Comparative Nephrotoxicity of a Novel Platinum Compound, Cisplatin, and Carboplatin in Male Wistar Rats

The nephrotoxicity of three platinum-containing antitumor agentswas compared at doses that approximate the LDIO (cisplatin)or the LD5O (CI-973, carboplatin) doses. Male Wistar rats wereadministered single iv doses of 45 mg/kg CI-973, 6.5 mg/kg cisplatin,or 65 mg/kg carboplatin and observed for 4 days. Cisplatin treatmentincreased blood urea nitrogen (4X), creatinine (3x), glucose,and fractional electrolyte excretions, and decreased creatinineclearance by Day 4. These parameters were not significantlyaltered in CI-973- and carhoplatin-treated animals. Cisplatinincreased urinary excretion of LDH (six fold), GGT (twofold),and NAG (twofold); CI-973 and carbo platin increased GGT excretion(approximately twofold). Cis platin induced the following functionalchanges as a conse quence of direct nephrotoxicity: decreasesin GFR (84%), ERPF (97%), ERBF (96%), and ERTS (95%), and increasesin FF (fivefold). Functional changes, attributed to prerenaleffects of CI-973, included a decrease in ERPF (35%) and anincrease in FF (48%). No changes were seen following carboplatintreat ment. All cisplatin-treated rats had proximal tubularnecrosis in the outer stripe of the outer medulla, extendingmultifocally into inner cortical medullary rays. No renal lesionswere de tected by light or electron microscopy in the controlor Cl-973- or carboplatin-treated rats. Cisplatin produced markednephro toxicity as determined by biochemical, functional, andhisto pathologic endpoints. CI-973 and carboplatin were significantlyless nephrotoxic than cisplatin.     

What Is the Most Appropriate Stimulation Mode in Patients with Sinus Node Dysfunction?

Sinus node disease (SND) has caused many controversies about the appropriate stimulation mode. We compared the advantages and disadvantages of VVI, AAI, DDD, and DDI mode. In an additional study, left ventricular function at rest [R] and during exercise [E] was investigated in dual chamber and ventricular stimulation mode with a stimulation rate of 70 ppm [R] and 110 ppm [E]. A total of 223 patients [pts] was investigated (67 AAI, 87 VVI, 69 DDI]. Hemodynamic disadvantages in VVI mode resulted in a 55% actuarial incidence of atrial fibrillation after five years. In AAI mode, we found another 25% complication rate due to impaired AV conduction [n = 9] or a bradyarrhythmia [n = 6] with slow ventricular response. DDD mode implies the possibility of sustaining a pacemaker mediated tachycardia. Single ventricular stimulation with a high stimulation rate (110 ppm] under E showed a worse left ventricular performance as compared to dual chamber stimulation. DDI mode shows none of the aforementioned disadvantages. To sum it up: Until a dual chamber rate responsive pacemaker becomes available, the DDI mode represents the best stimulation mode for patients with a SND.     

What's the Price to be Paid for Rate Response: AV Sequential Versus Ventricular Pacing?

The purpose of this study was to compare the effects of atrioventricular (AV) sequential and ventricular pacing at rest and during exercise on parameters of left ventricular performance. Twenty-five patients were studied by means of first pass radionuclide angiography. Pacing rates increased significantly (P < 0.001) during exercise in both pacing modes, resulting in a significant increase in the cardiac index (P < 0.001). Pulmonary transit times decreased significantly (P < 0.001) during exercise in both pacing modes with a significantly shorter pulmonary transit time for AV sequential pacing at rest (P < 0.01) and during exercise (P < 0.05), indicating impaired left ventricular function in ventricular pacing. Regional left ventricular wall movement deteriorated significantly during exercise in both pacing modes (P < 0.02), with a significantly worse performance during ventricular pacing at rest (P < 0.05) and during exercise (P < 0.05). Therefore, the price to be paid for rate response is a deterioration of regional wall movement. An additional loss of AV synchrony worsens the situation. It is concluded that rate modulated pacing requires preservation of AV coordination to optimize left ventricular performance.     

Intracoronary Beta-Radiation Therapy for In-stent Restenosis: Long-Term Success Rate and Prediction of Failure

Objective: The following retrospective observational study assesses the long-term results of intracoronary beta-radiation therapy for patients with in-stent restenosis.
Background: Beta-radiation has been used to treat patients with coronary in-stent restenosis. However, long-term clinical success using this technique has not at this time been established.
Methods: Two-hundred and thirteen consecutive patients received intracoronary brachytherapy (noncentered beta-emitter, Novoste BetaCath™) for in-stent restenosis and were followed up over a period of 39.1 ± 18.4 months. The combined end-point was defined as a major adverse clinical event (MACE) and comprised mortality, acute myocardial infarction, or target vessel revascularization (TVR).
Results: MACE occurred in 110 patients (51.6%): death in 27 patients (12.7%), acute myocardial infarction in 8 patients (3.8%), TVR in 90 patients (42.3%). TVR comprised percutaneous coronary reinterventions in 76 patients (35.7%) and coronary bypass surgery in 24 patients (11.3%). Secondary end-point was determined as target vessel failure and occurred in 93 patients (43.7%). Of note, the frequency of at least two previous target lesion interventions as well as impairment of left ventricular function was associated with reduced success rate, whereas other clinical parameters did not indicate outcome after treatment with intracoronary radiation therapy.
Conclusion: During the mean, a period of 3 years, more than half of the patients receiving intracoronary radiation therapy reached primary end-point, representing, in the main, TVR. During this period a mortality rate of nearly 13% was documented. These results signify a delayed, though continued, restenotic process after index procedure. (J Interven Cardiol 2010;23:60–65)     

Clinical Validation of New Pacing-Sensing Configurations for Atrial Automatic Capture Verification in Pacemakers

INTRODUCTION: This study evaluated an atrial automatic capture verification scheme based on atrial evoked response (AER). Atrial pacing was between Atip and Can (Atip-Can) using different coupling capacitances (CCs). Independent pairs of sensing electrodes between Aring and Vtip (Aring-Vtip) or between Aring and a separate indifferent electrode (Aring-Indiff) were used to reduce pacing-induced afterpotentials. METHODS AND RESULTS: A custom-made external pacing system was used to perform automatic step-up and step-down pacing (0.1 to 7.1 V at 0.5 msec, step size of 0.1 V) using different CCs (2 or 15 microF). Intracardiac signals from Aring-Indiff and Aring-Vtip were independently recorded and analyzed both in real time and off-line to detect AER. Every paced beat also was visually inspected and compared with surface ECG to verify the captures. With the intracardiac signals properly filtered, AER detection was based on the signal within a window of 12 to 65 msec after the stimulus. Data from 27 patients (4 chronic and 23 acute implantations; age 65.6+/-13.9 years) were analyzed. Bipolar atrial lead measurements using a standard pacing system analyzer were as follows (mean +/- SD): impedance 695+/-227 ohms, P wave amplitude 4.2+/-2.3 mV, slew rate 1.1+/-0.9 V/sec, and pacing threshold at 0.5 msec 1.0+/-0.5 V. The results with CC = 2 microF showed that of 9,500 atrial paced beats, correct capture verification rates were 99.8% (Aring-Indiff) and 99.4% (Aring-Vtip). Similar results were achieved with CC = 15 microF (99.7% and 99.5%, respectively). CONCLUSION: AER can be reliably detected using independent pacing (Atip-Can) and sensing (Aring-Vtip or Aring-Indiff) electrodes. Therefore, atrial automatic capture verification by AER detection is feasible.     

Maternal alloimmunization against fetal platelet antigens: a prospective study

Summary. Neonatal alloimmune thrombocytopenia (NAIT) is induced by maternal alloantibodies to fetal platelet antigens. This prospective study was carried out to evaluate the incidence of anti-platelet antibodies in 933 mother-child pairs where the mother and child were typed for the human platelet antigens (HPA)-l, -2,-3,-5. Sera from mismatched mother-child pairs were screened for anti-platelet antibodies, anti-HLA class I and blood group ABO IgG antibodies. Platelet-specific antibodies were anti-HPA-3a in one and anti-HP A-5b in 17 neonates, respectively. All these neonates had normal platelet counts. One woman had autoreactive antibodies. Anti-HLA class I and anti-blood group A IgG antibodies were detected in five and four neonates, respectively, born with a platelet count <150×10⁹/l. None of the 11 homozygous HP A-lb mothers became immunized against their heterozygous offspring. The maternal HLA-allotypes HLA-DR52 and -DR6, typically found in individuals immunized against HPA-la and -5b, respectively, were found in three of 11 HPA-b/b non-responders and eight of the anti-HPA-5b responders. The results indicate that a risk for NAIT due to HPA-2 and -3 alloimmunization is low. The HLA allotypes do not predict the risk for NAIT due to HPA-1 or -5 alloimmunization. Maternal anti-HPA-5b antibodies do not correlate with the platelet count in the neonate.     

Microglial Dystrophy in the Aged and Alzheimer＇s Disease Brain Is Associated with Ferritin Immunoreactivity

小胶质细胞变性对认识衰老相关的神经退变和神经退行性疾病的发病机制非常重要。本研究通过铁蛋白免疫组织化学方法来分析非痴呆和阿茨海默病患者大脑中的小胶质细胞形态特征。作者的主要假设为，铁储存蛋白-铁蛋白的表达提高小胶质细胞对退化的敏感性，尤其是在老年大脑中，因为衰老的小胶质细胞越来越无力维持铁环境稳定，而游离铁可促进氧化损伤。在24例34—97岁的病例中，小胶质细胞对铁蛋白的免疫反应被发现组成一个较大的HLA—DR抗体标记的小胶质细胞池。在老年尤其是AD大脑中，铁蛋白阳性的大部分小胶质细胞呈现出异常的形态学变化，即营养不良。铁蛋白阳性的营养不良小胶质细胞和AD组织中的老年斑之间并未发现空间相关性。对平均死亡时间（10．94&#177;5．69）h的人脑组织的研究显示，小胶质细胞营养不良的出现不依赖于死亡时间，因而不是组织自溶的产物。这些结果均提示，包含铁储存和新陈代谢的小胶质细胞的变性可能是通过其高暴露于氧化应激。作者推论，铁蛋白免疫组织化学法可能是检测人脑小胶质细胞退行性变的有效方法。     

Systolic and Diastolic Function with Alternate and Combined Site Pacing in the Right Ventricle

We hypothesized that pacing at two ventricular sites simultaneously would activate the myocardium more rapidly and improve ventricular function. We studied the effect of pacing at the right ventricular outflow tract (RYOT) and the RV apex (EVA) on systolic and diastolic function. In 14 patients with a reduced systolic ejection fraction < 40% (mean EF 32%±4%)we measured RV pressures, left ventricular pressures, EF, cardiac output, peak dP/dt, peak negative dP/dt, and the time constant of relaxation, Tau, during intrinsic rhythm, atrial pacing and DVI pacing at the RVA, the RVOT, and both RV sites combined in random order. Repeated measures analysis of variance showed no significant differences in any of these parameters. The highest absolute values of dP/dt were observed during sinus rhythm and the lowest with RVA pacing. This parameter tended to improve progressively with pacing in the RVOT and at both sites. Peak negative dP/dt showed a similar nonsignificant trend. Conclusion: These data suggest that in patients with poor LV function, there may be subtle improvements in diastolic and systolic function with pacing in the RVOT and at combined sites in the RV compared to traditional RVA pacing.     

Investigation on the stability of the Dde protecting group used in peptide synthesis: migration to an unprotected lysine1

An investigation of the stability of the Dde protecting group for amines, used in solid-phase peptide synthesis, shows that an unprotected ε-NH₂ group of lysine can acquire the Dde protection from another ε-NH₂ group or from an α-NH₂ group. An unprotected α-NH₂, however, cannot remove Dde from an ε-NH₂ function. This migration takes place during Fmoc removal from the ε-NH₂ with piperidine and/or during the subsequent washing steps. The Dde migration is also possible in neat dimethylformamide by a direct nucleophilic attack of the free ε-NH₂ group. Addition of piperidine to the reaction medium accelerates the side reaction, probably because of the formation of an unstable piperidine-Dde adduct. Dde migration can he prevented if the 9-fluorenylmethyloxycarbonyl is cleaved with 1,8-diazabicyclo[5,4,0]undec-7-ene for a short reaction time (2%, 3 × 3 min). Finally, this rearrangement is shown to occur both as an intra- and intermolecular reaction between peptides on the same resin bead.