Engineering of NIR fluorescent PEGylated poly(RGD) proteinoid polymers and nanoparticles for drug delivery applications in chicken embryo and mouse models

Proteinoids are non-toxic biodegradable polymers based on thermal step-growth polymerization of natural or synthetic amino acids. Hollow proteinoid nanoparticles (NPs) may then be formed via a self-assembly process of the proteinoid polymers in an aqueous solution. In the present article polymers and NPs based on d-arginine, glycine and l-aspartic acid, poly(R^DGD), were synthesized for tumor targeting, particularly due to the high affinity of the RGD motif to areas of angiogenesis. Near IR fluorescent P(R^DGD) NPs were prepared by encapsulating the fluorescent NIR dye indocyanine green (ICG) within the formed P(R^DGD) NPs. Here, we investigate the effect of the covalent conjugation of polyethylene glycol (PEG), with different molecular weights, to the surface of the near IR encapsulated P(R^DGD) NPs on the release of the dye to human serum due to bio-degradation of the proteinoid NPs and on the uptake by tumors. This work illustrates that the release of the encapsulated ICG from the non-PEGylated NPs is significantly faster than for that observed for the PEGylated NPs, and that the higher molecular weight is the bound PEG spacer the slower is the dye release profile. In addition, in a chicken embryo model, the non-PEGylated ICG-encapsulated P(R^DGD) NPs exhibited a higher uptake in the tumor region in comparison to the PEGylated ICG-encapsulated P(R^DGD) NPs. However, in a tumor xenograft mouse model, which enables a prolonged experiment, the importance of the PEG is clearly noticeable, when a high concentration of PEGylated P(R^DGD) NPs was accumulated in the area of the tumor compared to the non-PEGylated P(R^DGD). Moreover, the length of the PEG chain plays a major role in the ability to target the tumor. Hence, we can conclude that selectivity towards the tumor area of non-PEGylated and the PEGylated ICG-encapsulated P(R^DGD) NPs can be utilized for targeting to areas of angiogenesis, such as in the cases of tumors, wounds or cuts, etc.

Synthesis of NIR/ICG PEGylated poly(R^DGD) proteinoid NPs and their drug delivery towards mCherry-labeled 4T1 tumor.     

Detection of severe pulmonary hypertension based on computed tomography pulmonary angiography

The International Journal of Cardiovascular Imaging - Pulmonary hypertension (PH) is often diagnosed late in the disease course. As many patients may undergo computed tomography pulmonary...     

Correlation between body mass index and chondral lesions in isolated medial meniscus tears

Background:

Chondral lesions of the knee are commonly found during arthroscopic partial meniscectomy. The literature advises against arthroscopic medial meniscectomy in the presence of advanced chondral derangement because of unfavorable outcome. Recent studies have shown an association between obesity and chondropathy in patients with meniscal tears. The aim of this study was to assess whether body mass index (BMI) correlates with the severity of chondral lesions in patients with isolated medial meniscus tears (i.e. without ligamentous or lateral meniscal injury).

Materials and Methods:

837 knee arthroscopies were performed in a regional referral center of arthroscopic surgery between January 2011 and December 2012. Of these 168 (109 males, 59 females) patients with no axial knee deformity and no radiological signs of osteoarthritis who have had arthroscopic debridement for isolated torn medial meniscus were included in the study. The correlation between different demographic factors and the level of chondral damage reported at surgery was evaluated. The mean age of patient was 50 years (range 13-82 years) and an average BMI was 28.2 kg/m² (range17.5-42.5 kg/m²).

Results:

Overall, regression analysis showed both age and BMI to be linearly correlated to chondral score (r = 0.53, P < 0.04); however, there were no advanced chondral lesions found in patients younger than 40 years of age and all severe lesions were at age 50 years or more. Therefore, further analysis was performed for age subgroups: patients were grouped as younger than 40, between the age of 40 and 50 (middle age) and older than 50 years. The BMI was linearly correlated to the severity of chondral score exclusively in the middle aged group (i.e. 40-50 years old). There was no correlation between activity level and chondral damage. Women had worse chondral lesions than men in all age groups.

Conclusion:

Higher BMI in middle aged patients with isolated medial meniscus tears and unremarkable radiographs may predict more advanced chondral lesions at arthroscopy.     

RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy

We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.     

Current status and future opportunities for controlling acromegaly

Growth-hormone (GH) secreting adenomas, including acromegaly, account for approximately one-sixth of all pituitary adenomas and are associated with mortality rates at least twice that of the general population. The ultimate goal of therapy for acromegaly is normalization of morbidity and mortality rates achieved through removal or reduction of the tumor mass and normalization of insulin-like growth factor I (IGF-I) levels. Previously published efficacy results of current treatment modalities (surgery, conventional radiation, and medical therapy with dopamine agonists and somatostatin analogs) are often difficult to compare because of the different criteria used to define cure (some of which are now considered inadequate). For each of these modalities, pooled data from a series of acromegaly studies were reviewed for rates of IGF-I normalization, a currently accepted definition of cure. The results showed overall cure rates of approximately 10% for bromocriptine, 34% for cabergoline, 36% for conventional radiation, 50–90% for surgery for microadenomas and less than 50% for macroadenomas, and 54–66% for octreotide. These cure rates based on IGF-I normalization are generally less than those reported for cure based solely on GH levels. Novel new therapies for acromegaly include the somatostatin analog, lanreotide, Gamma Knife radiosurgery, and pegvisomant, the first in its class of new GH receptor antagonists. Although it does not appear that Gamma Knife radiosurgery results in significantly higher cure rates or fewer complications, it does provide a notable improvement in delivery compared with conventional radiation. Early studies have reported IGF-I normalization in 48% of lanreotide-treated patients and up to 97% of pegvisomant-treated.     

Percutaneous coronary interventions in diabetic patients: is complete revascularization important?

BACKGROUND: The long-term prognosis of diabetic patients with multivessel coronary artery disease (CAD) treated by surgical or percutaneous coronary revascularization is significantly worse as compared to non-diabetics. Lower rates of complete revascularization may be one factor that influences the poor long-term outcome in the diabetic population. Our study assessed the impact of complete revascularization on the long-term prognosis in diabetic patients with CAD treated by percutaneous coronary intervention (PCI). The study included 658 consecutive diabetic patients (mean age, 60.9+/-10.1 years) who underwent PCI. Multivessel disease was present in 352 patients (53.5%). Revascularization was complete in 94 (26.7%) and incomplete in 258 (73.3%) patients with multivessel disease. Reasons for incomplete revascularization included angioplasty of only the culprit lesion (43.4%); small vessel size (22.8%); moderate lesion, defined as diameter stenosis 50-69% (18.6%); chronic total occlusion of the non-intervened vessel (6.6%); and others (8.5%). Overall survival rate at 5 years was 87.4%. Patients who underwent complete revascularization had a 94.5% survival rate, compared to 83.0% for those with incomplete revascularization (p<0.001). Similarly, the rates of myocardial infarction-free survival were significantly higher in patients with complete versus incomplete revascularization (92.9% versus 79.9%, respectively). Incomplete revascularization was the most powerful independent predictor of mortality at follow-up (relative risk 95% confidence interval, 1.54-7.69; p=0.003). Our data suggest that complete myocardial revascularization may improve the long-term prognosis after PCI of diabetic patients with multivessel CAD.     

Ultrasonically Guided Fine-Needle Aspiration of Liver Lesions

The aim of the present study was to determine the diagnostic accuracy of ultrasonically guided fine-needle aspiration for liver lesions detected by ultrasound scan. A total of 142 aspirations were carried out in 129 patients with unifocal or multifocal liver lesions suspected of malignancy. The aspiration was made with a 22-gauge needle, guided by ultrasound. Based on histological, cytological, and clinical findings, final diagnoses were reached in 123 patients, 96 of whom had malignant liver disease and 27 benign liver disease. Among the 96 patients with malignant liver disease, the cytological findings revealed malignancy in 78 patients (81.3%) and suspected malignancy in five patients (5.1%), but failed to demonstrate malignancy in 13 patients (13.3%). Among 27 patients with benign liver disease, all the cytological findings indicated benignancy. The overall sensitivity, specificity, and positive and negative predictive values for cytological findings were 86.5%, 100%, 100%, and 76.9%, respectively. The diagnostic accuracy of ultrasonically guided fine-needle aspiration was 89.4%. In one patient with incipient chronic disseminated intravascular coagulation, a fatal intraperitoneal bleeding complicated the procedure. We conclude that ultrasonically guided FNA for cytologic diagnosis of liver lesions is highly accurate and is only rarely associated with fatal complication.     

Transient electromechanical dissociation in hypertrophic cardiomyopathy

We describe a patient with hypertrophic cardiomyopathy who experienced several episodes of syncopal attacks, in whom the mechanism was transient electromechanical dissociation.     

Management and outcomes of elderly women and men with acute coronary syndromes in 2000 and 2002

BACKGROUND: Previous studies have suggested that women with myocardial infarction are treated less aggressively and have worse outcomes compared with men. The objective of this study was to evaluate sex differences in the management and outcomes of elderly (age > or = 70 years) women and men with acute coronary syndromes (ACSs) in the new millennium. METHODS: This study includes 1331 consecutive elderly patients with ACSs admitted to all intensive coronary care units and cardiology departments in Israel from 2 prospective nationwide ACS surveys conducted in 2000 and 2002. RESULTS: The mean age of women vs men was comparable (79 vs 78 years). Comorbidities were more frequent in women, whereas previous coronary disease and typical anginal pain on admission were more frequent in men. Medical treatments and revascularization procedures during the index hospitalization were comparable in both groups. Crude and covariate-adjusted mortality rates were higher in women at 7 days (12% vs 7%; P = .007; adjusted odds ratio [OR], 1.83; 95% confidence interval [CI], 1.15-2.91) but not at 6 months (21% vs 19%; adjusted OR, 1.10; 95% CI, 0.79-1.52). This difference was attributed to ST elevation (STE)-ACS in women vs men (19% vs 12%; P = .007; adjusted OR, 1.97; 95% CI, 1.14-3.46). Seven-day mortality rates were highest in patients with STE-ACS denied coronary angiography, especially women (23% vs 15%; P = .06). CONCLUSIONS: In the 2000s, elderly women and men with ACSs are receiving similar medical and invasive management during the index hospitalization; however, women with STE-ACS have higher mortality rates at 7 days but not at 6 months. Mortality rates are highest in patients with STE-ACS denied coronary angiography. The benefit of invasive procedures on mortality rates in elderly patients with STE-ACS needs further investigation.