The impact of advanced chronic kidney disease on in-hospital mortality following percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: The impact of advanced chronic kidney disease (CKD) on the outcomes of patients undergoing percutaneous coronary intervention (PCI) in the acute phase of myocardial infarction is poorly understood. We assessed the impact of CKD (stages 3-5) on the in-hospital outcomes of patients undergoing PCI for acute myocardial infarction (AMI) in a statewide registry. METHODS: This study evaluated all patients who underwent PCI in New York State between 1997 and 1999. Of the 9,015 patients, 94 (1%) had at least stage 3 CKD (serum creatinine for AMI > 2.5 mg/dL) and were not on dialysis. Patients with advanced CKD were compared with those without advanced CKD using univariate and multivariate methods. The primary outcome of interest was in-hospital mortality. RESULTS: Patients with advanced CKD had a higher incidence of diabetes, hypertension, and peripheral vascular disease. Patients with advanced CKD presented more commonly with cardiogenic shock or heart failure. The unadjusted in-hospital mortality was 23.4% for patients with advanced CKD compared with 4.2% for patients without advanced CKD (P < 0.001). After adjusting for the increased comorbidity and high risk clinical features, advanced CKD remained an independent predictor of in-hospital mortality (odds ratio 2.4, 95% Confidence Interval, 1.002-5.804, P = 0.049). CONCLUSIONS: Patients with AMI and advanced CKD who undergo PCI have more comorbidities and significantly worse in-hospital outcomes than patients without advanced CKD. Even after adjusting for these comorbidities, advanced CKD remains an independent predictor of increased in-hospital mortality.     

Predictive value of ventricular arrhythmias in resuscitated out-of-hospital cardiac arrest victims

Twenty-four hour ambulatory electrocardiograms recorded in 103 survivors of out-of-hospital cardiac arrest were analyzed to find those characteristics of the ventricular premature complex (VPC) which provide the best combination of sensitivity, specificity, and predictive accuracy for subsequent mortality. VPC characteristics were grouped as: (1) frequent (greater than or equal to 25 h-1), (2)bigeminal, (3) multiform, (4) early coupled, (5) pairing, (6) repetitive greater than or equal to 2, (7) repetitive greater than or equal to 3, (8) repetitive greater than or equal to 6, (9) the combination of frequent and repetitive, or (10) complex defined as any multiform, early, bigeminal or repetitive VPC. In an average follow-up period of 43 months, 42 deaths occurred, 17 of which were classified as sudden. Each characteristic was a significant predictor for all causes of subsequent death except early coupled VPCs and repetitive VPCs greater than 6. None of the characteristics reached significance as predictors for sudden death. The number of repetitive VPCs when stratified to none, greater than or equal to 2 and greater than or equal to 3 successive VPCs correlated with mortality in an incremental fashion. The combination of frequent VPCs and repetitive VPCs provided the best combination of sensitivity, specificity and predictive accuracy for death from all causes within five years.     

The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims

The effect of bystander cardiopulmonary resuscitation (CPR) was studied in 2142 emergency medical service (EMS) cardiac arrest runs. When bystander CPR was administered to cardiac arrest victims, 22.9% of the victims survived until they were admitted to the hospital and 11.9% were discharged alive. In comparison, the statistics for cardiac arrest victims who did not receive bystander CPR were 14.6% and 4.7%, respectively (p less than 0.001). A critical factor in patient survival was the amount of time that elapsed before the EMS personnel arrived and administered CPR. Patients who received bystander CPR were more likely to have ventricular fibrillation when the EMS arrived. Other factors relating to patient survival were the location of the victim at the time of the cardiac arrest and the age of the victim. Understanding these factors is important in developing community strategies to treat patients with cardiac arrest out of hospital.     

A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice

Aims/hypothesis

We designed a chemically modified, enzyme-resistant peptide with triple-acting properties based on human glucagon with amino acid substitutions aligned to strategic positions in the sequence of glucose-dependent insulinotropic polypeptide (GIP).

Methods

Y¹-dA²-I¹²-N¹⁷-V¹⁸-I²⁷-G^28,29-glucagon (termed YAG-glucagon) was incubated with dipeptidylpeptidase IV (DPP-IV) to assess stability, BRIN-BD11 cells to evaluate insulin secretion, and receptor-transfected cells to examine cAMP production. Acute glucose-lowering and insulinotropic properties of YAG-glucagon were assessed in National Institutes of Health (NIH) Swiss mice, while longer-term actions on glucose homeostasis, insulin secretion, food intake and body weight were examined in high-fat-fed mice.

Results

YAG-glucagon was resistant to DPP-IV, increased in vitro insulin secretion (1.5–3-fold; p?<?0.001) and stimulated cAMP production in GIP receptor-, glucagon-like peptide-1 (GLP-1) receptor- and glucagon receptor-transfected cells. Plasma glucose levels were significantly reduced (by 51%; p?<?0.01) and insulin concentrations increased (1.2-fold; p?<?0.01) after acute injection of YAG-glucagon in NIH Swiss mice. Acute actions were countered by established GIP, GLP-1 and glucagon antagonists. In high-fat-fed mice, twice-daily administration of YAG-glucagon for 14 days reduced plasma glucose (40% reduction; p?<?0.01) and increased plasma insulin concentrations (1.8-fold; p?<?0.05). Glycaemic responses were markedly improved (19–48% reduction; p?<?0.05) and insulin secretion enhanced (1.5-fold; p?<?0.05) after a glucose load, which were independent of changes in insulin sensitivity, food intake and body weight.

Conclusions/interpretation

YAG-glucagon is a DPP-IV-resistant triple agonist of GIP, GLP-1 and glucagon receptors and exhibits beneficial biological properties suggesting that it may hold promise for treatment of type 2 diabetes.     

Diagnosing and preventing inherited disease: Non-syncytial sources of fetal DNA in transcervically recovered cell populations

We have previously shown that fetal DNA can be detected in swabsand flushings obtained from the lower uterine pole prior tothe termination of pregnancy. The presence of syncytiotrophoblastvesicles in transcervically retrieved samples suggested thatthis distinctive placental tissue was an abundant source offetal DNA and a valuable resource in prenatal diagnosis strategies.In a more extensive study involving 150 terminations of pregnancybetween 7 and 17 weeks gestational age, 29% of transcervicallyretrieved samples contained visible syncytial vesicles. Flushingof the uterine pole more frequently contained syncytia thandirect aspiration (39% compared with 26% of samples) but thisdifference was not statistically significant. No samples >14weeks gestational age contained syncytia. Polymerase chain reactionanalysis using Y-sequence specific-nested primers indicatedthe presence of fetal DNA in the absence of intact syncytialvesicles. We therefore examined samples by in-situ hybridizationusing Y-specific DNA probes. Positive labelling was observedin syncytial vesicles where present and in clumps of unidentifiedfetal cells. In addition, high numbers of naked nuclei werelabelled in samples devoid of syncytia. These isolated nucleiare possibly derived from disrupted syncytia, and may be animportant and hitherto overlooked contributory factor in fetalmaterial which collects at the lower uterine pole.     

Improved Delivery Through Biological Membranes LX: Intradermal Targeting of Acyclovir Using Redox-Based Chemical Drug Delivery Systems

Two types of novel chemical drug delivery systems (CDS's) for acyclovir, A-CDS-1 (based on oxidation, which utilized the 1,4-dihydrotrigonelline moiety) and A-CDS-2 (based on reduction, which utilized the lipoic acid moiety), were designed to create reservoirs of metabolic precursors for the enhanced local delivery of the antiviral agent acyclovir to the skin. They were evaluated in two-compartment diffusion cells using hairless-mouse skin in vitro. This approach could be useful in the treatment of mucocutaneous herpes simplex virus (HSV-1) infection in the epidermal region of the skin. Upon application to the freshly excised hairless-mouse skin, A-CDS-1 was rapidly oxidized to form the quaternary metabolite AQ⁺, which was extensively localized in the skin. AQ⁺ then served as a reservoir for the release of the antiviral agent in the skin. A-CDS-1 delivered almost equivalent amounts of acyclovir not only to the skin but also transdermally. On the other hand, A-CDS-2 specifically localized acyclovir delivery to the skin as opposed to transdermal delivery. Due to their redox properties, both CDS's demonstrated significant depot formation of metabolic precursors, thus enhancing intradermal acyclovir delivery. The CDS's exhibited greater skin membrane partition coefficients than the parent underivatized acyclovir and were able to release the antiviral agent in the skin tissue. The CDS's were susceptible to hydrolysis in biological media, resulting in the release of acyclovir under near physiological conditions. Thus, the CDS's can serve to enhance intradermal targeting and delivery of the antiviral agent acyclovir.     

The Plated Femur: Relationships Between the Changes in Bone Stresses and Bone Loss

Calculations were made of the alterations in the in vivo cyclic bone stresses due to the application of various plates on the canine femoral shaft. The plate configurations analyzed were those used by previous investigators when studying the influence of plating on bone remodeling. The magnitude of the reduction in the loads borne by the bone tissue and the degree of shift in the bone stress neutral axis during the stance phase of gait was influenced by the geometry of the plate, the plate elastic modulus, and the location of plate application. From a correlation of the calculated alterations in bone stresses with the resulting measured changes in bone mass, it appears that bone remodeling is very sensitive to small changes in cyclic bone stresses. Changes in cyclic bone stresses of 1 MPa (less than 1 percent of the ultimate strength) can cause measurable differences in bone remodeling after a period of a few months.     

HIV integrase inhibitors with nucleobase scaffolds: discovery of a highly potent anti-HIV agent

HIV integrase is essential for HIV replication. However, there are currently no integrase inhibitors in clinical use for AIDS. We have discovered a conceptually new beta-diketo acid that is a powerful inhibitor of both the 3'-processing and strand transfer steps of HIV-1 integrase. The in vitro anti-HIV data of this inhibitor were remarkable as exemplified by its highly potent antiviral therapeutic efficacy against HIV(TEKI) and HIV-1(NL4)(-)(3) replication in PBMC (TI >4,000 and >10,000, respectively).     

Investigation of factors responsible for low oral bioavailability of cefpodoxime proxetil

Learning about the behavior of a drug in biological environment enables application of better formulation strategies to improve bioavailability of the same. Cefpodoxime proxetil (CP) is a prodrug, which is orally administered cephalosporin with only 50% absolute bioavailability. Despite previous studies, reasons responsible for low bioavailability of CP remain poorly understood. The present study tries to ascertain reasons for the low oral bioavailability of CP. The in vitro, in situ and ex vivo studies showed interesting results, where metabolism of CP into cefpodoxime acid (CA) inside the intestinal epithelial cell and preferential efflux of CA into lumen was identified as primary reason for low oral bioavailability of CP. Presence of specific carriers or transportation mechanism on the apical side membrane of enterocyte, than basal side of the same was observed.