Preservation of myocardial microcirculation during mechanical reperfusion for myocardial ischemia with either abciximab or eptifibatide

Myocardial Blush Grade (MBG) is an angiographic method of assessing myocardial microcirculation and provides independent risk stratification among patients with normal TIMI 3 flow. Although the beneficial effect of abciximab on microvascular perfusion is well established, the efficacy of eptifibatide in the prevention of platelet aggregation and distal microembolization is less proven. After a pharmacologic shift by our institution towards the use of eptifibatide in patients with unstable angina presenting for PCI, we sought to evaluate our experience by retrospectively comparing the effect on myocardial perfusion between abciximab and eptifibatide following PCI in stable angina or acute coronary syndrome. Microcirculatory perfusion was reviewed in 101 consecutive patients (23 stable angina, 61 unstable angina, 17 non-q MI) undergoing PTCA/stenting. This comparison was between the last group of 51 patients who routinely received standard bolus and infusion of abciximab and the first group of 50 patients who began receiving standard bolus and infusion of eptifibatide. Baseline characteristics between the two groups were balanced, except for more patients with previous CABG in the eptifibatide group. Angiograms were evaluated by 2 blinded independent reviewers for MBG as follows: 0, no blush; 1, minimal blush; 2, moderate blush; and 3, normal blush. TIMI 3 flow was seen in 98 patients. MBG scores were not significantly different in the abciximab group (67% MBG 3; 31% MBG 2; 2.0% MBG 0 1) than in the eptifibatide group (58% MBG 3; 36% MBG 2; 6.0% MBG 0 1); p = 0.34. Patients with prior PTCA/stenting had lower MBG scores (0 2) compared to patients without prior PTCA (58% vs 31%; p = 0.03). There were significantly lower MBG scores in all patients with prior PTCA or CABG compared to patients without (55% vs 30%; p = 0.03). MBG scores significantly and inversely correlated with peak troponin I levels (r = -0.18, one-tailed p = 0.04). The similarity in myocardial perfusion between abciximab and eptifibatide suggests that both compounds are equally effective in reducing platelet aggregation and microembolization during mechanical reperfusion. Lower MBG scores in patients with prior PTCA or revascularization may be explained by irreversible microvascular dysfunction resulting from distal microembolization during the previous procedure. Lower MBG scores in patients with higher troponin I levels may reflect more frequent microemboli and microinfarcts during an ischemic event. Larger prospective studies need to be performed to validate these findings.     

Pituitary Apoplexy in a Patient with Acute Myeloid Leukemia and Thrombocytopenia

We describe a 72-year-old woman with a history of acute myeloid leukemia who developed pituitary apoplexy associated with thrombocytopenia secondary to chemotherapy. She presented with new onset severe headache, nausea, vomiting and blurred vision. Initial physical examination was unremarkable. CT scan of the head was initially negative. Upon admission for further work up, She developed a high-grade fever, hypotension and obtundation. Subsequent physical examination revealed bitemporal visual fields defects and decreased visual acuity. Repeat imaging of head revealed a hemorrhagic pituitary mass compressing the optic chiasm. Laboratory results were compatible with the diagnosis of pan-hypopituitary syndrome. She received high dose steroids and was transferred for transnasal sphenoidotomy decompression surgery. The visual defects improved postoperatively. A literature review of Pituitary apoplexy is presented. Pituitary apoplexy secondary to thrombocytopenia has never been reported.     

结肠黑变病的研究现状及进展

随着便秘的发病率增加和结肠镜检查率提高,结肠黑变病的检出率明显升高,其具体的病因及发病机制不清,多与服用泻药和便秘有关.随着分子生物学技术的广泛应用及动物实验研究的深入,会逐步认识结肠黑变这种现象.目前研究的重点多集中于结肠黑变与结肠上皮细胞增殖与凋亡;泻剂滥用造成的结肠运动功能的改变的原理;该病与结肠肿瘤、息肉、息肉病等细胞增殖性疾病相关性.我们综述近年的相关文献,从流行病学、发病相关因素、病理形态学改变及治疗和预后等方面加以分析和总结,以期对该病以及相关疾病加深认识.     

Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress

Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.     

Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study

We assessed the prognostic accuracy of urinary N-acetyl-β-D-glucosaminidase (NAG), an early proximal tubular damage marker for the onset of diabetic nephropathy. The study included 491 eligible participants with 76 healthy controls, 194 type 2 diabetes mellitus (T2DM) patients with 0–5, 5–10, 10–15, and 15–20 years of T2DM duration, 71 microalbuminuric patients, 100 diabetic nephropathy patients, and 50 non-diabetic nephropathy patients. Fasting glucose, serum fructosamine, HbA1C, urinary microalbumin, serum creatinine, estimated glomerular filtration rate (eGFR), serum NAG, and urinary NAG were estimated. We compared urinary NAG activity with other well-established markers of diabetic nephropathy like microalbuminuria, eGFR, and serum creatinine. Urinary NAG excretion was increased by 8 and 12 folds in T2DM patients of 10–15 and 15–20 years of diabetes duration (p < 0.0001), respectively, without the appearance of microalbuminuria. The urinary NAG activity increased 16 and 18 fold in moderately increased albuminuria and diabetic nephropathy patients, respectively (p < 0.0001), without any change in non-diabetic nephropathy patients. A cutoff value of 3 U/L of urinary NAG has demonstrated a sensitivity of 96.1 % and a specificity of 100 % discriminating healthy controls from patients with T2DM duration of 10–15 years (AUC 1.000) and 15–20 years (AUC 0.999); microalbuminuria (AUC 0.999), and diabetic nephropathy (AUC 1.000). Urinary NAG excretion gradually increases with the increase in duration of diabetes and appeared much before the microalbuminuria, decreased eGFR, and increased serum creatinine. Thus, the urinary NAG may be considered as a potential site-specific early tubular damage marker leading to diabetic nephropathy.

     

Disclosure of Personalized Rheumatoid Arthritis Risk Using Genetics,Biomarkers, and Lifestyle Factors to Motivate Health Behavior Improvements: A Randomized Controlled Trial

Objective

To determine the effect of disclosure of rheumatoid arthritis (RA) risk personalized with genetics, biomarkers, and lifestyle factors on health behavior intentions.

Methods

We performed a randomized controlled trial among first‐degree relatives without RA. Subjects assigned to the Personalized Risk Estimator for Rheumatoid Arthritis (PRE‐RA) group received the web‐based PRE‐RA tool for RA risk factor education and disclosure of personalized RA risk estimates, including genotype/autoantibody results and behaviors (n = 158). Subjects assigned to the comparison arm received standard RA education (n = 80). The primary outcome was readiness for change based on the trans‐theoretical model, using validated contemplation ladder scales. Increased motivation to improve RA risk–related behaviors (smoking, diet, exercise, or dental hygiene) was defined as an increase in any ladder score compared to baseline, assessed immediately, 6 weeks, and 6 months post‐intervention. Subjects reported behavior change at each visit. We performed intent‐to‐treat analyses using generalized estimating equations for the binary outcome.

Results

Subjects randomized to PRE‐RA were more likely to increase ladder scores over post‐intervention assessments (relative risk 1.23, 95% confidence interval [95% CI] 1.01, 1.51) than those randomized to nonpersonalized education. At 6 months, 63.9% of PRE‐RA subjects and 50.0% of comparison subjects increased motivation to improve behaviors (age‐adjusted difference 15.8%; 95% CI 2.8%, 28.8%). Compared to nonpersonalized education, more PRE‐RA subjects increased fish intake (45.0% versus 22.1%; P = 0.005), brushed more frequently (40.7% versus 22.9%; P = 0.01), flossed more frequently (55.7% versus 34.8%; P = 0.004), and quit smoking (62.5% versus 0.0% among 11 smokers; P = 0.18).

Conclusion

Disclosure of RA risk personalized with genotype/biomarker results and behaviors increased motivation to improve RA risk–related behaviors. Personalized medicine approaches may motivate health behavior improvements for those at risk for RA and provide rationale for larger studies evaluating effects of behavior changes on clinical outcomes, such as RA‐related autoantibody production or RA development.

     

Heterosis and Combining Ability for Mineral Nutrients in Snowball Cauliflower (<Emphasis Type="Italic">Brassica oleracea</Emphasis> var. <Emphasis Type="Italic">botrytis</Emphasis> L.) Using <Emphasis Type="Italic">Ogura</Emphasis> Cytoplasmic Male Sterile Lines

Development of nutritionally rich hybrids is one of the main breeding objectives in vegetable crops to counter micronutrient malnutrition. The present study evaluates the combining ability and heterosis for different dietary minerals in snowball cauliflower. Five genetically diverse Ogura cytoplasmic male sterile (CMS) lines of cauliflower and seven male fertile testers were crossed in line × tester mating scheme to obtain 35 F₁ hybrids. The assessment of the F₁s along with their parental lines for 8 important macro- and microelements revealed a wide range of heterosis. The CMS line, Ogu 13-85 was identified as a good general combiner for sodium (Na), calcium (Ca), iron (Fe), zinc (Zn) and manganese (Mn) content, whereas Ogu 101 for Mn, Zn, sulphur (S) and magnesium (Mg) contents. The lines with better general combining ability (GCA) produced majority of the heterotic hybrids. However, GCA alone was not sufficient to determine and identify the potential parental lines. The hybrid, Ogu 101 × Lalchowk Maghi was found to be the best heterotic combination for potassium (K), S and Zn content. The cross Ogu 13-85 × Lalchowk Maghi was the best heterotic hybrid for Na and Ca content. The cross-combinations Ogu 13-85 × DB-187, Ogu 13-01 × DB-187 and Ogu 13-01 × Sel-26 showed high heterosis for accumulation of Mg, Fe and Mn, respectively. It was observed that both GCA and specific combining ability were important for heterosis of mineral content in snowball cauliflower.     

Transdermal Delivery of Cytochrome C—A 12.4 kDa Protein—Across Intact Skin by Constant–Current Iontophoresis

Purpose To demonstrate the transdermal iontophoretic delivery of a small (12.4 kDa) protein across intact skin. Materials and Methods The iontophoretic transport of Cytochrome c (Cyt c) across porcine ear skin in vitro was investigated and quantified by HPLC. The effect of protein concentration (0.35 and 0.7 mM), current density (0.15, 0.3 or 0.5 mA.cm⁻² applied for 8 h) and competing ions was evaluated. Co-iontophoresis of acetaminophen was employed to quantify the respective contributions of electromigration (EM) and electroosmosis (EO). Results The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for ∼90% of delivery; correlation between EM flux and electrophoretic mobility was consistent with earlier results using small molecules. Modest EO inhibition was observed at 0.5 mA.cm⁻². Cumulative permeation at 0.3 and 0.5 mA.cm⁻² was significantly greater than that at 0.15 mA.cm⁻²; fluxes using 0.35 and 0.7 mM Cyt c in the absence of competing ions (J _tot  = 182.8 ± 56.8 and 265.2 ± 149.1 μg.cm⁻².h⁻¹, respectively) were statistically equivalent. Formulation in PBS (pH 8.2) confirmed the impact of competing charge carriers; inclusion of ∼170 mM Na⁺ resulted in a 3.9-fold decrease in total flux. Conclusions Significant amounts (∼0.9 mg.cm⁻² over 8 h) of Cyt c were delivered non-invasively across intact skin by transdermal electrotransport.     

Synthesis and evaluation of the antiinflammatory activity of N-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxo-thiazolidin-3-yl]-nicotinamide

A new molecule incorporating nicotinoyl moiety, thiazolidin-4-one ring and 3,5-di-tert-butyl-4-hydroxyphenyl group (a potent antioxidant moiety) was synthesized and evaluated for anti-inflammatory activity in acute as well as chronic phase models of inflammation. The compound exhibited significant anti-inflammatory activity in three experimental models of inflammation, comparable to the positive control drug, ibuprofen (CAS 15687-27-1). It is suggested that besides the hypolipidemic and anti-oxidant potential of the molecule, its anti-inflammatory action could possibly act as an additional mechanism of its hypothesized anti-atherosclerotic activity.     

Controlled non-invasive transdermal iontophoretic delivery of zolmitriptan hydrochloride in vitro and in vivo

The objective was to investigate the transdermal delivery kinetics of zolmitriptan from an iontophoretic patch system in Yorkshire swine in vivo. Preliminary in vitro experiments showed that cumulative drug transport during a 6-h current application (0.25 mA cm⁻²) was independent of patch load (263.7 ± 92.7, 357.2 ± 85.9, 374.9 ± 74.3 and 335.9 ± 27.7 μg cm⁻² for 7.5, 15, 45 and 90 mg patch loads, respectively; ANOVA, p < 0.05); the steady-state flux was ∼92 μg cm⁻² h⁻¹. The in vivo studies used multistep current profiles to demonstrate (i) rapid drug uptake and (ii) the effect of superposing a bolus input on basal drug levels. In both studies, zolmitriptan was detected in the blood after 2.5 min; drug levels were 7.1  1.7 and 10.4 ± 3.5 ng ml⁻¹ at t = 30min in Studies 1 and 2, respectively. In Study 2, increasing current intensity from 0.2 to 1.4 mA (0.05-0.35 mA cm⁻²) at t = 180 min caused zolmitriptan levels to rise from 9.38 ± 0.93 ng ml⁻¹ at t = 180 min to 13.57 ± 1.85 ng ml⁻¹ at t = 190 min; a ∼50% increase in 10 min. Extrapolation of these results to humans suggests the feasibility of delivering therapeutic amounts of zolmitriptan at faster rates than those from existing dosage forms.