Functionalized poly(lactic-co-glycolic acid) enhances drug delivery and provides chemical moieties for surface engineering while preserving biocompatibility

Poly(lactic-co-glycolic acid) (PLGA) is one of the more widely used polymers for biomedical applications. Nonetheless, PLGA lacks chemical moieties that facilitate cellular interactions and surface chemistries. Furthermore, incorporation of hydrophilic molecules is often problematic. The integration of polymer functionalities would afford the opportunity to alter device characteristics, thereby enabling control over drug interactions, conjugations and cellular phenomena. In an effort to introduce amine functionalities and improve polymer versatility, we synthesized two block copolymers (PLGA-PLL 502H and PLGA-PLL 503H) composed of PLGA and poly(ε-carbobenzoxy-l-lysine) utilizing dicyclohexyl carbodiimide coupling. PLGA-PLL microspheres encapsulated approximately sixfold (502H) and threefold (503H) more vascular endothelial growth factor, and 41% (503H) more ciliary neurotrophic factor than their PLGA counterparts. While the amine functionalities were amenable to the delivery of large molecules and surface conjugations, they did not compromise polymer biocompatibility. With the versatile combination of properties, biocompatibility and ease of synthesis, these block copolymers have the potential for diverse utility in the fields of drug delivery and tissue engineering.     

Monoclonal antibodies directed to the erbB-2 receptor inhibit in vivo tumour cell growth.

Four monoclonal antibodies (MAbs) specific for the extracellular domain of the human erbB-2/HER2 protein (FRP5, FSP16, FWP51 and FSP77) have been isolated (Harwerth et al., J. Biol. Chem., 267, 15160-15167, 1992). In this paper we describe the effects of erbB-2 specific MAb administration on the tumorigenic growth of human erbB-2 transformed NIH3T3 cells implanted into athymic nude mice. Two antibodies, FWP51 and FSP77, inhibited the onset of tumour growth, while the administration of FRP5 and FSP16 did not affect tumour growth. In addition, administration of MAbs FWP51 and FSP77 led to a retardation in the growth of established tumours. Treatment was not curative in that tumours regrew within two weeks of the final treatment. The administration of a combination of MAbs FWP51 and FSP77 which react with two distinct regions on the erbB-2 molecule was more effective than treatment with either MAb alone. The two growth-inhibitory antibodies were also effective in the treatment of tumours established from SKOV3 cells, a human ovarian tumour cell line with high levels of the erbB-2 protein. The effect of the MAbs on the anchorage-independent growth of erbB-2 transformed cells and on erbB-2 receptor turnover was also measured.     

Folate analogues as inhibitors of thymidylate synthase

Recent demonstrations that deazafolate analogues may act as potent inhibitors of thymidylate synthase (TS) provided a firm rationale for the synthesis of N10-propargyl derivatives of 8-deazafolate and 8-deazaaminopterin (4). A complete assignment of the 1H NMR spectra of these compounds was made possible through application of 2D (COSY) techniques at 200 MHz. Data describing the inhibition of TS derived from human leukemia (K562) cells are presented. IC50 values of 2.25 and 1.26 microM were determined for 8-deaza-10-propargylfolate (3) and 8-deaza-10-propargylaminopterin, respectively. Comparison of the data for various folate analogues reveals a striking dependence of TS inhibitory potency upon the number of nitrogens in the folate pyrazine ring.     

Interest in multipurpose prevention technologies to prevent HIV/STIs and unintended pregnancy among young women in the United States

Objective

High rates of sexually transmitted infections (STIs) and unintended pregnancy suggest a role for multipurpose prevention technologies (MPTs) designed to combine contraception and infection prophylaxis into one unified method. This study aims to determine factors associated with interest in MPTs among US women.

A prospective study of urinary electrolytes and bone turnover in adolescent males

BACKGROUND & AIMS: The role of excessive salt on bone metabolism in children is uncertain. The aim of this 6-week prospective study was to describe the association between urinary electrolytes and bone turnover markers in a convenience sample of adolescent boys (N = 136, mean age 16 yr). METHODS: Urinary electrolytes (sodium, potassium, calcium and magnesium) were assessed on spot overnight urines on three occasions to minimise regression dilution bias. Bone turnover was assessed by bone specific alkaline phosphatase (BAP) and urinary pyridinoline (PYR) at baseline and follow up. RESULTS: In multivariate analysis, urinary sodium (but not other electrolytes) was positively associated with both PYR and BAP both before and after taking short-term growth into account (both p < 0.05) and explained 3-6% of the variation in bone turnover markers. Urinary sodium was associated with urinary magnesium (r = +0.26, p < 0.05) but only weakly with calcium (r = +0.18, p = 0.08). Urinary potassium was significantly associated with urinary magnesium (r = -0.24, p < 0.05). CONCLUSION: High urinary sodium (which largely reflects dietary sodium intake in our location) results in a high bone turnover state in adolescent boys which is most likely detrimental for bone. Other urinary electrolytes are not related to bone turnover but may influence bone via other pathways.     

Patient satisfaction and use of Veterans Affairs versus non-Veterans Affairs healthcare services by veterans

OBJECTIVES: Chronically ill patients who are not satisfied with their care may change healthcare providers or systems, which could disrupt continuity of care and impede management of their conditions. We examined whether patient satisfaction affected subsequent use of non-Veterans Affairs (VA) services among chronically ill veterans discharged from VA hospitals. METHODS: The data used in this study came from a multicenter trial of increased access to primary care. We enrolled patients with diabetes, heart failure, and/or chronic obstructive pulmonary disease who were discharged from 1 of 9 VA medical centers. At baseline, we assessed satisfaction using the Patient Satisfaction Questionnaire. VA and non-VA utilization over the subsequent 6 months were assessed using VA and Medicare administrative data, non-VA billing data, and patient interviews. Using multivariable logistic regression analyses, we examined whether baseline patient satisfaction was associated with non-VA inpatient or outpatient utilization during the next 6 months. We conducted the same analysis for Medicare-eligible veterans, a group with better access to non-VA care. RESULTS: Of 1375 study patients, 174 (13%) used non-VA healthcare. Patients with non-VA utilization were older and lived farther from a VA. The odds of non-VA use decreased by 11% as satisfaction increased (odds ratio 0.89; 95% confidence interval 0.83-0.97; P = 0.005). This relationship was strongest among Medicare-eligible veterans (odds ratio 0.85; 95% confidence interval 0.77-0.93; P = 0.001). CONCLUSIONS: Dissatisfied veterans discharged from the hospital were more likely to go outside VA for care. Thus, improvements in patient satisfaction may lead to improvements in continuity of care.     

Hormone-responsive expression of an endogenous proviral gene of mouse mammary tumor virus after molecular cloning and gene transfer into cultured cells

A recombinant lambda phage containing mouse mammary tumor virus (MMTV) proviral DNA was isolated from a gene library constructed from GR mouse liver DNA. Restriction enzyme analyses reveal that the cloned molecule contains a copy of one of the GR endogenous MMTV proviruses flanked on both sides by 2--3 kb of mouse genomic DNA. In this report we have examined the expression of the cloned MMTV provirus after cotransfection with the herpes thymidine kinase (TK; ATP:thymidine 5'-phosphotransferase,, EC 2.7.1.21) gene and integration into mouse LTK- cells. Nine individual TK+ transformants were selected, and all were found to contain MMTV-transfected DNA. One of the TK+ transformants was chosen for further study. Total poly(A)-containing RNA was isolated from the cells, and liquid hybridization analyses with MMTV cDNA showed that it contained 0.02% MMTV-specific RNA. The sizes of the MMTV-specific species were determined and found to correspond to the 35S and 24S mRNAs synthesized in MMTV-infected cells. Glucocorticoid hormones have been shown to increase the concentration of MMTV RNA in virus-infected cultured cells. Therefore, we tested the effect of dexamethasone on the concentration of MMTV-specific RNA in cells transfected with the MMTV proviral DNA. The amount of MMTV-specific poly(A)-containing RNA found in the cells grown in the presence of hormone was 0.17%. Therefore, dexamethasone causes an 8-fold increase in the amount of MMTV-specific RNA in mouse cells containing several copies of a cloned and transfected MMTV proviral gene.     

Obstructive sleep apnea is associated with alterations in markers of fetoplacental wellbeing

Background: Obstructive sleep apnea (OSA) has been associated with adverse fetal outcomes in some studies. Second trimester Down syndrome screening markers reflect fetal and fetoplacental wellbeing. We aimed to compare markers of fetal and feto-placental wellbeing in women with OSA and low risk controls.

Methods: A retrospective case-control study of pregnant women with OSA and available second trimester markers was performed. Controls were screened for sleep disordered breathing (SDB) at the time of delivery using a questionnaire. Women at low risk for OSA were selected. Marker levels were adjusted for gestational age and race and reported as multiples of median and later adjusted for body mass index (BMI).

Results: Twenty-four OSA cases and 166 controls were identified. Women with OSA had a higher mean BMI when compared to controls (37.1?±?12.7 versus 24.1?±?5.1, p?=?0.03). Estriol (uE3) multiples of the median (MoM) levels were lower in women with OSA compared to controls, even after adjusting for BMI, 0.74 (interquartile range (IQR) 0.45) versus 1.06 (IQR 0.38), respectively, p?=?0.026. Once adjusted for BMI, alpha feto-protein (AFP) MoM levels were no longer significantly different in women with OSA compared to controls.

Conclusion: OSA is associated with reduced serum uE3 levels, independently of BMI, possibly indicating fetal distress.