A Longitudinal Examination of the Relationships between Childhood Maltreatment and Patterns of Adolescent Substance Use among High-Risk Adolescents

Background: Childhood maltreatment has been linked to adolescent substance use in cross-sectional studies but the studies were unable to test the associations between childhood maltreatment and changes in substance use patterns during adolescence. The present study investigated the linkages between exposure to childhood maltreatment and developmental trends of alcohol, cannabis, cocaine, opioid, and hallucinogen use among high-risk adolescents. Methods: We used a sample of 937 adolescents (mean age: 15.9 years; range: 13-18), who were selected from five publicly-funded service systems, to examine the extent to which childhood maltreatment may influence changes in patterns of adolescent substance use over time. Results: The present study identified a 3-class model of adolescent substance use. Mover-stayer latent transition analyses (LTA) indicated that progression toward heavy polysubstance use increased with experience of childhood maltreatment. Findings also suggested that older male adolescents (ages 15-18) who are involved with public service systems are at high risk for developing and maintaining multiple-substance use in adolescence. Conclusions: Experience of childhood maltreatment is associated with problematic patterns of adolescent substance use and may shape the longitudinal course of substance use during adolescence. (Am J Addict 2012;21:453-461).     

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

An obstacle in the utilization of catalytic Abs for selective prodrug activation in cancer therapy has been systemic tumor targeting. Here we report the generation of catalytic Abs that effectively target tumor cells with undiminished prodrug activation capability. Ab conjugates were prepared by covalent conjugation of an integrin alpha(v)beta(3)-targeting antagonist to catalytic Ab 38C2 through either sulfide groups of cysteine residues generated by reduction of the disulfide bridges in the hinge region or surface lysine residues not involved in the catalytic activity. Using flow cytometry, the Ab conjugates were shown to bind efficiently to integrin alpha(v)beta(3)-expressing human breast cancer cells. The Ab conjugates also retained the retro-aldol activity of their parental catalytic Ab 38C2, as measured by methodol and doxorubicin (dox) prodrug activation. Complementing these Ab conjugates, an evolved set of dox prodrugs was designed and synthesized. Dox prodrugs that showed higher stability and lower toxicity were evaluated both in the presence and absence of the integrin alpha(v)beta(3)-targeting 38C2 conjugates for cell-killing efficacy by using human breast cancer cells. Our study reveals that cell targeting and prodrug activation capabilities can be efficiently combined for selective chemotherapy with novel dox prodrugs.     

Experimental model simulating right ventricular outflow tract tachycardia: a novel technique to initiate RVOT-VT

BACKGROUND: The mechanism(s) whereby a discrete area of myocardium in the RVOT becomes arrhythmogenic remains unknown. METHODS: In 13 dogs, a circular catheter was placed in the proximal pulmonary artery (PA) to contact the endovascular circumference of the PA. A 50-msec train of high-frequency stimulation (HFS, 200 Hz), coupled to atrial pacing, was applied at each bipolar pair of the circular catheter. The coupling interval was adjusted so that the 50-msec train occurred during the ventricular refractory period, that is, the QRS complex, in order to prevent stimulation of the myocardial sleeve within the proximal PA. RESULTS: In all dogs, HFS induced ventricular premature depolarizations and VTs with a left bundle branch block (LBBB) morphology and inferior axis (average 6.8 +/- 1.6 V). Earliest activation was consistently recorded from the proximal PA. Esmolol, a short-acting beta-blocker (1 mg/kg), was administered intravenously in 11 dogs. The inducible ventricular ectopy was abolished in 10 dogs (>12 V, P < 0.05) and the response to HFS was blunted in one dog (10-11 V). After 30 minutes, the response to HFS returned to pre-esmolol levels. CONCLUSIONS: Stimulation of the sympathetic input to the proximal PA induces ventricular ectopy and VTs exhibiting a left bundle branch block morphology and inferior axis, closely simulating clinical RVOT-VT. Beta-blockade either abolishes or blunts this response, corroborating the sympathetic etiology in this model and in some clinical cases of RVOT tachycardias.     

Microtiter Assay for Detecting Campylobacter spp. and Helicobacter pylori with Surface Gangliosides Which Bind Cholera Toxin

Campylobacter jejuni with Gm1 ganglioside in the core of its lipopolysaccharide has been associated with Guillain-Barré syndrome. Since this epitope may be of considerable pathophysiologic importance and since this ganglioside binds cholera toxin, a rapid screening assay to detect bacteria that bind cholera toxin as an indication of Gm1 on their surfaces was developed. In the assay, bacterial lawns were grown on agar plates, harvested with phosphate-buffered saline, boiled, and incubated with a standard concentration of cholera B subunit. Preparations from strains with Gm1 were observed to inhibit the binding of cholera B subunit to Gm1 in a microtiter enzyme-linked immunosorbent assay. By using this assay with two groups of strains, 37 positive strains were detected among the 197 tested. Species with positive isolates included C. jejuni, Campylobacter coli, and Helicobacter pylori. The assay is capable of testing large numbers of isolates and should prove useful in future clinical and epidemiological studies of bacteria with this epitope.     

Effect of the super-flux cellulose triacetate dialyser membrane on the removal of non-protein-bound and protein-bound uraemic solutes.

BACKGROUND: Uraemic solutes accumulate in haemodialysis (HD) patients and interfere with physiological functions. Low-flux (LF) HD does not efficiently remove all uraemic compounds. We investigated whether large pore super-flux (SF) cellulose triacetate membranes (CTA) result in a better removal of uraemic solutes. METHODS: Eleven patients were dialysed consecutively with LF-CTA and SF-CTA during 3 weeks. Urea (UR), creatinine (CR), uric acid (UA), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), indole-3-acetic acid (IAA), indoxyl sulfate (IS), hippuric acid (HA), pentosidine (PENT), low-molecular weight (MW) AGEs (AGEs) and albumin were determined in pre-HD, post-HD blood and in dialysate. Reduction rate (RR), dialytic clearance and mass transfer-area coefficient (KoA) were calculated. RESULTS: SF-HD resulted in a higher RR than LF-HD for IS and AGEs. Urea RR correlated with HA (r=0.59), IS (r=0.68) and IAA (r=0.67), (P<0.05) for SF. Dialytic clearance ranged from 20+/-5 to 179+/-20 ml/min for LF and from 24+/-6 to 191+/-24 ml/min for SF; being higher with SF for UA, HA, IS and IAA (SF vs LF, P<0.05). KoA was higher for most compounds with SF-HD. Albumin loss per SF session was 3.4+/-1.3 g. The retrieved amount of uraemic solutes in dialysate with LF and SF was comparable. CONCLUSIONS: In conventional HD, SF-CTA was superior to LF-CTA for removal of most protein-bound compounds, especially IS. Reduction rate, dialytic clearance and KoA were higher with SF. The SF-CTA membrane is albumin-leaking; however, this property could not completely explain the amount of retrieved protein-bound compounds in dialysate.     

Effect of Hospital Volume on Outcomes of Transcatheter Mitral Valve Repair: An Early US Experience

Background

Transcatheter mitral valve repair (TMVR) is a complex procedure for patients with mitral regurgitation who cannot get surgery. However, there is a lack of data on how hospital volumes affect these outcomes.

Methods

We performed a cross sectional study based on Healthcare Cost and Utilization Project's Nationwide Inpatient Sample database of 2012 and identified subjects using the ICD‐9‐CM procedure code of 35.97, which was introduced in October 2010 for percutaneous mitral valve repair if present in the primary or secondary procedure field. Hospital volumes were divided into tertiles. The primary outcome was a composite of in‐hospital mortality and peri‐procedural complications. Length of stay and hospitalization cost were also assessed.

Results

A total of 95 (weighted n = 475) TMVR procedures were identified. The mean age of the overall cohort was 70 years; 43.2% were female and 63.2% had a significant baseline burden of co‐morbidities. The composite of in‐hospital mortality and peri‐procedural complications decreased with increasing TMVR hospital volume: 48.7% in the first tertile, 17.4% in the second tertile, and 9.1% in the third tertile. Additionally, we saw a decrease in the length of stay and a trend in decrease in the hospitalization cost.

Conclusion

In hospitals performing TMVR, higher hospital volumes are associated with a reduction in a composite of in‐hospital mortality and post‐procedural complications, in addition to the shorter length of stay. (J Interven Cardiol 2015;28:464–471)