Coronary aneurysm formation in a patient early after everolimus-eluting stent implantation

Coronary aneurysm formation after drug-eluting stent (DES) implantation is a rare complication with late stent thrombosis as a potentially fatal sequela. One possible mechanism involved in aneurysm formation is thought to be late-acquired stent malapposition due to a local inflammatory response to the polymer and/or the drug. Coronary aneurysm formation has been documented with sirolimus- and paclitaxel-eluting stents. We report a case of coronary aneurysm formation in a patient with an everolimus-eluting stent (EES; Xience(R) Abbott Vascular, Redwood City, California) relatively early (3 months) after stent implantation. This case illustrates that even with second-generation DES like the EES, which is thought to be highly biocompatible, there can be adverse reactions to the polymer and/or to the drug.

Endothelialization of sirolimus-eluting stents with slow and extended drug release in the porcine overstretch model

BACKGROUND: Vascular healing of intracoronary stents has been shown to be delayed in drug-eluting stents (DES) due to the cytotoxic compounds on the stent surface that prevent stent ingrowth and endothelialization. The lack of endothelialization explains the occurrence of late and very late stent thrombosis in DES. MATERIALS AND METHODS: In 11 house swines (body weight 38-45 kg), 3 stents were implanted randomly into the 3 large epicardial coronary arteries, namely a bare-metal stent (BMS), a sirolimus-eluting stent with slow-release (SES) and a SES with extended-release (SESXR). Stent length was 18 mm, and stent diameter 3 mm. All stents were of identical design. Animals were followed for 3 (n = 3), 7 (n = 4) and 14 (n = 4) days, respectively. One animal died before implantation due to hyperthermia. On the day of explantation, the animals were euthanized and endothelialization was tested by scanning electron microscopy after drying and sputtering the samples. Endothelial coverage was determined semiquantitatively by 2 observers. RESULTS: Endothelialization was more rapid with BMS and SESXR than SES at 3 and 14 days. At 7 days there were no significant differences between the 2 SES. CONCLUSIONS: Endothelialization of intracoronary stents is faster with BMS and SESXR at 3 days than with SES. These differences persist at 14 days, suggesting delayed vascular healing with the slow-release SES.

Targeting vessels to treat hepatocellular carcinoma

The process of blood vessel proliferation, known as angiogenesis, is essential during embryonic development and organogenesis. In adult life, it participates in normal tissue repair, wound healing, and cyclical growth of the corpus luteum and the endometrium. Crucial as it is, angiogenesis can become pathological, and abnormal angiogenesis contributes to the pathogenesis of inflammatory and neoplasic diseases. The present review highlights the evidence for the role of angiogenesis in HCC (hepatocellular carcinoma) and discusses the increasing importance of inhibitors of angiogenesis in HCC therapy.

The copper-responsive repressor CopR of Lactococcus lactis is a 'winged helix' protein

CopR of Lactococcus lactis is a copper-responsive repressor involved in copper homoeostasis. It controls the expression of a total of 11 genes, the CopR regulon, in a copper-dependent manner. In the absence of copper, CopR binds to the promoters of the CopR regulon. Copper releases CopR from the promoters, allowing transcription of the downstream genes to proceed. CopR binds through its N-terminal domain to a 'cop box' of consensus TACANNTGTA, which is conserved in Firmicutes. We have solved the NMR solution structure of the N-terminal DNA-binding domain of CopR. The protein fold has a winged helix structure resembling that of the BlaI repressor which regulates antibiotic resistance in Bacillus licheniformis. CopR differs from other copper-responsive repressors, and the present structure represents a novel family of copper regulators, which we propose to call the CopY family.

Intimal proliferation and restenosis in paclitaxel-eluting stents with aminoparylene as carrier substance in swines

BACKGROUND: Polymer as carrier substance for drugeluting stents (DES) has been accused of inducing inflammation and hypersensitivity reactions leading to restenosis and stent thrombosis. Thus, a new paclitaxel-eluting stent (PES) with aminoparylene as a carrier substance is tested in the present study. METHODS: In 10 pigs, stents were implanted in the epicardial coronary arteries: 1) bare-metal stents (BMS, control stent); 2) cobalt-chromium stents (CCS); and 3) PES. Stent length was 15 mm, and diameter was 3 mm. The animals were restudied after 6 weeks. Quantitative coronary angiography was performed at baseline and follow up. Minimum luminal diameter (MLD) and late loss were calculated in all animals. Histologic vessel lumen, intimal proliferation and restenosis were determined by morphometry. Disruption of the lamina elastica interna (LEI) and inflammatory reactions were assessed by histology. RESULTS: The MLD at baseline was 2.83 +/- 0.28 mm, and at follow up it was 2.29 +/- 0.44 (p < 0.05; n = 30). Late loss and angiographic restenosis were smallest in the CCS and largest in the PES (ns). Neointimal proliferation was similar for all 3 stents, ranging between 1.38 and 1.64 mm(2) (ns). There was a significant correlation between disruption of the LEI and inflammatory reactions. CONCLUSIONS: PTs with aminoparylene as a carrier substance show similar late loss and angiographic restenosis to that of BM and CCS. The incidence of inflammatory reactions (35% of all histologic sections) is similar in all stents, but highest in PES. The mechanism of this reaction is unclear, but may be either due to the drug itself, the disruption of the LEI or to a hypersensitivity reaction.

Myocardial infarction due to paradoxical embolism in a patient with large atrial septal defect

We present the case of a patient who presented with acute inferior myocardial infarction and embolic occlusion of the distal left anterior descending and proximal right coronary artery. A large atrial septal defect (ASD) was seen on transesophageal echocardiography and the ASD was closed during the same session as coronary angiography and percutaneous coronary intervention. The presence of embolic or thrombotic occlusions of coronary arteries should prompt interventional cardiologists to look for a patent foramen ovale or ASD and perform percutaneous closure right away.

Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98)

Daily administration of 2-chlorodeoxyadenosine (Cladribine, CDA) is a standard treatment for hairy cell leukemia, but may cause severe neutropenia and neutropenic fever. This trial compared toxicity and efficacy of weekly versus daily CDA administration. One hundred patients were randomized to receive standard (CDA 0.14 mg/kg/day day 1-5 [Arm A]) or experimental treatment (CDA 0.14 mg/kg/day once weekly for 5 weeks [Arm B]). The primary endpoint was average leukocyte count within 6 weeks from randomization. Secondary endpoints included response rates, other acute hematotoxicity, acute infection rate, hospital admission, remission duration, event-free, and overall survival. There was no significant difference in average leukocyte count. Response rate (complete + partial remission) at week 10 was 78% (95% confidence interval (CI) 64-88%) in Arm A and 68% (95% CI 54-80%) in Arm B (p = 0.13). Best response rates during follow-up were identical (86%) in both arms. No significant difference was found in the rate of grade 3+4 leukocytopenia (94%vs. 84%), grade 3+4 neutropenia (90%vs. 80%), acute infection (44%vs. 40%), hospitalization (38%vs. 34%), and erythrocyte support (22%vs. 30%) within 10 weeks. Overall, these findings indicate that there are no apparent advantages in toxicity and efficacy by giving CDA weekly rather than daily.

Use of concatamers to study GABAA receptor architecture and function: application to delta-subunit-containing receptors and possible pitfalls

Many membrane proteins, including the GABA(A) [GABA (gamma-aminobutyric acid) type A] receptors, are oligomers often built from different subunits. As an example, the major adult isoform of the GABA(A) receptor is a pentamer built from three different subunits. Theoretically, co-expression of three subunits may result in many different receptor pentamers. Subunit concatenation allows us to pre-define the relative arrangement of the subunits. This method may thus be used to study receptor architecture, but also the nature of binding sites. Indeed, it made possible the discovery of a novel benzodiazepine site. We use here subunit concatenation to study delta-subunit-containing GABA(A) receptors. We provide evidence for the formation of different functional subunit arrangements in recombinant alpha(1)beta(3)delta and alpha(6)beta(3)delta receptors. As with all valuable techniques, subunit concatenation has also some pitfalls. Most of these can be avoided by carefully titrating and minimizing the length of the linker sequences joining the two linked subunits and avoiding inclusion of the signal sequence of all but the N-terminal subunit of a multi-subunit construct. Maybe the most common error found in the literature is that low expression can be overcome by simply overloading the expression system with genetic information. As some concatenated constructs result by themselves in a low level of expression, this erroneous assembly leading to receptor function may be promoted by overloading the expression system and leads to wrong conclusions.

Magic angle spinning magnetic resonance: a novel method opening up translational research into NAFLD?

NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) are of increasing importance, both in connection with insulin resistance and with the development of liver cirrhosis. Histological samples are still the 'gold standard' for diagnosis; however, because of the risks of a liver biopsy, non-invasive methods are needed. MAS (magic angle spinning) is a special type of NMR which allows characterization of intact excised tissue without need for additional extraction steps. Because clinical MRI (magnetic resonance imaging) and MRS (magnetic resonance spectroscopy) are based on the same physical principle as NMR, translational research is feasible from excised tissue to non-invasive examinations in humans. In the present issue of Clinical Science, Cobbold and co-workers report a study in three animal strains suffering from different degrees of NAFLD showing that MAS results are able to distinguish controls, fatty infiltration and steatohepatitis in cohorts. In vivo MRS methods in humans are not obtainable at the same spectral resolution; however, know-how from MAS studies may help to identify characteristic changes in crowded regions of the magnetic resonance spectrum.

High-field 1H T1 and T2 NMR Relaxation Time Measurements of H2O in Homeopathic Preparations of Quartz, Sulfur and Copper Sulfate

Quantitative meta-analyses of randomized clinical trials investigating the specific therapeutic efficacy of homeopathic remedies yielded statistically significant differences compared to placebo. Since the remedies used contained mostly only very low concentrations of pharmacologically active compounds, these effects cannot be accounted for within the framework of current pharmacology. Theories to explain clinical effects of homeopathic remedies are partially based upon changes in diluent structure. To investigate the latter, we measured for the first time high-field (600/500 MHz) 1H T1 and T2 nuclear magnetic resonance relaxation times of H2O in homeopathic preparations with concurrent contamination control by inductively coupled plasma mass spectrometry (ICP-MS). Homeopathic preparations of quartz (10c–30c, n = 21, corresponding to iterative dilutions of 100−10–100−30), sulfur (13x–30x, n = 18, 10−13–10−30), and copper sulfate (11c–30c, n = 20, 100−11–100−30) were compared to n = 10 independent controls each (analogously agitated dilution medium) in randomized and blinded experiments. In none of the samples, the concentration of any element analyzed by ICP-MS exceeded 10 ppb. In the first measurement series (600 MHz), there was a significant increase in T1 for all samples as a function of time, and there were no significant differences between homeopathic potencies and controls. In the second measurement series (500 MHz) 1 year after preparation, we observed statistically significant increased T1 relaxation times for homeopathic sulfur preparations compared to controls. Fifteen out of 18 correlations between sample triplicates were higher for controls than for homeopathic preparations. No conclusive explanation for these phenomena can be given at present. Possible hypotheses involve differential leaching from the measurement vessel walls or a change in water molecule dynamics, i.e., in rotational correlation time and/or diffusion. Homeopathic preparations thus may exhibit specific physicochemical properties that need to be determined in detail in future investigations.