, embolization was performed as a primary surgery, and it was successful in six. In the other seven patients, hysterectomy was performed as an emergency surgery, but bleeding continued. Of these, in six patients, hemostasis was achieved with embolization. Complications associated with emergency embolization were observed in three patients. These were thrombosis of left popliteal artery, vaginal necrosis, and paresthesia of the right leg. CONCLUSIONS. Arterial embolization is of significant value in treating obstetric hemorrhage. Prophylactic insertion of balloon catheters before cesarean section seems to be a safe and effective method in controlling anticipated bleeding. In patients with persistent bleeding following cesarean section and hysterectomy, embolization could be a primary procedure before re-surgery.     

MRI-guided percutaneous nephrostomy: a feasibility study

The purpose of this study was to assess the feasibility and safety of magnetic resonance imaging (MRI)-guided PCN in an open-configuration low-field MRI system. Eight patients were prospectively enrolled in the study. The degree of the dilatation of the renal collecting system varied from minimal to severe. All procedures were performed solely under MRI guidance with a 0.23-T open configuration C-arm-shaped MRI system with interventional optical tracking. In each case, PCN was performed with a MRI-compatible drainage kit using the Seldinger technique. Seven out of eight nephrostomies were successfully performed under MRI guidance. All PCN procedures in dilated renal collection systems were successful; however, nephrostomy catheter could not be placed in a nondilated system. The mean time needed for the MRI-guided PCN was 26 min. No major complications occurred during the procedure or follow-up. MRI-guided PCN in dilated renal collection system is feasible and safe. The presented technique has limitations that necessitate further technical developments before the procedure can be applied to nondilated kidneys and recommended for routine clinical use.     

New method for analysing sensitivity distributions of electroencephalography measurements

In this paper, we introduce a new modelling related parameter called region of interest sensitivity ratio (ROISR), which describes how well the sensitivity of an electroencephalography (EEG) measurement is concentrated within the region of interest (ROI), i.e. how specific the measurement is to the sources in ROI. We demonstrate the use of the concept by analysing the sensitivity distributions of bipolar EEG measurement. We studied the effects of interelectrode distance of a bipolar EEG lead on the ROISR with cortical and non-cortical ROIs. The sensitivity distributions of EEG leads were calculated analytically by applying a three-layer spherical head model. We suggest that the developed parameter has correlation to the signal-to-noise ratio (SNR) of a measurement, and thus we studied the correlation between ROISR and SNR with 254-channel visual evoked potential (VEP) measurements of two testees. Theoretical simulations indicate that source orientation and location have major impact on the specificity and therefore they should be taken into account when the optimal bipolar electrode configuration is selected. The results also imply that the new ROISR method bears a strong correlation to the SNR of measurement and can thus be applied in the future studies to efficiently evaluate and optimize EEG measurement setups.     

Seasonality of striatal dopamine synthesis capacity in Parkinson's disease

Recent neuroimaging evidence suggests that the healthy human brain dopaminergic system may show seasonal rhythmicity, as striatal dopamine synthesis capacity has been reported to be higher during fall and winter. There is additional evidence about season of birth effects on morbidity in several neuropsychiatric disorders. We investigated possible seasonal changes in dopamine synthesis capacity in a relatively large sample of Parkinson's disease patients. 6-[¹⁸F]fluoro-l-DOPA brain PET scans for 109 Parkinson's disease patients were performed during different seasons and the effects of season of scanning and season of birth on striatal tracer uptake were studied, controlling for covariates such as age, sex and disease severity. The patients scanned during fall and winter had 15% higher tracer uptake in the right putamen compared to patients scanned during spring and summer (p = 0.04). Patients born during winter and spring had 10% higher dopamine synthesis capacity in the left caudate (p = 0.008), 8% higher capacity in the right caudate (p = 0.04) and 16% higher capacity in the putamen contralateral to the side of predominant motor symptoms (p = 0.02) compared to patients born during summer and fall (after correcting for differences in age, sex, disease severity, scanner and season of scanning). The results suggest that there are seasonal oscillations also in the hypoactive dopaminergic system of Parkinson's disease patients. Findings concerning season of birth further suggest that there may be gestational or perinatal seasonal factors, which influence dopaminergic function in adulthood.     

Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck.

Squamous cell carcinomas (SCCs) of the head and neck are malignant tumors with high capacity to invade and metastasize. We have examined expression of the new collagenase, collagenase-3 (MMP-13), in SCCs of the head and neck. MMP-13 mRNAs were detected in 22 of 29 SCC cell lines: in 14 of 15 primary SCC cell lines and in 8 of 14 SCC cell lines from recurrent tumors or metastases. MMP-13 mRNAs were expressed by all 6 cell lines from highly invasive primary tumors and in all 4 cell lines from small aggressive tumors. Using in situ hybridization, MMP-13 mRNAs were detected in 15 of 17 SCC tumor samples. In most tumors, MMP-13 was expressed by tumor cells at the invading front of the tumors, but in a subset of SCCs, MMP-13 mRNA was also expressed by stromal fibroblasts. No MMP-13 expression was detected in intact skin or oral mucosa. MMP-13 mRNA levels in SCC cells were enhanced by transforming growth factor-beta, tumor necrosis factor-alpha, transforming growth factor-alpha, and keratinocyte growth factor. Specific expression of MMP-13 by SCC cells in vitro and in vivo strongly suggests a role for MMP-13 in the high invasion capacity of SCC cells.     

Albumin-Coated Porous Hollow Poly(Lactic-co-Glycolic Acid) Microparticles Bound with Palmityl-Acylated Exendin-4 as a Long-Acting Inhalation Delivery System for the Treatment of Diabetes

Purpose  

To study the development of porous poly(lactic-co-glycolic acid) microparticles (PLGA MPs) coated initially with albumin and then with palmityl-acylated exendin-4 (Pal-Ex4) as an inhalation system for treating diabetes.     

Enhanced expression of human metalloelastase (MMP-12) in cutaneous granulomas and macrophage migration

Accumulation of inflammatory cells such as macrophages may lead to degeneration of connective tissue matrix in various skin diseases. Macrophage metalloelastase, is a matrix metalloproteinase (MMP-12) capable of degrading elastin as well as various basement membrane components. To investigate the role of human macrophage metalloelastase in skin, we assessed by in situ hybridization and immunohistochemistry 66 specimens representing skin diseases characterized either by changes in elastic fibers or by pronounced infiltrations of extravasating and migrating macrophages. CD68 immunostaining was performed to identify the human macrophage metalloelastase-positive cells and Weigert's Resorcin-Fuchsin staining to reveal the status of elastic fibers. We found abundant expression of human macrophage metalloelastase mRNA in macrophages in areas devoid of normal elastic fibers in granulomatous skin diseases sarcoidosis, necrobiosis lipoidica diabeticorum, and granuloma annulare. Positive cells for human macrophage metalloelastase protein could be detected in the same regions as well as positive immunostaining for urokinase plasminogen activator. Of the other matrix metalloproteinases capable of degrading elastin, 92 kDa gelatinase colocalized with human macrophage metalloelastase, while 72 kDa gelatinase was produced by surrounding fibroblast-like cells. Furthermore, human macrophage metalloelastase was expressed by macrophages in areas with disrupted basement membrane, as assessed by type IV collagen staining, in pityriasis lichenoides and dermatitis herpetiformis. Specimens of anetoderma, acrodermatitis chronica atrophicans and pseudoxanthoma elasticum showed no signal for human macrophage metalloelastase. Matrilysin was not detected in any of the samples investigated. Our study suggests that human macrophage metalloelastase may contribute to elastin degradation occurring in granulomatous skin diseases and may aid macrophage migration through the epidermal and vascular basement membranes in inflammatory disorders.